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WO2007002172A2 - Inhibiteurs de la protease du vih-1 - Google Patents

Inhibiteurs de la protease du vih-1 Download PDF

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Publication number
WO2007002172A2
WO2007002172A2 PCT/US2006/024108 US2006024108W WO2007002172A2 WO 2007002172 A2 WO2007002172 A2 WO 2007002172A2 US 2006024108 W US2006024108 W US 2006024108W WO 2007002172 A2 WO2007002172 A2 WO 2007002172A2
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WO
WIPO (PCT)
Prior art keywords
alkyl
heterocyclyl
compound
aralkyl
aryl
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PCT/US2006/024108
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English (en)
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WO2007002172A3 (fr
Inventor
Celia Schiffer
Tariq M. Rana
Michael Gilson
Bruce Tidor
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University Of Massachusetts
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Publication date
Application filed by University Of Massachusetts filed Critical University Of Massachusetts
Priority to JP2008518347A priority Critical patent/JP2008546789A/ja
Priority to AU2006262274A priority patent/AU2006262274A1/en
Priority to CA002667445A priority patent/CA2667445A1/fr
Priority to EP06785252A priority patent/EP1937631A2/fr
Publication of WO2007002172A2 publication Critical patent/WO2007002172A2/fr
Publication of WO2007002172A3 publication Critical patent/WO2007002172A3/fr
Priority to US11/960,120 priority patent/US20110178092A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/03—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C311/05—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms to acyclic carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/35—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/36—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/50—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

  • PIs Protease inhibitors
  • IAS-USA International AIDS Society-USA
  • DHHS U.S. Department of Health and Human Services
  • HIV-I protease inhibitors are generally considered to be the most potent drugs currently available for the treatment of AIDS. These agents are often combined with other agents to establish highly active antiretroviral therapy (HAART), which is credited with an approximately three-fold drop in the death rate from AIDS since about 1995. Despite this remarkable success, there is still much concern regarding the treatment of AIDS, largely because of the emergence of HIV mutants that resist current therapy. Drug resistance occurs when mutations in the target protein allow the protein to retain function while no longer being inhibited efficiently by the drug.
  • HAART highly active antiretroviral therapy
  • HIV-I protease drug resistance occurs when, even in the presence of protease inhibitors, the enzyme is able to cleave the Gag and Pol polyproteins in at least nine different locations, allowing viral maturation. Viral resistance is regarded as a critical factor in clinical failure of antiviral therapy. The relatively rapid appearance of resistant viral mutants among treated HIV patients is attributable to the virus's high rate of replication, coupled with a high intrinsic rate of mutation due to the infidelity of the HIV reverse transcriptase. In addition, the current HIV-I protease inhibitors were designed specifically to inhibit primarily a single variant of HIV-I protease.
  • 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.
  • 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 (zidovudine, RetrovirTM)/3TC (lamivudine, EpivirTM) and d4T (stavudine, ZeritTM)/3TC, and d-drugs (ddl [didanosine, VidexTM/VidexECTM], ddC [zalcitabine, HividTM], d4T); a nucleotide reverse transcriptase inhibitor, such as tenofovir (VireadTM); and
  • NRTI non-
  • Figures la-b depict possible synthetic routes to selected inventive compounds.
  • Figures 2a-f depict selected compounds of formula I and associated Ki values.
  • Figures 3a-d depict selected compounds of formula III.
  • Figures 4a-c depicts additional selected compounds of formula I.
  • Figure 5 depicts additional selected compounds of formula I.
  • Figures 6a-k depict anti-HIV drugs by class.
  • Figure 7 depicts the synthesis of protease inhibitors containing [A] a hydroyethylarnine (HEA) core or [B] a hydroxyethylene (HE) core.
  • HOA hydroyethylarnine
  • HE hydroxyethylene
  • Figure 8 depicts the synthesis of protease inhibitors containing an aza- hydroxyethylamine (Aza-HEA) core. Key: (a) (CH 3 ) 2 CHOH, 80 oC (b) H 2 , Pd/C, MeOH, r. t; (c) R 4 X 2 CO 2 H, EDCI, HOBt, DIPEA, 0 oC to r. t; (d) TFA, CH 2 Cl 2 ; and (e) R 3 XiCO 2 H, EDCI, HOBt, DIPEA, 0 oC to r. t; aq. NaHCO 3 , EtOAc.
  • protease inhibitors described herein were designed rationally using an ensemble of HIV-I protease variant sequences (available online at hivdb.stanford.edu) and three- dimensional structures that the homodimeric HTV protease can tolerate, to maximize the likelihood that these HIV-I protease inhibitors that will evade mutational resistance. Recently, a structure-based strategy was proposed to reduce the probability of drug resistance by designing inhibitors that interact only with the same residues that are necessary to recognize substrate. (King, N. M. et al. Chem. Biol. 2004, 11, 1333-1338; and Prabu-Jeyabalan, M. et al. J. Virol.
  • the inhibitors are designed to form hydrogen bonds with relatively conserved residues and preferably with the backbone atoms of the protease rather than the side chain atoms.
  • the new compounds are competitive inhibitors that bind in the center of the substrate envelope, which is the active site of the protease molecule.
  • the new compounds are designed such that they do not significantly protrude beyond the substrate envelope, and therefore are less likely to induce escape mutations.
  • the new protease inhibitors are useful in the treatment of HIV in susceptible mammals, e.g., humans and certain other primates, and can be administered as a monotherapy, or in combination with other therapeutic agents, e.g., as part of a highly active antiretroviral therapy (HAART) regimen.
  • 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:
  • Xi is absent, -O-, -S- or -NR-;
  • X 2 is absent, -O-, -S- or -NR-;
  • 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)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xj is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent. In certain embodiments, the present invention relates to the aforementioned 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 R 1 is OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 2 is aralkyl.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ; and Ai, A 2 , A 3 , A 4 and A 5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ; Ai, A 2 , A 4 and A 5 are hydrogen; and A 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ;
  • Ai, A 2 , A 3 and A 5 are hydrogen; and
  • a 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is 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)alkyl, (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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X] is absent; X 2 is absent; Ri is OH; R 2 is aralkyl; R 3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; and R 5 is alkyl, (cycloalkyl)alkyl or (heterocyclyl)alkyl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula II:
  • Xi is absent or -O-;
  • R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, heteroaryl, aralkyl or heteroaralkyl;
  • R 6 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is alkyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • 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
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; and R 3 is
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • 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, -0-, -S- or -NR-;
  • X 2 is absent, -0-, -S- or -NR-;
  • R 1 is -OH, -SH or -NHR;
  • R is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl;
  • R 2 is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl
  • R 3 is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, ' aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 5 is hydrogen, alkyl, aralkyl, heteroaralkyl or acyl
  • R 7 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3 is wherein
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is not wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein 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. 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
  • R 2 is and Ai, A 2 , A 3 , A 4 and A 5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 1 , A 2 , A 4 and A 5 are hydrogen; and A 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is A 5 A 4 ;
  • Ai, A 2 , A 3 and A 5 are hydrogen; and
  • a 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is alkyl, aryl or heteroaryl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 5 is hydrogen.
  • the present invention relates to the aforementioned
  • R 7 is and B 1 , B 2 , B 3 , B 4 and B 5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 7 is B 1 , B 2 , B 4 and B 5 are hydrogen; and B 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 7 is B 15 B 2 , B 3 and B 5 are hydrogen; and B 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; X 2 is absent; Ri is OH; R 2 is aralkyl; R 3 is aryl or heteroaryl; R 4 is alkyl, aryl or heteroaryl; R 5 is hydrogen; and R 7 is alkyl, (cycloalkyl)alkyl or aralkyl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula IV:
  • Xi is absent or -O-;
  • R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl;
  • R 7 is alkyl, cycloalkyl, (cycloalkyl)alkyl or aralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and provided that when X 2 is absent;
  • R 4 is wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl.
  • 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 Xi is absent; and R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; R 3 is (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; R 4 is aryl, (amino)alkyl, (amido)alkyl, (keto)alkyl (heterocyclyl)alkyl or heterocyclyl; and R 7 is alkyl, cycloalkyl or (cycloalkyl)alkyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xj is absent; and R 3 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; R 3 is
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; R 3 is
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent; 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, of formula V:
  • X 1 is absent, -O-, -S- or -NR-;
  • X 2 is absent, -O-, -S- or -NR-;
  • 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)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3 is not wherein
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is -O- .
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 2 is absent. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein 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 R] 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. In certain embodiments, the present invention relates to the aforementioned
  • R 2 is and A 1 , A 2 , A 3 , A 4 and A 5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 is Ai, A 2 , A 4 and A 5 are hydrogen; and
  • a 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is ;
  • a 1 , A 2 , A 3 and A 5 are hydrogen; and
  • a 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is heterocyclyl. In certain embodiments, 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 VI:
  • Xi is absent or -O-;
  • Ri is -OH or -NH 2 ;
  • R 3 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, (amino)alkyl, (amido)alkyl, heterocyclyl, (heterocyclyl)alkyl, heteroaryl, aralkyl or heteroaralkyl; and provided that when Xi is absent; R 3 is no ; wherein
  • R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aiyl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is no ; wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is -OH.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Ri is -NH 2 .
  • 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 R 3 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is -O-; and R 3 is heterocyclyl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is heterocyclyl. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is alkyl. n certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 6 is -CH(CH 3 ) 2 . Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VII:
  • Xi is absent, -O-, -S- or -NR-;
  • X 2 is absent, -O-, -S- or -NR-; 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)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl
  • R 5 is hydrogen, alkyl, (cycloalkyl)alkyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; and the stereochemical configuration at any stereocenter is R, S, or a mixture of these configurations;
  • R 3 is no wherein R 3 A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl; wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein 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 X] 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 .
  • 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
  • R 2 and Ai, A 2 , A 3 , A 4 and A 5 are independently selected from the group consisting of hydrogen, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl and cyano.
  • the present invention relates to the aforementioned
  • R 2 i and A 5 axe hydrogen; and
  • a 3 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned
  • R 2 is Ai, A 2 , A 3 and A5 are hydrogen; and
  • a 4 is halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aryl, heteroaryl, trifluoromethyl or cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • R 3 is alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl
  • 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.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X 1 is absent; X 2 is absent; Ri is - OH; R 2 is aralkyl; R3 is (amido)alkyl or heterocyclyl; R 4 is (amido)alkyl or heterocyclyl; and R 5 is alkyl or aryl.
  • Another aspect of the present invention relates to a compound, or a pharmaceutically acceptable salt thereof, of formula VIII: wherein, independently for each occurrence, Xi is absent or -O-; R 3 is alkyl, alkenyl, (amino)alkyl, (amido)alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is aryl, heteroaryl, aralkyl or heteroaralkyl
  • Re is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aralkyl or heteroaralkyl;
  • R 3 is no o wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl;
  • R 4 is no ; wherein R 3A is hydrogen, alkyl, alkenyl, (amino)alkyl, (amido)alkyl, (keto)alkyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, heteroaryl, (heterocyclyl)alkyl, aralkyl or heteroaralkyl.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein Xi is absent.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 3 is (amino)alkyl, (amido)alkyl or heterocyclyl. In certain embodiments, the present invention relates to the aforementioned
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein R 4 is (amino)alkyl, (amido)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 6 is alkyl or aryl.
  • the present invention relates to the aforementioned
  • the present invention relates to the aforementioned
  • protease inhibitors I- VIII can be synthesized using the synthetic schemes outlined in Figures la-b. The definition of each of the variables may be the same as shown in formulae I-Vi ⁇ above.
  • Protease inhibitors I, II, V and VI 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, V or VI.
  • 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.
  • an epoxide for example, can be reacted with a protected hydrazine in a stereoselective manner to yield hydrazine 9, after deprotection. Hydrazine 9 is reacted with an acid to yield amide 10. Further deprotection yields amine 11 followed by reaction with acid chloride yields inhibitor VII or VIII.
  • 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.
  • 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. 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.
  • 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.
  • 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.
  • Pharmaceutical compositions are typically formulated to be compatible with their intended route(s) of 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 ethylenedianiinetetraacetic 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
  • 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, Crem ⁇ phor ELTM (BASF, Parsippany, NJ) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent necessary to allow administration via syringe. It should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols, such as mannitol, sorbitol, and/or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying, which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules, e.g., gelatin capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder, such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant, such as colloidal silicon dioxide; a sweetening agent, such as sucrose or saccharin; or a flavoring agent, such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the compounds can be delivered in the form of an aerosol spray from a pressured container or dispenser that contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration of a therapeutic compound as described herein can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.
  • the pharmaceutical compositions can also be prepared in the form of suppositories (e.g., with conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • the therapeutic compounds are prepared with carriers that will protect the therapeutic compounds against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
  • Such formulations can be prepared using standard techniques.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811; hereby incorporated by reference.
  • kits may comprise one or more compounds described herein and/or one or more other therapeutic compounds and/or a device for their administration, e.g., a syringe.
  • HIV protease inhibitor activities were determined by fluorescence resonance energy transfer (FRET) method.
  • FRET fluorescence resonance energy transfer
  • Glu(EDANS)-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln-Lys(DABCYL)-Arg was labeled with the energy transfer donor (EDANS) and acceptor (DABCYL) dyes at its two ends to perform FRET.
  • Inhibitor binding dissociation constant (Ki value) was obtained by nonlinear regression fitting to the plot of initial velocity as a function of inhibitor concentration based on Morrison equation. (Greco, W. R. et al. J. Biol. Chem. 1979, 254, 12104-12109.)
  • Q7K 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.
  • 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.
  • HIV-I infections 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 HTV 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(1-2): 103-12 (1996); Paxton et al., Clin. Diagn. Lab. Immunol.
  • Healthy adults and teenagers generally have a CD4 count of at least 800 cells per cubic millimeter of blood; a CD4 count below 200 is associated with severe risk of illness (e.g., AIDS-related diseases, such as Kaposi's sarcoma or pneumocystic pneumonia).
  • Current guidelines suggest treatment for HIV should be started when the CD4 count is less than about 350 and/or the viral load is greater than about 50,000.
  • a “therapeutically effective amount” is an amount sufficient to effect a desired therapeutic effect, e.g., a reduction in viral load, and/or an increase in number of CD4+ T cells.
  • An effective amount can be administered in one or more administrations, applications or dosages.
  • a therapeutically effective amount of a composition may depend on the composition selected.
  • the compositions can be administered once, one or more times per day, and/or one or more times per week; including once every other day. In certain embodiments, the compositions will be administered two or three times per day.
  • Treatment of a subject with a therapeutically effective amount of a protease inhibitor described herein can include a single treatment or a series of treatments.
  • Dosage, toxicity and therapeutic efficacy of the compounds can be determined, e.g., by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Compounds that exhibit high therapeutic indices are preferred. While compounds that exhibit toxic side effects may be used, care should be taken to select a dose and administration schedule that minimizes severe side effects while maximizing therapeutic efficacy.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a therapeutically effective dosage range can be estimated initially from cell culture assays.
  • a dose can be further formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound that achieves a half-maximal inhibition of symptoms) as determined in cell culture. 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, DPC083, calanolide A, SJ-1366, TSAO, 4"-deaminated TSAO, MV150 and MV026048; a nucleoside reverse transcriptase inhibitor (NRTI), such as AZT (zidovudine, Retro virTM)/3 TC (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 CYP2C 19, CYP 1A2, CYP2D6, or CYP2C9.
  • CYP3A4 e.g., Ritonavir
  • Exemplary inhibitors of 2G9 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 HTV 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.
  • 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 l ,3'-didehydro-3 l -deoxythymidine; D4T; Zerit®), abacavir succinate (1592U89 succinate; Ziagen® ABC), Combivir® (lamivudine & zidovudine; (-)-3TC & AZT), and Trizivir® (abacavir & lamivudine & zidovudine; ABC & (-)-3TC & AZT) .
  • the second therapeutic agent is selected from the group consisting of zidovudi
  • 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. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately.
  • Compositions comprising at least two inhibitors described herein and/or one or more other protease inhibitors and/or other therapeutic agents are also provided herein.
  • the compounds of the invention can be combined with one or more of any anti-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
  • HIV Human Immunodeficiency Virus
  • HIV-I HIV-I
  • HIV-2 HIV-2
  • 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.
  • 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 HTV in this application includes all of these tupes and strains.
  • retroviruses are diploid positive-strand RNA viruses that replicate through an integrated DNA intermediate (pro viral DNA).
  • pro viral DNA an integrated DNA intermediate
  • the lentiviral genome is reverse-transcribed into DNA by a virally encoded reverse transcriptase that is carried as a protein in each retrovirus.
  • the viral DNA is then integrated pseudo-randomly into the host cell genome of the infecting cell, forming a "provirus” which is inherited by daughter cells.
  • the retrovirus genome contains at least three genes: gag codes for core and structural proteins of the virus; 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).
  • heteroatom is art-recognized and refers to an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 3 O for straight chain, C 3 -C 3 O 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.
  • alkyl 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, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF 3 , -CN, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.
  • heterocyclyl refers to 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroa toms.
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy
  • polycyclyl or “polycyclic group” are art-recognized and refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
  • the term "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
  • 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.
  • R50 is as defined above
  • R54 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are as defined above.
  • 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.
  • 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,p-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations .
  • 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.
  • Example 1 Synthesis of protease inhibitors containing a hvdroxyethylamine (HEA) core
  • the designed inhibitors with a hydroxyethylamine (HEA) core isostere can be synthesized in four steps starting with commercially available chiral epoxide (1S,2S enantiomer) 12. Ring opening of epoxide 12 with various primary and secondary amines provided compounds 13. Reaction of 13 with various sulfonyl chlorides gave compounds 14. After deprotecting the Boc group, the resulting amines 15 were coupled with either (R) or (S) isomer of activated carboxylic acids to provide the designed inhibitors 16 ( Figure 7A).
  • HOA hydroxyethylamine
  • Example 2 Synthesis of protease inhibitors containing cyclic carbamates: HE Series The synthesis of protease inhibitors containing hydroxyethylene (HE) isostere starts with the synthesis of the core 17, which was obtained from L-phenylalanine in 5 steps. After coupling 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
  • Example 5 Inhibition of HIV-I Protease HIV-I protease inhibitor activities were determined using a standard fluorescence resonance energy transfer (FRET) method, using a protease substrate that becomes fluorescent upon cleavage of a specific peptide sequence separating a fluorescent donor and a nonfiuorescent acceptor.
  • Protease substrate 1 was labeled with energy transfer donor (EDANS) and acceptor (DABCYL) at its two ends, respectively (see, e.g., Maggiora et al., J. Med. Chem. 35:3727-3730 (1992); Shakhsher and Seitz, Anal. Chem. 62(17):1758-1762 (1990); Wang et al., Tetrahedron Lett. 31(45): 6493 -6496 (1990); the labeled substrates are available from Molecular Probes/Invitrogen (cat. No H2930)). The general methodology is described in Science 247:954 (1990).

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Abstract

L'invention concerne de nouveaux inhibiteurs de protéase et des méthodes d'utilisation de ces inhibiteurs de protéase dans le traitement d'une infection par le virus de l'immunodéficience humaine (VIH).
PCT/US2006/024108 2005-06-22 2006-06-21 Inhibiteurs de la protease du vih-1 WO2007002172A2 (fr)

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AU2006262274A AU2006262274A1 (en) 2005-06-22 2006-06-21 HIV-1 protease inhibitors
CA002667445A CA2667445A1 (fr) 2005-06-22 2006-06-21 Inhibiteurs de la protease du vih-1
EP06785252A EP1937631A2 (fr) 2005-06-22 2006-06-21 Inhibiteurs de la protease du vih-1
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WO2011061590A1 (fr) 2009-11-17 2011-05-26 Hetero Research Foundation Nouveaux dérivés carboxamides comme inhibiteurs du vih
US10294234B2 (en) 2017-02-06 2019-05-21 Gilead Sciences, Inc. HIV inhibitor compounds
US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds
US12083099B2 (en) 2020-10-28 2024-09-10 Accencio LLC Methods of treating symptoms of coronavirus infection with viral protease inhibitors

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CN105315178B (zh) * 2014-07-09 2018-07-06 浙江九洲药业股份有限公司 达芦那韦相关物质及其制备方法
CN108558808B (zh) * 2018-05-22 2020-05-05 中国医学科学院医药生物技术研究所 一种酰胺类衍生物或其药学上可接受的盐及其制备方法和应用

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WO1999067254A2 (fr) * 1998-06-23 1999-12-29 The United States Of America Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de protease retrovirale resistant a l'action de plusieurs medicaments et procedes associes
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US6046190A (en) * 1992-08-25 2000-04-04 G.D. Searle & Co. Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors
US5783701A (en) * 1992-09-08 1998-07-21 Vertex Pharmaceuticals, Incorporated Sulfonamide inhibitors of aspartyl protease
WO1999067254A2 (fr) * 1998-06-23 1999-12-29 The United States Of America Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de protease retrovirale resistant a l'action de plusieurs medicaments et procedes associes

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061590A1 (fr) 2009-11-17 2011-05-26 Hetero Research Foundation Nouveaux dérivés carboxamides comme inhibiteurs du vih
US10294234B2 (en) 2017-02-06 2019-05-21 Gilead Sciences, Inc. HIV inhibitor compounds
US10752636B2 (en) 2017-02-06 2020-08-25 Gilead Sciences, Inc. HIV inhibitor compounds
US11078208B1 (en) 2017-02-06 2021-08-03 Gilead Sciences, Inc. HIV inhibitor compounds
US12084455B2 (en) 2017-02-06 2024-09-10 Gilead Sciences, Inc. HIV inhibitor compounds
US11052087B2 (en) 2018-07-30 2021-07-06 Gilead Sciences, Inc. Anti-HIV compounds
US12083099B2 (en) 2020-10-28 2024-09-10 Accencio LLC Methods of treating symptoms of coronavirus infection with viral protease inhibitors

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