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US20090306112A1 - Antiviral protease inhibitors - Google Patents

Antiviral protease inhibitors Download PDF

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Publication number
US20090306112A1
US20090306112A1 US12/307,674 US30767407A US2009306112A1 US 20090306112 A1 US20090306112 A1 US 20090306112A1 US 30767407 A US30767407 A US 30767407A US 2009306112 A1 US2009306112 A1 US 2009306112A1
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alkyl
substituted
aryl
heterocyclyl
group
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Inventor
Carina E. Cannizzaro
James M. Chen
Manoj C. Desai
Michael L. Mitchell
Sundaramoorthi Swaminathan
Lianhong Xu
Zheng-Yu Yang
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Gilead Sciences Inc
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Gilead Sciences Inc
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Priority to US12/307,674 priority Critical patent/US20090306112A1/en
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MITCHELL, MICHAEL L., YANG, ZHENG-YU, CANNIZZARO, CARINA E., CHEN, JAMES M., DESAI, MANOJ C., SWAMINATHAN, SUNDARAMOORTHI, XU, LIANHONG
Publication of US20090306112A1 publication Critical patent/US20090306112A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • This invention relates to novel HIV protease inhibitors, pharmaceutical compositions thereof, processes for making the novel HIV protease inhibitors, and methods for inhibiting and treating an HIV infection.
  • HIV protease inhibitors are especially effective when administered in combination with other classes of HIV therapeutic agents, especially inhibitors of HIV reverse transcriptase, e.g. in “cocktails” of two or more HIV therapeutic agents.
  • new HIV protease inhibitors must be effective not only against wild-type strains of HIV, but must also demonstrate efficacy against the newly emerging mutant strains that are resistant to the commercially available protease inhibitors. Accordingly, there continues to be a need for new HIV protease inhibitors, for example those targeting the HIV protease in both wild type and mutant strains of HIV.
  • the present application provides novel HIV protease inhibitor compounds of Formula (I):
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the present application provides a method for treating HIV infections which comprises administering to a patient in need of such treatment a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the present application provides a method for treating HIV infections which comprises administering to a patient in need of such treatment a therapeutically effective combination of (a) one or more compounds of Formula I and (b) another therapeutic agent (e.g., one or more compounds selected from HIV reverse transcriptase inhibitors and HIV protease inhibitors).
  • a therapeutically effective combination of e.g., one or more compounds selected from HIV reverse transcriptase inhibitors and HIV protease inhibitors.
  • the present invention provides a method of treating HIV infection which comprises administering to a patient in need thereof a therapeutically effective amount of: (a) a compound of Formula (I); and, (b) at least one compound selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, non-nucleoside inhibitors of HCV, and CCR5 inhibitors.
  • the present invention provides a kit or container comprising a compound of Formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical compound to inhibit HIV protease and/or HIV growth.
  • a compound of the invention or “a compound of formula (I)” means a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof.
  • a compound of formula (number) means a compound of that formula and pharmaceutically acceptable salts, solvates and physiologically functional derivatives thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 10 carbon atoms (i.e., C 1 -C 10 alkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, —CH 3 ), ethyl (Et, —CH 2 CH 3 ), 1-propyl (n-Pr, n-propyl, —CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i-propyl, —CH(CH 3 ) 2 ), 1-butyl (n-Bu, n-butyl, —CH 2 CH 2 CH 2 CH 3 ), 2-methyl-1-propyl (i-Bu, i-butyl, —CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, —CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH 3 ) 3 ), 1-pentyl (n-pentyl, —CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (—CH(CH 3 )
  • Alkoxy means a group having the formula —O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkoxy), 1 to 12 carbon atoms (i.e., C 1 -C 12 alkoxy), or 1 to 6 carbon atoms(i.e., C 1 -C 6 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (—O—CH 3 or —OMe), ethoxy (—OCH 2 CH 3 or —OEt), t-butoxy (—O—C(CH 3 ) 3 or -OtBu) and the like.
  • Haloalkyl is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms (i.e., C 1 -C 12 haloalkyl), or 1 to 6 carbon atoms (i.e., C 1 -C 6 alkyl).
  • suitable haloalkyl groups include, but are not limited to, —CF 3 , —CHF 2 , —CFH 2 , —CH 2 CF 3 , and the like.
  • Alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 10 alkenyl), 2 to 12 carbon atoms (i.e., C 1 -C 12 alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • alkenyl groups include, but are not limited to, ethylene or vinyl (—CH ⁇ CH 2 ), allyl (—CH 2 CH ⁇ CH 2 ), cyclopentenyl (—C 5 H 7 ), and 5-hexenyl (—CH 2 CH 2 CH 2 CH 2 CH ⁇ CH 2 ).
  • Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 20 alkynyl), 2 to 12 carbon atoms (i.e., C 2 -C 12 alkyne), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (—C ⁇ CH), propargyl (—CH 2 C ⁇ CH), and the like.
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (—CH 2 —), 1,1-ethyl (—CH(CH 3 )—), 1,2-ethyl (—CH 2 CH 2 —), 1,1-propyl (—CH(C 2 CH 3 )—), 1,2-propyl (—CH 2 CH(CH 3 )—), 1,3-propyl (—CH 2 CH 2 CH 2 —), 1,4-butyl (—CH 2 CH 2 CH 2 CH 2 —), and the like.
  • Alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (—CH ⁇ CH—).
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkynylene radicals include, but are not limited to, acetylene (—C ⁇ C—), propargyl (—CH 2 C ⁇ C—), and 4-pentynyl (—CH 2 CH 2 CH 2 C ⁇ CH—).
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.
  • the arylalkyl group can comprise 6 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 6 to 20 carbon atoms, e.g., the alkenyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 6 to 20 carbon atoms, e.g., the alkynyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, heterocyclyl, etc., for example, “substituted alkyl”, “substituted alkylene”, “substituted aryl”, “substituted arylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl” means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Typical substituents include, but are not limited to, —X, —R, —O ⁇ , ⁇ O, —OR, —SR, —S ⁇ , —NR 2 , —NR 3 , ⁇ NR, —CX 3 , —CN, —OCN, —SCN, —N ⁇ C ⁇ O, —NCS, —NO, —NO 2 , ⁇ N 2 , —N 3 , NC( ⁇ O)R, —C( ⁇ O)R, —C( ⁇ O)NRR—S( ⁇ O) 2 O ⁇ , —S( ⁇ O) 2 OH, —S( ⁇ O) 2 R, —OS( ⁇ O) 2 OR, —S( ⁇ O) 2 NR, —S( ⁇ O)R, —OP( ⁇ O)O 2 RR, —P( ⁇ O)O 2 RR—P( ⁇ O)(O ⁇ ) 2 , —P( ⁇ O)(OH
  • Bioavailability is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH 3 , etc.), an amine (e.g., —NHCH 3 , —N(CH 3 ) 2 , etc.), or a thioalkyl group (e.g., —SCH 3 ).
  • heteroalkyl groups are, respectively, an alkyl ether (e.g., —CH 2 CH 2 —O—CH 3 , etc.), an alkyl amine (e.g., —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , etc.), or a thioalkyl ether (e.g., —CH 2 —S—CH 3 ).
  • an alkyl ether e.g., —CH 2 CH 2 —O—CH 3 , etc.
  • alkyl amine e.g., —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , etc.
  • thioalkyl ether e.g., —CH 2 —S—CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., —CH 2 CH 2 —OH), an aminoalkyl group (e.g., —CH 2 NH 2 ), or an alkyl thiol group (e.g., —CH 2 CH 2 —SH).
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • a C 1 -C 6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • Heterocycle or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9 ; The Chemistry of Heterocyclic Compounds, A Series of Monographs ” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc . (1960) 82:5566.
  • heterocycle includes a “carbocycle” as defined herein, wherein one or more (e.g.
  • heterocycle or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings).
  • Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3,4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene-moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH 2 —, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry .
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 6 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.
  • 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl,
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp 2 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry , and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 6 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is to 14 carbon atoms.
  • Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 6 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 5 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • Non-limiting examples of heteroaryl rings include all of those listed in the definition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated, partially unsaturated or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 6 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system.
  • Examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, and naphthyl.
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-5-aryl, -alkylene-5-alkylene-aryl, etc.
  • any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non-limiting examples of heteroarylalkyl include —CH 2 -pyridinyl, —CH 2 -pyrrolyl, —CH 2 -oxazolyl, —CH 2 -indolyl, —CH 2 -isoindolyl, —CH 2 -purinyl, —CH 2 -furanyl, —CH 2 -thienyl, —CH 2 -benzofuranyl, —CH 2 -benzothiophenyl, —CH 2 -carbazolyl, —CH 2 -imidazolyl, —CH 2 -thiazolyl, —CH 2 -isoxazolyl, —CH 2 -pyrazolyl, —CH 2 -isothiazolyl, —CH 2
  • optionally substituted in reference to a particular moiety of the compound of Formula I (e.g., an optionally substituted aryl group) refers to a moiety having 0, 1, 2, or more substituents.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • heteroaryl refers to an aromatic five or six-membered ring where at least one atom is selected from the group consisting of N, O, and S, and the remaining atoms are carbon.
  • heteroaryl also includes bicyclic systems where a heteroaryl ring is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • heteroaryl also includes tricyclic systems where a bicyclic system is fused to a phenyl group, a monocyclic cycloalkyl group, as defined herein, a heterocycle group, as defined herein, or an additional heteroaryl group.
  • the heteroaryl groups are connected to the parent molecular moiety through any substitutable carbon or nitrogen atom in the groups.
  • heteroaryl groups include benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, dibenzofuranyl, dihydrobenzothiazolyl, furanyl (furyl), imidazolyl, imidazopyridinyl, indazolyl, indolyl, isoindolyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, oxazolyl, thiazolyl, thienopyridinyl, thienyl, triazolyl, thiadiazolyl, tetrazolyl, pyridoimidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl, tetrahydroquinolinyl, tetrahydropyranyl and
  • heteroaryl groups of the present invention can be substituted or unsubstituted.
  • the nitrogen heteroatoms can be optionally quaternized or oxidized to the N-oxide.
  • the nitrogen containing rings can be optionally N-protected.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • d and l or (+) and ( ⁇ ) are employed to designate the sign of rotation of plane-polarized light by the compound, with ( ⁇ ) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • Linker refers to a chemical moiety comprising a covalent bond or a chain or group of atoms that covalently attaches a phosphonate group to a drug.
  • Linkers include portions of substituents A 1 and A 3 , which include moieties such as: repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • phosphonate and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to a heteroatom, 3) single-bonded to a heteroatom, and 4) single-bonded to another heteroatom, wherein each heteroatom can be the same or different.
  • the terms “phosphonate” and “phosphonate group” also include functional groups or moieties that comprise a phosphorous in the same oxidation state as the phosphorous described above, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having the characteristics described above.
  • the terms “phosphonate” and “phosphonate group” include phosphonic acid, phosphonic monoester, phosphonic diester, phosphonamidate, and phosphonthioate functional groups.
  • the terms “phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen, and 4) single-bonded to another oxygen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteristics.
  • the terms “phosphonate” and “phosphonate group” include functional groups or moieties within a molecule that comprises a phosphorous that is 1) single-bonded to a carbon, 2) double-bonded to an oxygen, 3) single-bonded to an oxygen or nitrogen, and 4) single-bonded to another oxygen or nitrogen, as well as functional groups or moieties that comprise a prodrug moiety that can separate from a compound so that the compound retains a phosphorous having such characteristics.
  • prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s).
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically-active compound.
  • Prodrug moiety refers to a labile functional group which separates from the active compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in A Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191).
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a prodrug moiety may include an active metabolite or drug itself.
  • prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters —CH 2 C( ⁇ O)R a and acyloxymethyl carbonates —CH 2 C( ⁇ O)OR a where R a is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • R a is C 1 -C 6 alkyl, C 1 -C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • the acyloxyalkyl ester was first used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al., (1983) J. Pharm. Sci. 72: 324; also U.S. Pat. Nos.
  • acyloxyalkyl ester was used to deliver phosphonic acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH 2 C( ⁇ O)C(CH 3 ) 3 .
  • An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (POC)—CH 2 OC( ⁇ O)OC(CH 3 ) 3 .
  • the phosphonate group may be a phosphonate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to a pivaloyloxymethyl carbonate (POC) or POM group.
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • protecting groups include prodrug moieties and chemical protecting groups.
  • Protecting groups are available, commonly known and used, and are optionally used to prevent side reactions with the protected group during synthetic procedures, i.e. routes or methods to prepare the compounds of the invention. For the most part the decision as to which groups to protect, when to do so, and the nature of the chemical protecting group “PG” will be dependent upon the chemistry of the reaction to be protected against (e.g., acidic, basic, oxidative, reductive or other conditions) and the intended direction of the synthesis. The PG groups do not need to be, and generally are not, the same if the compound is substituted with multiple PG. In general, PG will be used to protect functional groups such as carboxyl, hydroxyl, thio, or amino groups and to thus prevent side reactions or to otherwise facilitate the synthetic efficiency. The order of deprotection to yield free, deprotected groups is dependent upon the intended direction of the synthesis and the reaction conditions to be encountered, and may occur in any order as determined by the artisan.
  • protecting groups for —OH groups include “ether- or ester-forming groups”.
  • Ether- or ester-forming groups are capable of functioning as chemical protecting groups in the synthetic schemes set forth herein.
  • some hydroxyl and thio protecting groups are neither ether- nor ester-forming groups, as will be understood by those skilled in the art, and are included with amides, discussed below.
  • Ester-forming groups include: (1) phosphonate ester-forming groups, such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates; (2) carboxyl ester-forming groups, and (3) sulphur ester-forming groups, such as sulphonate, sulfate, and sulfinate.
  • phosphonate ester-forming groups such as phosphonamidate esters, phosphorothioate esters, phosphonate esters, and phosphon-bis-amidates
  • carboxyl ester-forming groups such as sulphonate, sulfate, and sulfinate.
  • the invention includes compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabelled (e.g., C 14 or H 3 ) compound of the invention, administering it parenterally in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • an animal such as rat, mouse, guinea pig, monkey, or to man
  • sufficient time for metabolism to occur typically about 30 seconds to 30 hours
  • isolating its conversion products from the urine, blood or other biological samples typically isolating its conversion products from the urine, blood or other biological samples.
  • the metabolite structures are determined in conventional fashion, e.g., by MS or NMR analysis.
  • the present application provides compounds according to Formula I, as described herein.
  • X is —C(O)—, —S(O 2 )—, or —S(O)—; and R 3 is H, or substituted alkyl.
  • X is —C(O)— or —S(O 2 )—; and R 3 is H.
  • R 2 is H.
  • R 1 is OR 1c ; and R 1c is alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said substituted heterocyclyl alkyl is substituted on the heterocyclyl moiety, and said heterocyclyl is selected from the group consisting of: (i) a mono-cyclic 5- or 6-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 4 heteroatoms selected from N, O, and S; and (ii) a bi-cyclic 8-, 9-, or 10-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 6 heteroatoms selected from N, O, and S.
  • R 1 is OR 1c ; and R 1c is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
  • R 1 is OR 1c ; and R 1c is selected from the group consisting of
  • a 1 , A 2 , A 3 , and A 4 are independently NR 9 or O;
  • R 8 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, —O-(alkyl), or —O-(substituted alkyl);
  • R 9 is H, alkyl, or substituted alkyl;
  • m is 1 or 2; and a and b are independently 0, 1, or 2.
  • R 1 is OR 1c ; and R 1c is selected from the group consisting of
  • a 1 , A 2 , A 3 , and A 4 are O;
  • R 8 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, —O-(alkyl), or —O-(substituted alkyl);
  • m is 1; and a and b are independently 0, 1, or 2.
  • R 1 is OR 1c ; and R 1c is heterocyclyl having one of the following structures:
  • D 1 , D 2 , D 3 , D 4 , and D 5 are independently selected from the group consisting of C, N, O, and S; n is 0 or 1; each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent; and is a single or double bond.
  • R 1 is
  • R 1d and R 1e are each independently selected from the group consisting of H, alkyl, and substituted alkyl; or R 1d and R 1e taken together with the carbon atom to which they are shown attached form a heterocyclyl or a substituted heterocyclyl, wherein said heterocyclyl or said substituted heterocyclyl is a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring having from 1 to 3 heteroatoms selected from N, O, and S, R 1f is H, alkyl, or substituted alkyl; and R 1g is alkyl or substituted alkyl.
  • R 1 is a 5- or 6-membered aryl, 5- or 6-membered substituted aryl, 5- or 6-membered heteroaryl, 5- or 6-membered substituted heteroaryl, 8- to 10-membered bi-cyclic heteroaryl, or 8- to 10-membered bi-cyclic substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl is independently substituted with one or more substituents selected from the group consisting of alkyl, substituted alkyl, hydroxy, —O-alkyl, and —(substituted alkyl).
  • R 5 is H.
  • L 3 is alkylene
  • Ar 3 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the substituted aryl or substituted heteroaryl of Ar 3 is substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, haloalkoxy, —NH-alkyl, —NH-(alkyl) 2 , —NH-acyl, —N(alkyl)-acyl, —NR a —S(O) 2 —R b , —C(O)—R c , —S(O) 2 R b , —S(O) 2 NHR a , —C(O)—NH—R a , and —O-alkylene-R 7 ;
  • R 7 is aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, —NR 7a
  • R 13 is H, alkyl, substituted alkyl, hydroxy, alkoxy; or R 13 is one of the following structures:
  • a 1 is NR 14 or 0;
  • R 14 is H, alkyl, or substituted alkyl;
  • R 10 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl;
  • m is 1 or 2;
  • p is 0, 1, or 2;
  • L 5 is —C(O)—, —C(O)—O—, or —S(O 2 )—;
  • R 7b is alkyl, substituted alkyl, heteroaryl, or substituted heteroaryl;
  • d is 1, 2, 3, or 4; and
  • R 7c and R 7d are independently alkyl or substituted alkyl.
  • R 4 is H.
  • p is 1; L 1 is alkylene; L 2 is a covalent bond; Ar 1 is aryl or substituted aryl; Ar 3 is heteroaryl or substituted heteroaryl;
  • substituted aryl or said substituted heteroaryl is substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, haloalkyl, halo, nitro, cyano, hydroxy, amino, alkoxy, haloalkoxy, —NH-alkyl, —NH-(alkyl) 2 , —NH-acyl, —N(alkyl)-acyl, —NR a —S(O) 2 —R b , C(O)—R c , —S(O) 2 R b , —S(O) 2 NHR a , —C(O)—NH—R a ;
  • R a is H, alkyl, or substituted alkyl; and
  • R b is alkyl, aryl, or substituted aryl.
  • R 11 is H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl; d is 1, 2, 3, or 4; Q is a heterocyclyl having one of the following structures:
  • D 1 , D 2 , D 3 , D 4 , and D 5 are independently selected from the group consisting of C, N, O, and S; J is CR 12 or N; each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent; and is a single or double bond.
  • D 1 , D 2 , D 3 , and D 4 are independently selected from the group consisting of C, N, O, and S; each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent; and R 11 is H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl; d is 1, 2, 3, or 4; m is 1 or 2; and is a single or double bond.
  • Ar 1 -L 2 -Ar 2 is
  • D 1 , D 2 , D 3 , and D 4 are independently selected from the group consisting of C, N, O, and S; and each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent.
  • p is 0; L 1 is alkylene; Ar 1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or said substituted heteroaryl is substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, —NR a —S(O) 2 —R b , —C(O)—R c , —S(O) 2 R b , —S(O) 2 NHR a , —C(O)—NH—R a , and —O-alkylene-R 7 ; R 7 is aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, —NR 7a -L 5 -R 7b , —O—PO 3 R 7c R 7d , a phosphonate group; L 5 is —C(O)—, —
  • p is 0; q is 1; L 1 and L 3 are independently alkylene; L 4 is a covalent bond; Ar 1 , Ar 2 , Ar 3 , and Ar 4 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl; wherein said substituted aryl or said substituted heteroaryl is substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, haloalkyl, hydroxy, alkoxy, and —O-alkylene-R 7 ; R 7 is aryl, heterocyclyl, substituted aryl, substituted heterocyclyl, —NR 7a -L 5 -R 7b , —O—PO 3 R 7c R 7d , or a phosphonates group; L 5 is —C(O)—, —C(O)O—, —C(O)NR 7e —, —S(O 2 )—,
  • p and q are both 0; L 1 and L 3 are independently alkylene; Ar 1 and Ar 3 are independently aryl or substituted aryl, wherein said substituted aryl is substituted by one or more substituents selected from the group consisting of alkoxy, haloalkoxy, —O-alkylene-R 7 ; and R 7 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl; with the proviso that Ar 1 and Ar 3 are not both phenyl.
  • R 6 is OR 6a , R 6a is alkyl or selected from the group consisting of
  • a 5 is NR 14 or O;
  • a 6 , A 7 , and A 8 are independently CR 14 R 15 , NR 14 , or O, with the proviso that at least one of A 6 and A 7 is NR 14 , or O;
  • R 10 and R 11 are independently H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl;
  • R 14 and R 15 are independently H, alkyl, or substituted alkyl;
  • a and b are independently 0, 1, or 2;
  • m is 1 or 2;
  • D 1 , D 2 , D 3 , D 4 , and D 5 are independently selected from the group consisting of C, N, O, and S;
  • each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r
  • R 6 is selected from the group consisting of
  • R 6d and R 6e are independently selected from the group consisting of H, alkyl, and substituted alkyl;
  • R 11 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl;
  • a 9 is CR 14 R 15 , NR 14 , or O;
  • J is CR 14 R 15 or N, with the proviso that A 9 and J are not both CR 14 R 15 ;
  • R 14 and R 15 are independently H, alkyl, or substituted alkyl;
  • a 10 and A 11 are independently CR 14 R 15 , NR 14 , S, or O, with the proviso that A 10 and A 11 are not both CR 14 R 15 ;
  • each R 14 and R 15 is independently H, alkyl, or substituted alkyl;
  • m is 1 or 2; and a is 0, 1, or 2.
  • R 6 is selected from a group consisting of
  • R 6d and R 6e are independently selected from the group consisting of H, alkyl, and substituted alkyl;
  • R 11 is H, alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, alkoxyalkyl, or substituted alkoxyalkyl;
  • d is 1, 2, 3, or 4;
  • D 1 , D 2 , D 3 , D 4 , and D 5 are independently selected from the group consisting of C, N, O, and S;
  • each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent; and is a single or double bond.
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; or R 6d and R 6e are taken together to form a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring; Z is —NR 14 or —O—; R 14 is H, alkyl, or substituted alkyl; R 6f1 is H, alkyl, or substituted alkyl; R 6f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy.
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; or R 6d and R 6e are taken together to form a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring;
  • Z is —NR 14 — or —O—;
  • R 14 is H, alkyl, or substituted alkyl;
  • R 6f1 is H, alkyl, or substituted alkyl;
  • R 6f2 is
  • D 1 , D 2 , D 3 , D 4 , and D 5 are independently selected from the group consisting of C, N, O, and S; each R 12 is independently H, alkyl, or substituted alkyl, with the proviso that in each occurrence of (R 12 ) r , r is 0, 1, or 2, whereby carbon is tetravalent, nitrogen is trivalent, and sulfur and oxygen are divalent; and is a single or double bond.
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy;
  • R 6f1 is H, alkyl, or substituted alkyl;
  • R 6f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy.
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy;
  • R 6f1 is H, alkyl, or substituted alkyl; and
  • R 6f3 is alkyl, substituted alkyl.
  • X is S(O 2 ) or S(O); and R 7 is alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein said heterocyclyl is selected from the group consisting of: (i) a 5-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 4 heteroatoms selected from N, O, and S; and (ii) a 6-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 4 heteroatoms selected from N, O, and S.
  • X is S(O) 2 and R 7 is methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, tert-butyl, and 2,2-dimethylpropyl
  • X is C(O); p is 1; q is 0; L 1 and L 3 are alkylene, L 2 is a covalent bond; R 1 is —C(R 1d R 1e )—NR 1f -L 6 -R 1g ; R 1d is alkyl; R 1e is H; R 1f is H; -L 6 -R 1g is —C(O)—O-alkyl; R 6 is —C(R 6d )R 6e )R 6f ; R 6d is alkyl; R 6e is H; R 6f is —NH—C(O)—O-alkyl; Ar 3 is -aryl-Z 1 -alkylene-O—PO 3 R 7c R 7d ; and Z 1 is O or NR 7a ; R 7a , R 7c , and R 7d are independently H, alkyl, or substituted alkyl.
  • X is C(O); p is 1; q is 0; L 1 and L 3 are alkylene; L 1 is a covalent bond; R 1 is —C(R 1d R 1e )—NR 1f -L 6 -R 1g ; R 1d is hydroxyalkyl; R 1e is H; R 1f is H; -L 6 -R 1g is —C(O)—O-alkyl; R 6 is —C(R 6d R 6e )R 6f ; and R 6d is hydroxyalkyl; R 6e is H; R 6f is —NH—C(O)—O-alkyl.
  • X is C(O); p and q are 0; L 1 and L 3 are alkylene; Ar 3 and Ar 1 are independently aryl or substituted aryl, wherein the substituted aryl contains one or more substituents selected from the group consisting of alkoxy, haloalkoxy, —O-alkylene-heterocyclyl, and —O-alkylene-(substituted heterocyclyl).
  • X is C(O); p is 0; q is 1; L 1 and L 3 are alkylene; and L 4 is a covalent bond.
  • the compounds of Formula I have one of the following structures:
  • stereoisomers or mixtures of stereoisomers of the compounds of the present application include enantiomers, diastereomers, and other stereoisomers. For example, for:
  • contemplated stereoisomers include at least:
  • n is 0,
  • X is H, alkyl, or substituted alkyl wherein alkyl and substituted alkyl are as defined and exemplified herein.
  • n is 1, X is —C(O)—, —S(O) 2 —, or —S(O)—, wherein alkyl, substituted alkyl are as defined and exemplified herein.
  • n 1
  • X is —S— and R 6 is alkyl or substituted alkyl.
  • alkyl include methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, tert-butyl, and 2,2-dimethylpropyl.
  • n is 1; X is —C(O)— and R 6 is —OR 6a wherein R 6a is alkyl, or substituted alkyl.
  • alkyl or substituted alkyl include —CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH(alkyl), —CH(substituted alkyl), —CH(heteroalkyl), —C(alkyl) 2 , —C(substituted alkyl) 2 , —C(heteroalkyl) 2 , —C(alkyl)(substituted alkyl), —C(heteroalkyl)(substituted alkyl), and —C(alkyl)(heteroalkyl), wherein alkyl, substituted alkyl, and heteroalkyl are as defined and exemplified herein.
  • n is 1;
  • X is —C(O)— and R 6 is —OR 6a wherein R 6a is aryl, substituted aryl, arylalkyl, or substituted arylalkyl, and wherein said substituted arylalkyl is substituted on the aryl moiety and wherein aryl or arylalkyl is any aryl or arylalkyl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • aryl or the aryl portion of arylalkyl is phenyl.
  • n is 1; X is —C(O)—; and R 6 is —OR 6a wherein R 6a is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, substituted heterocyclyl alkyl, wherein said substituted heterocyclyl alkyl is substituted on the heterocyclyl moiety and wherein heterocyclyl or heterocyclyl alkyl is any heterocyclyl or heterocyclyl alkyl defined or exemplified herein, and, when present, the substituents on said heterocyclyl include one or more of any substituents defined or exemplified herein.
  • R 6a is heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.
  • n is 1, X is —C(O)—; and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein alkyl is any alkyl defined or exemplified herein.
  • R 6d and R 6e is H, the other is isopropyl, and R 14 is methyl.
  • n is 1, X is —C(O)—; and R 6 is C(R 6d R 6c )—O-aryl wherein R 6d , R 6e are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein alkyl and aryl is any alkyl and aryl defined or exemplified herein.
  • n is 1
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 6f2
  • R 6d , R 6e or R 6f1 are independently selected from the group consisting of H, alkyl, and substituted alkyl and R 6f2 is aryl, arylalkyl, substituted arylalkyl, wherein said substituted arylalkyl is substituted on the aryl moiety and wherein aryl or arylalkyl is any aryl or arylalkyl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • aryl is phenyl.
  • n is 1, X is —C(O)— and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 6f2 wherein R 6d and R 6e are taken together to form a 5- or 6-membered spiro-fused non-aromatic tetrahydro heterocyclyl wherein heterocyclyl is any heterocyclyl defined or exemplified herein, and, when present, the substituents on said heterocyclyl include one or more of any substituents defined or exemplified herein.
  • n is 1, X is —C(O)— and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—NR 6f1 —R 6f2 wherein R 6d , R 6e or R 6f1 are independently selected from the group consisting of H, alkyl, and substituted alkyl and R 6f2 is alkyl or substituted alkyl, wherein heterocyclyl is any heterocyclyl defined or exemplified herein, and, when present, the substituents on said heterocyclyl include one or more of any substituents defined or exemplified herein.
  • n is 1, X is —C(O)— and R 6 is C(R 7d R 7e )—NR 7f1 —C(O)—R 7f2 wherein R 7d and R 7e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 7f1 is H, alkyl, or substituted alkyl; R 7f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy, wherein said alkyl, haloalkyl, hydroxyalkyl, or alkoxy are herein defined and exemplified.
  • n is 1, X is —C(O)— and R 6 is C(R 6d R 6e )—NR 6f1 —S(O) 2 —R 6f3 , R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 6f1 is H, alkyl, or substituted alkyl; and R 6f3 is alkyl, substituted alkyl, wherein said alkyl, haloalkyl, hydroxyalkyl, or alkoxy are herein defined and exemplified.
  • n is 1, X is —C(O)— and R 6 is C(R 6d R 6e )—NR 6f1 —S(O) 2 —N(alkyl) 2 , R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 6f1 is H, alkyl, or substituted alkyl, wherein said alkyl, haloalkyl, hydroxyalkyl, or alkoxy are herein defined and exemplified.
  • n is 1, X is —C(O)— and R 6 is heterocyclyl or substituted heterocyclyl, wherein X is attached to the heterocyclyl through a heteroatom and wherein said heterocyclyl includes any heterocyclyl defined or exemplified herein.
  • the substituents when present, include one or more of any substituent defined or exemplified herein.
  • n is 1, X is —C(O)— and R 6 heterocyclyl or substituted heterocyclyl, X is attached to the heterocyclyl through a carbon atom and wherein said heterocyclyl includes any heterocyclyl defined or exemplified herein.
  • the substituents, when present include one or more of any substituent defined or exemplified herein.
  • L 1 is alkylene or substituted alkylene.
  • L 1 include —CH 2 —, —CH(CH 3 )—, —CH(—CH 2 CH 3 )—, —CH(—CH 2 CH 2 CH 3 )—, —CH(—CH(CH 3 ) 2 )—, —CH(—CH 2 CH 2 CH 2 CH 3 )—, —CH(—CH 2 CH(CH 3 ) 2 )—, —CH(—CH(CH 3 )CH 2 CH 3 )—, —CH(—C(CH 3 ) 3 )—, —C(CH 3 ) 2 —, —CH(OCH 3 )—, —CH(CH 2 OH)—, —CH(CH 2 CH 2 OH)—, etc.
  • L 3 is an alkylene or substituted alkylene.
  • alkylene and substituted alkylene include any of the alkylenes defined or disclosed herein.
  • substituted alkylenes include alkylenes substituted with one or more —OH group, alkylenes substituted with one or more ether group, e.g., a —O—Bn group, alkylenes substituted with one or more halogen, or alkylenes substituted with combinations of two or more substituents (e.g., —OH and halogen, halogen and ether, etc.).
  • L 1 and L 3 are the same, i.e., L 1 and L 3 are the same alkylene or substituted alkylene group.
  • L 1 and L 3 are different, i.e., L 1 is an alkylene and L 3 is a substituted alkylene, L 1 is an alkylene and L 3 is a different alkylene, or L 1 is a substituted alkylene, and L 3 is a different substituted alkylene.
  • each L 4 are independently selected from the group consisting of a covalent bond, —O—, —NH, —O-alkylene-, and alkylene.
  • L 2 and L 4 are different.
  • L 2 is a covalent bond and L 4 is —;
  • L 2 is a covalent bond and L 4 is —NH—;
  • L 1 is a —O—,
  • L 4 is —NH—.
  • L 1 is —CH 2 — and p is 0.
  • L 1 is —CH 2 —
  • L 3 is —CH 2 — and p is 0.
  • L 3 is —CH 2 — and q is 0.
  • Ar 1 is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • aryl include phenyl, substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Ar 1 is phenyl.
  • Ar 1 is substituted or unsubstituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein, and, when present, the substituents on said heteroaryl include one or more of any substituents defined or exemplified herein.
  • Ar 2 is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • Ar 2 is phenyl or substituted phenyl.
  • Ar 2 is substituted or unsubstituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein.
  • heteroaryl include thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • Ar 3 is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • Ar 3 is phenyl or substituted phenyl.
  • Ar 3 is substituted or unsubstituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein, and, when present, the substituents on said heteroaryl include one or more of any substituents defined or exemplified herein.
  • heteroaryl include thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • Ar 4 is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • Ar 4 is phenyl or substituted phenyl.
  • Ar 4 is substituted or unsubstituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein.
  • heteroaryl include thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • L 1 is alkylene
  • Ar 1 is substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and the substituents on said aryl are any substituents defined and exemplified herein.
  • Ar 1 is phenyl or substituted phenyl.
  • L 1 is alkylene and Ar 1 is substituted or unsubstituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein, and, when present, the substituents on said heteroaryl include one or more of any substituent defined or exemplified herein.
  • L 3 is substituted or unsubstituted alkylene
  • Ar 3 is substituted or unsubstituted aryl, wherein alkylene and aryl are any alkylene or aryl defined or exemplified herein, and, when present, the substituents on said alkylene or aryl include one or more of any substituents defined or exemplified herein.
  • L 3 is substituted or unsubstituted alkylene
  • Ar 3 is substituted or unsubstituted heteroaryl
  • alkylene and heteroaryl are any alkylene or heteroaryl defined or exemplified herein, and, when present, the substituents on said alkylene or heteroaryl include one or more of any substituents defined or exemplified herein.
  • Ar 1 is substituted or unsubstituted aryl
  • Ar 3 is substituted or unsubstituted heteroaryl
  • aryl and heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on said aryl or heteroaryl include one or more of any substituents defined or exemplified herein.
  • Ar 3 is substituted or unsubstituted aryl, and Ar 3 is substituted or unsubstituted heteroaryl, wherein aryl and heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on said aryl or heteroaryl include one or more of any substituents defined or exemplified herein.
  • both Ar 1 and Ar 3 are substituted or unsubstituted aryl, wherein aryl is any aryl defined or exemplified herein, and, when present, the substituents on said aryl include one or more of any substituents defined or exemplified herein.
  • L 2 is a bond
  • Ar 2 is aryl, substituted aryl, wherein the aryl is any aryl defined or exemplified herein, and, when present, the substituents on the aryl include one or more of any substituents defined or exemplified herein.
  • L 2 is a bond
  • Ar 2 is heteroaryl, or substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • L 2 is O-alkylene (wherein the alkylene group is attached to either Ar 1 or Ar 2 ), Ar 2 is heteroaryl, or substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • p is 0, and Ar 1 is unsubstituted aryl.
  • p is 0, and Ar 1 is aryl substituted with haloalkoxy.
  • two of the Ar 1 , Ar 2 , Ar 3 , or Ar 4 are the same and the remaining two are different, e.g. two of Ar 1 , Ar 2 , Ar 3 , or Ar 4 are substituted or unsubstituted aryls and the other two of Ar 1 , Ar 2 , Ar 3 , or Ar 4 are substituted or unsubstituted heteroaryls, wherein aryl and heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on the aryl or heteroaryl include one or more of any substituents defined or exemplified herein.
  • q is 0, and Ar 3 is substituted aryl wherein the substituents are selected from the group consisting of hydroxyl, alkoxy, haloalkoxy.
  • R 7 is -Z 2 -L 5 -R 7b , or —O—PO 3 R 7c R 7d ;
  • L 5 is —C(O)—, —C(O)O—, —C(O)NR 7e —, —NR a —S(O) 2 —R b , —C(O)—R c , —S(O) 2 R b , —S(O) 2 NHR a , —C(O)—NH—R a , —S(O) 2 —, —S(O)—, —S(O) 2 NR 7e —, or —S(O)NR 7e —;
  • Z 1 and Z 2 are independently O
  • L 4 is a covalent bond
  • Ar 4 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein the aryl or heteroaryl are any aryl or heteroaryl defined or exemplified herein, and, when present, the substituents on the aryl or heteroaryl include one or more of any substituents defined or exemplified herein.
  • q is 1, L 4 is a covalent bond, Ar 4 is aryl, substituted aryl, wherein the aryl is any aryl defined or exemplified herein, and, when present, the substituents on the aryl include one or more of any substituents defined or exemplified herein such as —NH-acyl.
  • q is 1, L 4 is a covalent bond, Ar 4 is heteroaryl, or substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • q is 1, L 4 is O—, Ar 4 is aryl, or substituted aryl. In a particular embodiment, Ar 4 is phenyl.
  • L 4 is O-alkylene (wherein the alkylene portion of the —O-alkylene group is attached to either Ar 3 or Ar 4 ), Ar 4 is heteroaryl, or substituted heteroaryl, and wherein the heteroaryl is selected from the group consisting of thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, indazolyl, imidazopyridinyl, indolyl, benzimidazolyl, isoquinolinyl and quinolinyl.
  • R 1 is OR 1c , wherein R 1c is alkyl or substituted alkyl.
  • alkyl are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl.
  • R 1 is OR 1c , wherein R 1c is arylalkyl, substituted arylalkyl, heterocyclyl alkyl, and substituted heterocyclyl alkyl, wherein alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, heterocyclyl alkyl, and substituted heterocyclyl alkyl are any alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, arylalkyl, substituted arylalkyl, heterocyclyl alkyl, and substituted heterocyclyl alkyl defined or exemplified herein.
  • R 1 is OR 1c , wherein R 1c is aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, wherein the aryl, substituted aryl, heterocyclyl, and substituted heterocyclyl are any aryl, substituted aryl, heterocyclyl, substituted heterocyclyl defined or exemplified herein
  • R 1 is OR 1c , wherein R 1c is selected from the group consisting of
  • a 1 , A 2 , A 3 , and A 4 are O, and m is 1.
  • R 1 is aryl or substituted aryl, wherein aryl is any aryl defined or exemplified herein and, when present, the substituents on the aryl include one or more of any substituents defined or exemplified herein such as hydroxyl or methyl.
  • R 1 is heteroaryl or substituted heteroaryl, wherein heteroaryl is any heteroaryl defined or exemplified herein.
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl wherein alkyl and substituted alkyl include any of the alkyl or substituted alkyls defined or disclosed herein.
  • R 1d , R 1e , and R 1f may independently be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, or tert-butyl wherein the substituents may include a hydroxyl group.
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d and R 1e taken together with the carbon atom to which they are shown attached form a heterocyclyl or a substituted heterocyclyl, wherein said heterocyclyl or said substituted heterocyclyl is a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring having from 1 to 3 heteroatoms selected from N, O, and S, R 1f is H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl wherein alkyl, substituted alkyl, heterocyclyl or a substituted heterocyclyl include any of the alkyl, substituted alkyl, heterocyclyl, or substituted heterocyclyl defined or disclosed herein.
  • R 2 , R 4 , and R 5 are each independently H, alkyl, or substituted alkyl, wherein alkyl and substituted alkyl include any of the alkyl or substituted alkyls defined or disclosed herein.
  • R 2 , R 4 , and R 5 are each the same.
  • R 2 , R 4 , and R 5 are each H.
  • R 1 , R 3 , and R 5 are each alkyl, e.g. one of the alkyl groups defined or disclosed herein.
  • R 2 , R 4 , and R 5 are each different.
  • two of R 2 , R 4 , and R 5 are the same, and the other is different.
  • R 2 , R 4 , and R 5 are each independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein alkyl or substituted alkyl is any alkyl or substituted alkyl, defined or disclosed herein.
  • R 2 , R 4 , and R 5 are each independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein alkyl or substituted alkyl is any alkyl or substituted alkyl, defined or disclosed herein.
  • R 1 is —NR 1a R 1b , —OR 1c , —C(R 1d R 1e )—NR 1f -L 6 -R 1g , aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein aryl, substituted aryl, heteroaryl, or substituted heteroaryl is any aryl, substituted aryl, heteroaryl, or substituted heteroaryl, defined or disclosed herein.
  • R 1 is NR 1a R 1b , OR 1c , —C(R 1d R 1e )—NR 1f -L 6 -R 1g , aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein aryl, substituted aryl, heteroaryl, or substituted heteroaryl is any aryl, substituted aryl, heteroaryl, or substituted heteroaryl, defined or disclosed herein.
  • R 1 is —NR 1a R 1b , —OR 1c , —C(R 1d R 1e )—NR 1f -L 6 -R 1g , aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein aryl, substituted aryl, heteroaryl, or substituted heteroaryl is any aryl, substituted aryl, heteroaryl, or substituted heteroaryl, defined or disclosed herein.
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-CH 2 —O-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene, heteroaryl, and/or aryl with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) with q moiety is an -alkylene-aryl-O—CH 2 -heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)—O-alkyl group, wherein said alkylene, alkyl and aryl moieties are any alkylene, alkyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—S(O) 2 -alkyl group, wherein said alkylene, alkyl, and aryl moieties are any alkylene, alkyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)-heterocyclyl group, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-alkylene-heterocyclyl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p is an -alkylene-aryl-O-haloalkyl group, wherein said alkylene, haloalkyl, and aryl moieties are any alkylene, haloalkyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heteroaryl group, wherein said alkylene, aryl, and heteroaryl moieties are any alkylene, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl and/or heteroaryl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is ⁇ -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-aryl group, wherein said alkylene and aryl moieties are any alkylene and aryl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, wherein said alkylene, heterocyclyl and aryl moieties are any alkylene, heterocyclyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein such as hydroxyl and alkoxy.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -aryl group, wherein said alkylene, heterocyclyl and aryl moieties are any alkylene, heterocyclyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heterocyclyl group, wherein said alkylene, heterocyclyl, and aryl moieties are any alkylene, heterocyclyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)—O-alkyl group, wherein said alkylene, alkyl, heterocyclyl, and aryl moieties are any alkylene, alkyl, heterocyclyl, and, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—S(O) 2 —O-alkyl group, wherein said alkylene, alkyl, heterocyclyl, and aryl moieties are any alkylene, alkyl, heterocyclyl, and, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)-heteroaryl group, wherein said alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties are any alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group, wherein said alkylene, alkyl, heterocyclyl, and aryl moieties are any alkylene, alkyl, heterocyclyl, and aryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O alkylene-heterocyclyl group, -q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-haloalkyl, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, wherein said alkylene, haloalkyl, aryl, and heteroaryl moieties are any alkylene, haloalkyl, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-haloalkyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkyl group, wherein said alkylene, alkyl, haloalkyl, and aryl, moieties are any alkylene, alkyl, haloalkyl, and aryl heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties are any alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties are any alkylene, alkyl, heterocyclyl, aryl, and heteroaryl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is aryl or substituted aryl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein. In one particular embodiment, R 1 is optionally substituted with one or more hydroxyl and/or methyl groups.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is heteroaryl or substituted heteroaryl, wherein said alkylene, aryl, heteroaryl, and heterocyclyl moieties are any alkylene, aryl, heteroaryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moieties is an -alkylene-aryl group, R 1 is arylalkyl, substituted arylalkyl, heterocyclyl alkyl, and substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d and R 1e taken together with the carbon atom to which they are shown attached form a heterocyclyl or a substituted heterocyclyl, R 1f is H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -aryl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 1 -aryl group
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl and
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heterocyclyl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heteroaryl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)—O-alkyl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) q moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—S(O) 2 —O-alkyl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)-heteroaryl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heteroaryl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-alkylene-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-haloalkyl, -q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exe that amplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-haloalkyl, -q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is a -alkylene-aryl, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene and/or aryl and/or heterocyclyl with one or more of any substituents defined or exemplified herein.
  • p is 0, the L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heteroaryl moieties are any alkylene, alkyl,
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl,
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6c )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1e , wherein R 1e is alkyl or substituted alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heteroaryl moieties are any alkylene, alkyl, aryl, and heteroaryl moieties defined or exemplified
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene,
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is aryl or substituted aryl, X is —C(O)—, and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is heteroaryl or substituted heteroaryl, X is —C(O)—, and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted on the alkylene, aryl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is arylalkyl, substituted arylalkyl, heterocyclyl alkyl, and substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, X is —C(O)—, and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d and R 1e taken together with the carbon atom to which they are shown attached form a heterocyclyl or a substituted heterocyclyl, R 1f is H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 6f2 wherein R 6d and R 6e
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -aryl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e , R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocycl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -aryl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e , R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and hetero
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -aryl group
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl
  • X is —(O)—
  • R 6 is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moie
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O—CH 2 -heterocyclyl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl,
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)—O-alkyl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl,
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—S(O) 2 —O-alkyl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6e , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkylene, alkylene, alkylene
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-NH—C(O)-heteroaryl group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1
  • the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group
  • R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group
  • q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-O-alkylene-PO 3 (alkyl) 2 group
  • R 1 is —C(R 1d R 1e )—NR 1f —C(O)—O—R 1g wherein R 1d , R 1e , and R 1f are independently H, alkyl, or substituted alkyl, and R 1g is alkyl or substituted alkyl
  • X is —C(O)—
  • R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 1g wherein R 1d , R 6e R 6f1 or R 14 are independently
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-alkylene-heterocyclyl group, q is 0, -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is ⁇ -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substitute of d heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R, R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any alkylene
  • p is 0, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-O-haloalkyl, -q is 1, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl-heteroaryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, and R 6 is C(R 6d R 6e )—NR 6f1 —C(O)—O—R 14 wherein R 6d , R 6e R 6f1 or R 14 are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, aryl, and heterocyclyl moieties are any
  • p is 1, the -L 1 -Ar 1 -(L 1 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is heterocyclyl alkyl or substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein, optionally substituted with one or more
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is C(R 6d R 6e )—NR 6f1 —S(O) 2 —R 6f3 R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 6f1 is H, alkyl, or substituted alkyl; and R 6f3 is alkyl, substituted alkyl, substituted alkyl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)— and R 6 is C(R 7d R 7e )—NR 7f1 —C(O)—R 7f2 wherein R 7d and R 7e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; R 7f1 is H, alkyl, or substituted alkyl; R 7f2 is alkyl, haloalkyl
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O) — and R 6 is C(R 6d R 6e )—NR 6f1 —S(O) 2 —N(alkyl) 2 , wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—R 6 is heterocyclyl or substituted heterocyclyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)— and R 6 is C(R 6d R 6e )O-aryl wherein R 6d , R 6e are independently selected from the group consisting of H, alkyl, and substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —S—, and R 6 is alkyl or substituted alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substituents defined or exemplified herein.
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)— and R 6 is —OR 6a wherein R 6a is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, substituted heterocyclyl alkyl, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein,
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ), moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is heterocyclyl or substituted heterocyclyl, wherein X is attached to the heterocyclyl through a heteroatom, wherein said alkylene, alkyl, aryl, and heterocyclyl moieties are any alkylene, alkyl, aryl, and heterocyclyl moieties defined or exemplified herein, optionally substituted with one or more of any substitu
  • p is 1, the -L 1 -Ar 1 -(L 2 -Ar 2 ) p moiety is an -alkylene-aryl-heterocyclyl group, q is 0, the -L 3 -Ar 3 -(L 4 -Ar 4 ) q moiety is an -alkylene-aryl group, R 1 is OR 1c , wherein R 1c is heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, X is —C(O)—, R 6 is heterocyclyl or substituted heterocyclyl, wherein X is attached to the heterocyclyl through a carbon atom, wherein said heterocyclyl includes any heterocyclyl defined or exemplified herein, wherein said alkylene, alkyl, aryl, and heteroaryl moieties are any alkylene, alkyl, aryl, and heterocycly
  • X is C(O); p is 0; q is 1; L 1 and L 3 are alkylene; L 4 is a covalent bond; Ar 1 , Ar 3 , and Ar 4 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl,
  • substituted aryl or said substituted heteroaryl of Ar 1 , Ar 3 and Ar 4 are each independently substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, haloalkyl, halo, hydroxy, amino, alkoxy, haloalkoxy.
  • X is C(O); p is 0; q is 1; L 1 and L 3 are alkylene; L 4 is a covalent bond; wherein R 1 is OR 1c ; and R 1c is alkyl, substituted alkyl, heterocyclyl, substituted heterocyclyl, heterocyclyl alkyl, or substituted heterocyclyl alkyl, wherein said substituted heterocyclyl alkyl is substituted on the heterocyclyl moiety, and said heterocyclyl is selected from the group consisting of: (i) a mono-cyclic 5- or 6-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 4 heteroatoms selected from N, O, and S; and (ii) a bi-cyclic 8-, 9-, or 10-membered aromatic, nonaromatic dihydro, or nonaromatic tetrahydro heterocyclic ring having from 1 to 6 hetero
  • a 1 , A 2 , A 3 , and A 4 are independently NR 9 or O;
  • R 8 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, —O-(alkyl), or —O-(substituted alkyl);
  • R 9 is H, alkyl, or substituted alkyl;
  • m is 1 or 2; and a and b are independently 0, 1, or 2.
  • X is C(O); p is 0; q is 1; L 1 and L 3 are alkylene; L 4 is a covalent bond; R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; or R 6d and R 6e are taken together to form a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring;
  • Z is —NR 14 or —O—;
  • R 14 is H, alkyl, or substituted alkyl;
  • R 6f1 is H, alkyl, or substituted alkyl; and
  • R 6f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy.
  • X is C(O); p is 0; q is 1; L 1 and L 3 are alkylene; L 4 is a covalent bond; R 1 is OR 1c ; and R 1c is selected from the group consisting of
  • a 1 , A 2 , A 3 , and A 4 are independently NR 9 or O;
  • R 8 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, —O-(alkyl), or —O-(substituted alkyl);
  • R 9 is H, alkyl, or substituted alkyl;
  • m is 1 or 2;
  • a and b are independently 0, 1, or 2;
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; or R 6d and R 6e are taken together to form a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring;
  • Z is —NR 14 or —O—;
  • R 14 is H, alkyl, or substituted alkyl;
  • R 6f1 is H, alkyl, or substituted alkyl; and
  • R 6f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy.
  • X is C(O); p is 1; q is 0; L 1 and L 3 are alkylene; L 2 is a covalent bond; R 1 is OR 1c ; and R 1c is selected from the group consisting of
  • a 1 , A 2 , A 3 , and A 4 are independently NR 9 or O;
  • R 8 is alkyl, substituted alkyl, haloalkyl, substituted haloalkyl, hydroxyalkyl, substituted hydroxyalkyl, —O-(alkyl), or —O-(substituted alkyl);
  • R 9 is H, alkyl, or substituted alkyl;
  • m is 1 or 2;
  • a and b are independently 0, 1, or 2;
  • R 6 is
  • R 6d and R 6e are independently H, alkyl, haloalkyl, hydroxyalkyl, or alkoxy; or R 6d and R 6e are taken together to form a 5- or 6-membered non-aromatic tetrahydro heterocyclic ring;
  • Z is —NR 14 or —O;
  • R 14 is H, alkyl, or substituted alkyl;
  • R 6f1 is H, alkyl, or substituted alkyl;
  • R 6f2 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy.
  • Ar 1 , Ar 2 , and Ar 4 are independently aryl, substituted aryl, heteroaryl, or substituted heteroaryl, wherein said substituted aryl or said substituted heteroaryl of Ar 1 , Ar 2 and Ar 4 are each independently substituted by one or more substituents selected from the group consisting of alkyl, substituted alkyl, haloalkyl, halo, hydroxy, amino, alkoxy, haloalkoxy.
  • Compounds of general formula II are depicted as a “core” structure (Z) substituted with four moieties T1, T2, X1 and X2.
  • the core structures Z are depicted in Table 1.
  • the points of attachment of T1, T2, X1 and X2 are indicated on each of the core structures depicted in Table 1.
  • Tables 2-5 respectively, show the structures of the T1, T2, X1 and X2 moieties.
  • the point of attachment of the core structure Z is indicated in each of the structures of T1, T2, X1 and X2.
  • Each core structure Z in Table 1, and each substituent T1, T2, X1 and X2 and Tables 2-5 is represented by a “code” comprising a letter and a number.
  • Each structure of a compound of Formula II can be designated in tabular form by combining the “code” representing each structural moiety using the following syntax: ZT1.T2.X1.X2.
  • Z1.T1A.T2B.X1A.X2A represents the following structure:
  • Alk means a substituted or unsubstituted alkyl or alkylene group, wherein the terms “alkyl” and “alkylene” are as defined herein. “Alk” means an alkyl group when depicted as monovalent, and an alkylene group when depicted as divalent.
  • Het is a substituted or unsubstituted heterocyclyl or heterocyclylene group, wherein the term “heterocyclyl” is as defined herein, and the term “heterocyclylene” means a heterocyclyl group as defined herein, in which a hydrogen atom has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent heterocyclyl.
  • Het is a heterocyclyl when depicted as monovalent, and heterocyclylene when depicted as divalent.
  • “Ar” is a substitute or unsubstituted aryl or arylene group, wherein the term “aryl” is as defined herein, and the term “arylene” means an aryl group as defined herein, in which a hydrogen atom has been replaced by an open valence (in analogy to alkylene), thereby defining a divalent aryl.
  • “Ar” is aryl when depicted as monovalent, and arylene when depicted as divalent. When substituted, “Alk”, “Het”, and “Ar” can be substituted with any of the substituents defined or exemplified herein.
  • substituents of “Alk” can include ether, halogen, —OH, amide, amine, etc.
  • substituents of “Het” can include alkyl, aryl, carbonyl, —OH, halogen
  • substituents of “Ar” can include alkyl, aryl, —OH, halogen, etc., with the proviso that the resulting structure is chemically reasonable, and would provide compounds which are sufficiently stable for formulation in a pharmaceutically acceptable composition.
  • T1A O-Alk T1B —O-Het T1C —O-Alk-Het T1D -Alk-NH—C(O)—O-Alk T1E -Het-NH—C(O)—O-Alk T1F —N(Alk)(Het)
  • each structure of a compound of Formula III can be designated in tabular form by combining the “code” representing each structural moiety using the following syntax: z.t1.t2.x1.x2.
  • z1.t1a.t2b.x1a.x2a represents the following structure:
  • the compounds of this invention can be phosphonate prodrug compounds (or conjugates) derived from the compounds of Formula I.
  • the compounds of Formula I can be associated, e.g., structurally linked directly or indirectly with one or more phosphonate groups, especially phosphonate groups capable of modifying bioavailability, efficacy, or targeting site(s) of the compounds.
  • the compounds of Formula I can be directly linked to one or more phosphonate groups through a covalent bond or through a linking group, e.g., a linker.
  • the nature of the linker is not critical provided it does not interfere with the ability of the phosphonate containing compound to function as a therapeutic agent.
  • the phosphonate or the linker can be linked to the compound at any synthetically feasible position on the compound, e.g., any solvent accessible surface by removing a hydrogen or any portion of the compound to provide an open valence for attachment of the phosphonate or the linker.
  • the linking group or linker (which can be designated “L”) can include all or a portion of the group A 0 , A 1 , A 2 , A 3 , or W 3 described herein, such as for example, repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • alkyloxy e.g., polyethylenoxy, PEG, polymethyleneoxy
  • alkylamino e.g., polyethyleneamino, JeffamineTM
  • diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • the linking group or linker has a molecular weight of from about 20 daltons to about 400 daltons. In yet another embodiment, the linking group or linker has a length of about 5 angstroms to about 300 angstroms. In yet another embodiment, the linking group or linker separates the compound of this invention and the phosphorous of the phosphonate group by about 5 angstroms to about 200 angstroms, inclusive, in length.
  • the linking group or linker is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally replaced by (—O—), and wherein the chain is optionally substituted on carbon with one or more (e.g.
  • the linking group or linker is of the formula W-A wherein A is (C 1 -C 24 )alkyl, (C 2 -C 24 )alkenyl, (C 2 -C 24 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl or a combination thereof, wherein W is —N(R)C( ⁇ O)—, —C( ⁇ O)N(R)—, —OC( ⁇ O)—, —C( ⁇ O)O—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R)—, —C( ⁇ O)—, or a direct bond; wherein each R is independently H or (C 1 -C 6 )alkyl.
  • the linking group or linker is a divalent radical formed from a peptide or amino acid.
  • the linking group or linker is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine.
  • the linking group or linker is of the formula W—(CH 2 ) n wherein, n is between about 1 and about 10; and W is —N(R)C( ⁇ O)—, —C( ⁇ O)N(R)—, —OC( ⁇ O)—, —C( ⁇ O)O—, —O—, —S—, —S(O)—, —S(O) 2 —, —C( ⁇ O)—, —N(R)—, or a direct bond; wherein each R is independently H or (C 1 -C 6 )alkyl.
  • the linking group or linker is methylene, ethylene, or propylene.
  • the linking group or linker is attached to the phosphonate group through a carbon atom of the linker.
  • the compounds of this invention can be linked to one or more phosphonate groups capable of providing tissue or cell selection to the compounds, e.g., capable of directing the compounds to desired target tissue(s) or cell(s), especially tissues or cells associated with infections or inflammations including without any limitation white blood cells.
  • the compounds of this invention can be linked to one or more phosphonate groups capable of inducing or triggering an enzymatic activation, e.g., one or more in vivo enzymatic cleavages or modifications which could result in an intracellular accumulation of the cleaved or modified compounds.
  • the phosphonate group of the compounds of this invention may cleave in vivo in stages after they have reached the desired site of action, e.g., inside a cell.
  • One mechanism of action inside a cell may entail a first cleavage, e.g., by esterase, to provide a negatively-charged “locked-in” intermediate.
  • Cleavage of a terminal ester grouping in a compound of the invention thus affords an unstable intermediate which releases a negatively charged “locked in” intermediate.
  • intracellular enzymatic cleavage or modification of the phosphonate or prodrug compound may result in an intracellular accumulation of the cleaved or modified compound by a “trapping” mechanism.
  • the cleaved or modified compound may then be “locked-in” the cell by a significant change in charge, polarity, or other physical property change which decreases the rate at which the cleaved or modified compound can exit the cell, relative to the rate at which it entered as the phosphonate prodrug.
  • Other mechanisms by which a therapeutic effect is achieved may be operative as well.
  • enzymes capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphatases.
  • the compounds of this invention can be linked with one or more groups A 0 ; or a pharmaceutically acceptable salt thereof, wherein:
  • a 0 is A 1 , A 2 or W 3 ;
  • a 1 is:
  • a 2 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —;
  • R x is independently H, R 1 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , S(O)R x , —S(O) 2 R x , S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
  • R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12.
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle or a heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups.
  • a specific value for M12a is 1.
  • a 1 is of the formula:
  • a 1 is of the formula:
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 1 is of the formula:
  • W 5a is a carbocycle independently substituted with 0 or 1 R 2 groups
  • a 1 is of the formula:
  • W 5a is a carbocycle or heterocycle where W 5a is independently substituted with 0 or 1 R 2 groups.
  • a 1 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 2 is of the formula:
  • a 2 is of the formula:
  • M12b is 1.
  • M12b is 0, Y 2 is a bond and W 5 is a carbocycle or heterocycle where W 5 is optionally and independently substituted with 1, 2, or 3 R 2 groups.
  • a 2 is of the formula:
  • W 5a is a carbocycle or heterocycle where W 5a is optionally and independently substituted with 1, 2, or 3 R 2 groups.
  • M12a is 1.
  • a 2 is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.
  • a 2 is of the formula:
  • a 2 is of the formula:
  • M12b is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S; and Y 2a is O, N(R x ) or S.
  • a 3 is of the formula:
  • Y 2b is O or N(R x ).
  • a 3 is of the formula:
  • Y 2b is O or N(R x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • M12d is 1.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • W 5 is a carbocycle.
  • a 3 is of the formula:
  • W 5 is phenyl
  • a 3 is of the formula:
  • Y 1a is O or S; and Y 2a is O, N(R x ) or S.
  • a 3 is of the formula:
  • Y 2b is O or N(R x ).
  • a 3 is of the formula:
  • Y 2b is O or N(R x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • R 1 is H.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S; and Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2a is O or N(R 2 )
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • Y 1a is O or S; and Y 2a is O, N(R 2 ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 )
  • Y 2c is O, N(R y ) or S.
  • a 3 is of the formula:
  • Y 1a is O or S
  • Y 2b is O or N(R 2 )
  • Y 2d is O or N(R); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • Y 2b is O or N(R 2 ).
  • a 3 is of the formula:
  • Y 2b is O or N(R x ); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
  • a 3 is of the formula:
  • a 3 is of the formula:
  • a 3 is of the formula:
  • each R is independently (C 1 -C 6 )alkyl.
  • R x is independently H, R 1 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
  • Y 1a is O or S
  • Y 2c is O, N(R y ) or S.
  • Y 1a is O or S; and Y 2d is O or N(R y ).
  • R y is hydrogen or alkyl of 1 to 10 carbons.
  • Y 1 is O or S
  • Y 2 is O, N(R y ) or S.
  • na, m1b, m1c, m1d and m1e are independently 0 or 1;
  • m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • R y is H, W 3 , R 2 or a protecting group
  • m1a and m1d are 0 and m12c is not 0, then m1b and at least one of m1c and m1e are 0;
  • the phosphonate prodrug compound of this invention has the formula:
  • DRUG is a compound of this invention
  • nn is 1, 2, or 3;
  • a 0 is A 1 , A 2 or W 3 with the proviso that the compound includes at least one A 1 ;
  • a 1 is:
  • a 2 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 ;
  • R x is independently H, R 1 , W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 1 is independently H or alkyl of 1 to 18 carbon atoms
  • R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
  • R 3d is —C(Y 1 )R x , —C(Y)OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • R 5a is independently alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2-18 carbon atoms any one of which alkylene, alkenylene or alkynylene is substituted with 0-3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • X 66 is hydrogen or fluorine
  • X 67 is hydrogen, hydroxy, or acyloxy.
  • the phosphonate prodrug compound of this invention has the formula:
  • DRUG is a compound of this invention.
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —;
  • R x is independently H, W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x ) (R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x —)), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or N(R x )C(Y 1 )(N(R x )(R x ));
  • R 3d is C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • M2 is 1, 2, or 3;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • X 66 is hydrogen or fluorine
  • X 67 is hydrogen, hydroxy, or acyloxy
  • nn is 1, 2, or 3;
  • L is a linking group
  • the phosphonate prodrug compound of this invention has the formula:
  • DRUG is a compound of this invention.
  • nn is 1, 2, or 3;
  • a 0 is A 1 , A 2 , or W 3 with the proviso that the compound includes at least one A 1 ;
  • a 1 is:
  • a 2 is:
  • a 3 is:
  • Y 1 is independently O, S, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), or N(N(R x )(R x ));
  • Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(OR x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 —, or —S(O) M2 —S(O) M2 —;
  • R x is independently H, W 3 , a protecting group, or the formula:
  • R y is independently H, W 3 , R 2 or a protecting group
  • R 2 is independently H, R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups;
  • R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
  • R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
  • R 3b is Y 1 ;
  • R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), N(R x )C(Y 1 )R x —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
  • R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
  • R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
  • R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
  • W 3 is W 4 or W 5 ;
  • W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO 2 R 5 , or —SO 2 W 5 ;
  • W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
  • W 6 is W 3 independently substituted with 1, 2, or 3 A 3 groups
  • M2 is 0, 1 or 2;
  • M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • M1a, M1c, and M1d are independently 0 or 1;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • X 66 is hydrogen or fluorine
  • X 67 is hydrogen, hydroxy, or acyloxy.
  • X 61 is methoxy, ethoxy, n-propoxy, difluoromethoxy, trifluoromethoxy, ethyl, methyl, propyl, or n-butyl)
  • W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R 2 groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W 5 carbocycles and heterocycles may be independently substituted with 0 to 3 R 2 groups, as defined above.
  • substituted W 5 carbocycles include:
  • substituted phenyl carbocycles include:
  • phosphonate prodrug embodiments of the invention are named below in tabular format (Table 7). These embodiments are of the general formula “MBF”:
  • Sc is described in formulae 1-14 of Table 1.1 herein, wherein Sc is a generic formula for a compound of Formula I, A 0 is the point of covalent attachment of Sc to Lg, nn designates the number of -Lg-P(O)Pd 1 Pd 2 groups attached to Sc, and T1A, T2A, X1A, X2A, etc. and the terms “Alk”, “Ar”, and “Het” are as defined above (e.g., in Tables 1-5, and the text preceeding Tables 1-5).
  • Sc is a nucleus designated by a number, and each substituent is designated in order by letter or number.
  • Table 1.1 is a schedule of nuclei used in forming the embodiments of Table 7. Each nucleus (Sc) is given a number designation from Table 1.1, and this designation appears first in each embodiment name.
  • Tables 10.1 to 10.19 and 20.1 to 20.37 list the selected linking groups (Lg) and prodrug (Pd 1 and Pd 2 ) substituents, again by letter or number designation, respectively.
  • a compound of the formula MBF includes compounds having Sc groups based on formula 1-14 herein as well as compounds according to Table 7 below. In all cases, compounds of the formula MBF have groups Lg, Pd 1 and Pd 2 set forth in the Tables below.
  • each named embodiment of Table 7 is depicted by a number designating the nucleus from Table 1.1, followed by a letter designating the linking group (Lg) from Table 10.1-10.19, and two numbers designating the two prodrug groups (Pd 1 and Pd 2 ) from Table 20.1-20.36.
  • each embodiment of Table 100 appears as a name having the syntax:
  • Q 1 and Q 2 of the linking groups (Lg) do not represent groups or atoms but are simply connectivity designations.
  • Q 1 is the site of the covalent bond to the nucleus (Sc) and Q 2 is the site of the covalent bond to the phosphorous atom of formula MBF.
  • Each prodrug group (Pd 1 and Pd 2 ) are covalently bonded to the phosphorous atom of MBF at the A 0 symbol.
  • Some embodiments of Tables 10.1-10.19 and 20.1-20.36 may be designated as a combination of letters and numbers (Table 10.1-10.19) or number and letter (Table 20.1-20.36). For example there are Table 10 entries for BJ1 and BJ2.
  • entries of Table 10.1-10.19 always begin with a letter and those of Table 20.1-20.36 always begin with a number.
  • a nucleus (Sc) is shown enclosed within square brackets (“[ ]”) and a covalent bond extends outside the brackets, the point of covalent attachment of Sc to Lg may be at any substitutable site on Sc. Selection of the point of attachment is described herein. By way of example and not limitation, the point of attachment is selected from those depicted in the schemes and examples.
  • the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice.
  • Tablets will contain excipients, glidants, fillers, binders and the like.
  • Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986), herein incorporated by reference in its entirety.
  • Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.
  • the formulations of the invention both for veterinary and for human use, comprise at least one active ingredient, as defined above, together with one or more acceptable carriers and optionally other therapeutic ingredients.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.), herein incorporated by reference in its entirety. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise one or more compounds of the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as cellulose, microcrystalline cellulose, starch,
  • Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth herein, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned herein.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • a non-toxic parenterally acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophilized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 ⁇ m (including particle sizes in a range between 0.1 and 500 ⁇ m in increments such as 0.5 ⁇ m, 1 ⁇ m, 30 ⁇ m, 35 ⁇ m, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of infections as described herein.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.
  • Compounds of the invention can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds of the invention formulated for sustained or controlled release.
  • the effective dose of an active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active disease or condition, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies.
  • the effective dose can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about 0.01 to about 5 mg/kg body weight per day. More typically, from about 0.05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, or between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and a pharmaceutically acceptable carrier.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active therapeutic agent and a pharmaceutically acceptable carrier.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active therapeutic agent and a pharmaceutically acceptable carrier; wherein said at least one additional active therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HI nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase, HI nucleoside inhibitors of reverse transcriptase, HIV nucleot
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional active therapeutic agent and a pharmaceutically acceptable carrier; wherein said at least one additional active therapeutic agent is selected from the group consisting of (1) HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859; (2) HIV non-
  • the present application provides a combination pharmaceutical product or kit comprising: a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; and a second pharmaceutical composition comprising at least one additional active agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof
  • a second pharmaceutical composition comprising at least one additional active agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-
  • suitable combinations include combinations of one or more compounds of the present invention with one or more HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of (1) HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859; (2) HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etra
  • the present application provides for use of one or more compounds of the present invention, or pharmaceutically acceptable salts, solvates, and/or esters thereof, in the preparation of a medicament for the treatment of HIV and/or HCV.
  • the present application provides for use of one or more compounds of the present invention, or pharmaceutically acceptable salts, solvates, and/or esters thereof, in combination with one or more HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase
  • HIV nucleoside inhibitors of reverse transcriptase HIV nucleotide inhibitors of reverse transcriptase
  • HIV integrase inhibitors HIV integrase inhibitors
  • gp41 inhibitors CXCR4 inhibitors
  • entry inhibitors g
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • the compounds of the present invention can be administered alone, e.g., without other active therapeutic in ingredients or agents.
  • the compounds of the present invention are used in combination with other active therapeutic ingredients or agents.
  • the other active therapeutic ingredients or agents are HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • Combinations of the compounds of the present invention are typically selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination. For example, when treating and infection (e.g., HIV or HCV), the compositions of the invention are combined with active agents (such as those described herein).
  • active agents such as those described herein.
  • Non-limiting examples of suitable active agents suitable for combining with the compounds of the present invention include HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of
  • HIV protease inhibitors are selected from the group consisting of amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35, and AG 1859;
  • HIV non-nucleoside inhibitors of reverse transcriptase are selected from the group consisting of capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-
  • any compound of the invention with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient.
  • the combination therapy may be administered as a simultaneous or sequential regimen.
  • the combination When administered sequentially, the combination may be administered in two or more administrations.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours(e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
  • the combination therapy may provide “synergy” and “synergistic effect”, i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are administered together.
  • the present invention provides a method for inhibiting HIV protease comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof, to a patient in need of such treatment.
  • the present invention provides a method for inhibiting HIV protease, further comprising co-administering a therapeutic amount of at least one additional active agent selected from the group consisting of one or more HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • one or more HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, g
  • the present invention provides a method for treating AIDS or AIDS Related Complex comprising administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, to a patient in need of such treatment.
  • the present invention provides a method for treating AIDS or AIDS Related Complex comprising co-administering a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof and a therapeutic amount of at least one additional active agent selected from the group consisting of one or more HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase
  • HIV nucleoside inhibitors of reverse transcriptase HIV nucleotide inhibitors of reverse transcriptase
  • the present invention provides a method of inhibiting the replication of a retrovirus comprising contacting said retrovirus with a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof.
  • the present invention provides a method of inhibiting the replication of a retrovirus comprising contacting said retrovirus with a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof and at least one additional active agent selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, entry inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, CCR5 inhibitors, other drugs for treating HIV, and mixtures thereof.
  • HIV protease inhibiting compounds HIV non-nucleoside inhibitors of reverse transcriptase
  • HIV nucleoside inhibitors of reverse transcriptase HIV nucleotide inhibitors of reverse transcriptase
  • HIV integrase inhibitors HIV gp
  • EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (13.530 g, 77.6 mmol), HOBT (N-hydroxybenzotriazole) (10.805 g, 77.6 mmol), and 4-methylmorpholine (9.3 mL 84.7 mmol) were added to a solution of Compound 1 (13.354 g, 70.6 mmol) in ethyl acetate (177 mL) and the resulting reaction mixture was stirred at r.t. for 45 min.
  • Example B The residue from the first flask was dissolved in DMF (2.4 mL) and added to the second flask after the allotted stirring time. The resulting mixture was stirred at r.t. for 24 h. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous NaHCO 3 solution and brine. The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over Na 2 SO 4 and concentrated. The resulting residue was purified by reverse phase HPLC (Phenomenex Synergi® column, 25-100% acetonitrile/H 2 O+0.1% TFA) to give Example B as a white solid (30.9 mg, 0.040 mmol, 21%).
  • Compound 7b (1.080 g, 4.04 mmol, 41%) was prepared from (S)-( ⁇ )-alpha-hydroxy-gamma-butyrolactone, purchased from Aldrich, using procedures similar to those used to prepare Compound 7a.
  • Compound 7c (715 mg, 2.68 mmol, 26%) was prepared from (R)-(+)-alpha-hydroxy-gamma-butyrolactone, purchased from Aldrich, using procedures similar to those used to prepare Compound 7a.
  • Compound 7d was prepared from 3-hydroxysulfolane (available from Maybridge) using procedures similar to those used to prepare Compound 7a.
  • Example C was prepared from Compound 6 using procedures similar to those used to prepare Example A, except that Compound 7a was used instead of (R)-4-nitrophenyl tetrahydrofuran-3-yl carbonate. The product formed a precipitate which was filtered off and dried under vacuum to give Example C as a white solid (46.5 mg, 0.067 mmol, 50%).
  • Example D (27.7 mg, 0.036 mmol, 29%) was prepared from Compound 6 using procedures similar to those used to prepare Example A, except that Compound 7b was used instead of (R)-4-nitrophenyl tetrahydrofuran-3-yl carbonate.
  • Example E (36.4 mg, 0.047 mmol, 38%) was prepared from Compound 6 using procedures similar to those used to prepare Example A, except that Compound 7c was used instead of (R)-4-nitrophenyl tetrahydrofuran-3-yl carbonate.
  • Example F (177.5 mg, 0.22 mmol, 65%) was prepared from Compound 6 using procedures similar to those used to prepare Example A, except that Compound 7d was used instead of (R)-4-nitrophenyl tetrahydrofuran-3-yl carbonate.
  • Example G was purified by reverse phase HPLC (Phenomenex Synergi® column, 25-100% acetonitrile/H 2 O) and yielded Example G as a solid (14.2 mg, 0.09 mmol, 11%).
  • Example G Anhydrous acetonitrile (1.5 mL) was used to dissolve Example G (49.1 mg, 0.07 mmol) and then the solution was cooled to 0° C. DMAP (0.9 mg, 0.007 mmol) was added followed by DIPEA (42 ⁇ L, 0.24 mmol). Then, 4-nitrophenyl thiazol-4-ylmethyl carbonate, prepared according to Kempf et al in EP486948A2, (28.4 mg, 0.10 mmol) was added. The reaction mixture was stirred at 0° C. for 2 h, and then at r.t. for 18 h.
  • Example H a solid (12.2 mg, 0.02 mmol, 26%).
  • Example I (15.2 mg, 0.02 mmol, 22%) was prepared from Example G using a procedure similar to that used to prepare Example H, except that Compound 7d was used instead of 4-nitrophenyl thiazol-4-ylmethyl carbonate.
  • Boc-L-tert-leucine purchased from Acros (360.6 mg, 1.56 mmol) in DMF (3 mL) at r.t. was added TPTU (O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate) (463.1 mg, 1.56 mmol), and the reaction mixture was stirred for 20 min.
  • a solution of Example G (404.3 mg, 0.78 mmol) in DMF (4 mL) was added to the reaction mixture followed by 4-methylmorpholine (0.26 mL, 2.34 mmol). The reaction was stirred at r.t.
  • Example J as a solid (17.6 mg, 0.02 mmol, 77%).
  • Example K (11.5 mg, 0.014 mmol, 68%) was prepared from Compound 12 using procedure similar to those used to prepare Example J, except that ethyl chloroformate was used instead of isopropyl chloroformate.
  • Example L as a solid (1.7 mg, 0.002 mmol, 10%).
  • Example M was purified by reverse phase HPLC (25-100% acetonitrile/H 2 O+0.1% TFA) and yielded Example M as a solid (19.2 mg, 0.02 mmol, 52%).
  • Example N The in-situ generated Compound 13 reacted with Compound 12, and the reaction yielded Example N as a solid (11.4 mg, 0.013 mmol, 64%) after purification by reversed phase HPLC (Phenomenex Synergi® column, 25-100% acetonitrile/water with 0.1% TFA.
  • Example O as a solid (8.4 mg, 0.01 mmol, 35%).
  • Compound 15 was prepared using the method described in Bold, G., et al. New Aza-Dipeptide Analogues as Potent and Orally Absorbed HIV-1 Protease Inhibitors: Candidates for Clinical Development. J. Med Chem. 1998, 41, 3387-3401, which is herein incorporated by reference.
  • Example P as a solid (29.0 mg, 0.04 mmol, 31%).
  • Example Q was prepared from Compound 21 using procedures similar to those used to prepare Example P. Additional purification of the crude residue by reverse phase HPLC (Phenomenex Synergi® column, 25-100% acetonitrile/H 2 O+0.1% TFA) yielded Example Q as a solid (68.5 mg, 0.08 mmol, 55%).
  • Compound 27 was prepared from commercially available 4-(3-pyridyl)benzaldehyde using a method similar to that used to prepare Compound 24.
  • Example S (white solid, 12.0 mg, 0.017 mmol, 19%) was prepared from Compound 29 using a method similar to that used to prepare Example R.
  • Example T was purified by silica gel chromatography (75-100% ethyl acetate/hexane) and then by reverse phase HPLC (Phenomenex Synergi® column, 25-100% acetonitrile/H 2 O) to give Example T as a white solid (13.4 mg, 0.018 mmol, 19%).
  • Example U was prepared from Compound 33 using procedures similar to that used to prepare Example T, except that 2-pyridalcarbinol was used instead of 4-pyridylcarbinol.
  • Compound U (16.7 mg, 0.022 mmol, 17%).
  • Example U was prepared from Compound 33 using procedures similar to that used to prepare Example T, except that 3-furanamethanol was used instead of 4-pyridylcarbinol.
  • Example V (13.9 mg, 0.019 mmol, 11%).

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US7723380B2 (en) 2010-05-25
EP2069303B1 (en) 2016-03-30
AU2007275690B2 (en) 2013-01-17
JP2009544613A (ja) 2009-12-17
US20090105279A1 (en) 2009-04-23
NZ573887A (en) 2012-02-24
CA2657936A1 (en) 2008-01-24
WO2008011117A2 (en) 2008-01-24
JP2013151559A (ja) 2013-08-08
JP5599611B2 (ja) 2014-10-01
EP2069303A2 (en) 2009-06-17
CA2657936C (en) 2017-01-10
WO2008011117A3 (en) 2008-04-17
AU2007275690A1 (en) 2008-01-24
HK1127351A1 (zh) 2009-09-25

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