WO2009128964A2 - Recherche systématique virtuelle utilisant des ensembles pour mettre en évidence de nouveaux composés antiviraux dirigés contre la neuraminidase de la grippe aviaire - Google Patents

Recherche systématique virtuelle utilisant des ensembles pour mettre en évidence de nouveaux composés antiviraux dirigés contre la neuraminidase de la grippe aviaire Download PDF

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WO2009128964A2
WO2009128964A2 PCT/US2009/031732 US2009031732W WO2009128964A2 WO 2009128964 A2 WO2009128964 A2 WO 2009128964A2 US 2009031732 W US2009031732 W US 2009031732W WO 2009128964 A2 WO2009128964 A2 WO 2009128964A2
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group
hydrogen
optionally substituted
fluoro
alkyl optionally
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PCT/US2009/031732
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WO2009128964A3 (fr
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Rommie Amaro
Lily Cheng
J. Andrew Mccammon
Wilfred W. Li
Peter W. Arzberber
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/04—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
    • C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
    • C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/10—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
    • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
    • C07D253/06—1,2,4-Triazines
    • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
    • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/91—Dibenzofurans; Hydrogenated dibenzofurans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D331/00—Heterocyclic compounds containing rings of less than five members, having one sulfur atom as the only ring hetero atom
    • C07D331/04—Four-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to ensemble-based virtual screening of c ;ompound libraries, analogs of initial lead compounds obtained from screening methods a inndd compounds for treatment of avian influenza.
  • the subtype name is derived from the membrane glycoproteins hemagglutinin (HA) and neuraminidase (NA); there are 16 known types of HA and nine types of NA [2].
  • NA Neuraminidase
  • Tamiflu and Relenza are sialic acid analogs that competitively inhibit the protein's sialidase function and, consequentially, stall the viral infectious cycle [4].
  • High-throughput virtual screening is a fast, efficient method of finding novel inhibitors, but typical screens use only one crystal structure and assume the receptor is rigid. Due to the variable nature of the NA active site, however, the traditional method may fail to find inhibitors of the protein that have the greatest potential as drug candidates or drug candidate leads. Accommodating receptor flexibility in computer-aided drug design has been a longstanding challenge (reviewed in [8]) and only in the last decade have methods able to treat it been developed [1 1-18]. Treating protein backbone and side chain flexibility simultaneously has typically involved computationally intensive physically-based MD simulations in order to generate viable receptor conformations.
  • In vitro screening can identify compounds that show inhibitory activity to the neuraminidase protein of Influenza A virus subtype H5N1.
  • in vitro activity alone may not provide information for the rational design of further optimized compounds.
  • the novel conformations of the known binding sites of neuraminidase protein of Influenza A virus subtype H5N1 can provide information for designing drug candidates, especially if correlated to in vitro activity. Further, newly identified binding sites provide additional information for rational drug design.
  • Ranking of in vitro and computational results can provide correlation of the in vitro activity to a binding site and potentially the conformation of the compound in the binding site. The final rank recommendations provided by the current method are valuable in correlating binding site and conformation of compound in the binding site to in vitro activity.
  • One embodiment is the pharmaceutical composition
  • a pharmaceutically acceptable carrier wherein the agent is a compound having the formula (I):
  • R la and R lb are each separately selected from the group consisting of H (hydrogen), -C(0)NR lc R ld , -C(O)OR le , -C(S)NR lc R ld , -C(S)OR le , - NHC(O)R le , -NHC(O)NR lc R ld , -NHC(O)OR le , -NHC(S)NR lc R ld , - NHC(S)OR le , -OC(O)NR lc R ld , -OC(O)OR le , -OC(S)NR lc R ld , -OR lf , and -NR lc R Id ; or R Ia and R lb are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld is independently selected from the group consisting
  • R 2a and R 2b are each separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(O)OR 2e , -C(S)NR 2c R 2d , -C(S)OR 2e , - NHC(0)R 2e , -NHC(O)NR 2c R 2d , -NHC(O)OR 2e , -NHC(S)NR 2c R 2d , - NHC(S)0R 2e , -OC(O)NR 2c R 2d , -0C(0)0R 2e , -OC(S)NR 2c R 2d , -OR 2f , and -NR lc R ld ; or R 2a and R 2b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d is independently selected from the group consisting of H (hydrogen),
  • R 3 is selected from the group consisting of H (hydrogen), - NHC(O)R 3 ", -NHC(O)NR 3b R 3c , -NHC(O)OR 3d , -NHC(S)NR 3b R 3c , - NHC(S)0R 3d , -OC(S)NR 3b R 3c , -OR 3e , -SR 3e , -NR 3b R 3c , and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a is selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c are each separately selected from the group consisting of H (hydrogen), C] -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; R 3d is selected from the group consisting of aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e is selected from the group consisting of H (hydrogen), aryl, heteroaryl, and C i-6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent is a compound having the formula (II):
  • R 10 is selected from the group consisting of-(CH 2 ) n R 10a ;
  • R 1Oa is selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 10 ";
  • R 1Ob is selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and C L6 alkyl optionally substituted with up to 5 fluoro;
  • R l lb is selected from the group consisting of H (hydrogen), and C] -6 alkyl optionally substituted with up to 5 fluoro;
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • R 1Oa is -CH 2 C(O)R 10 * 5 .
  • X 2 is O (oxygen) and X 3 is -NH.
  • R 1Oa is -CH 2 C(O)OR 100 ; and R 11 is selected from the group consisting of -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R lla ) 2 , and -C(0)0R Ub .
  • R 1Oc is H (hydrogen);
  • R 11 is selected from the group consisting of nitro, -OP(O)(OR 1 la ) 2 , and -C(O)OR llb ;
  • R 1!a is selected from the group consisting of H (hydrogen), and
  • Ci -6 alkyl R ⁇ b is H (hydrogen); W is O (oxygen); and Y is O (oxygen).
  • composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent is a compound having the formula (III):
  • G is selected from the group consisting of CH and N (nitrogen);
  • J is selected from the group consisting of N + (nitrogen) and P + (phosphorous).
  • G is N (nitrogen).
  • R 13 is selected from the group consisting of H (hydrogen) and C 1-6 alkyl optionally substituted with up to 5 fluoro; and J is N + (nitrogen).
  • R 15 is selected from the group consisting of nitro, and -C(O)R 15a ;
  • R 15a is selected from the group consisting of H (hydrogen), -SR 15b , and
  • R 15b is selected from the group consisting of H (hydrogen) and Cj -6 alkyl;
  • R 1 is selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R , 16a a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R 17 is selected from the group consisting of:
  • n 0, 1, or 2;
  • R 18a is selected from the group consisting of -SR 18b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Cj -6 alkoxy optionally substituted with up to 5 fluoro, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • (k) X4 and X 5 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • R 17 is selected from the group consisting of: , and .
  • X 4 is O
  • R ,20 is selected from the group consisting of H (hydrogen), -OR 20a -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 20c and R 20d are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 2! is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21 ";
  • R 21a is selected from the group consisting of H (hydrogen), -SR 21 b , -OR 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 is selected from the group consisting of:
  • R 23 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 is -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • G 2 is selected from the group consisting of CH and N (nitrogen).
  • R 20 is H (hydrogen); and R 21 is H (hydrogen) or -S(O) 2 OH.
  • R 23 is H (hydrogen) or -S(O) 2 OH; R 24 is -OH; and R 25 is H (hydrogen), or -S(O) 2 OH.
  • Gi is N (nitrogen); and G 2 is N (nitrogen).
  • R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto group; and R 27a and R 27b are optionally taken together with the carbon to which they are attached to form a keto group.
  • Another embodiment is the pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent is a compound having the formula (VI):
  • R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 is :
  • R 33 is selected from the group consisting of H (hydrogen), -OH, halo, and C i-6 alkyl optionally substituted with up to 5 fluoro;
  • R 36 and R 37 are each separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • R 31 is H (hydrogen); and R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • Another embodiment is the compound having the formula (I): or a pharmaceutically acceptable salt or prodrug thereof wherein:
  • R Ia and R lb are each separately selected from the group consisting of H (hydrogen), -C(0)NR lc R ld , -C(0)0R le , -C(S)NR lc R ld , -C(S)OR le , - NHC(O)R 16 , -NHC(0)NR lc R ld , -NHC(0)0R le , -NHC(S)NR lc R ld , - NHC(S)0R lc , -0C(0)NR lc R ld , -0C(0)0R le , -OC(S)NR lc R ld , -OR If , and -NR lc R ld ; or R la and R lb are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld is independently selected from the group consisting of
  • R 2a and R 2b are each separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(0)0R 2e , -C(S)NR 2c R 2d , -C(S)OR 2e , -
  • R 2a and R 2b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d is independently selected from the group consisting of H (hydrogen), Ci -6 alkyl, and aryl, or R 2c and R 2d are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; each R 2e is independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; each R is independently selected from the group consisting of H (hydrogen), aryl,
  • R 3 is selected from the group consisting of H (hydrogen), - NHC(O)R 33 , -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)0R 3d , -OC(S)NR 3b R 3c , -OR 3e , -SR 3e , -NR 3b R 3c , and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a is selected from the group consisting of aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d is selected from the group consisting of aryl, heteroaryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e is selected from the group consisting of H (hydrogen), aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and C,. 6 alkyl optionally substituted with up to 5 fluoro; each R 4a is independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b is selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R Sa is independently selected from the group consisting of H (hydrogen), aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and (f) Xi is selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • R la and R lb are taken together with the carbon to which they are attached to form keto; and R 2a and R 2b are taken together with the carbon to which they are attached to form keto.
  • R 3 is - NH 2 ; and R 4 is -S(O) 2 OH.
  • R 5 is selected from the group consisting of -S(O) 2 OH, and -S(O) 2 NH 2 ; and Xi is -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • Another embodiment is the compound having the formula (II):
  • R 10 is selected from the group consisting of-(CH 2 ) n R l0a ;
  • R 1Oa is selected from the group consisting of tetrazole, -C(O)R 1 b , and -C(S)R 1Ob ;
  • R 1Ob is selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • n is ⁇ , I, or 2;
  • R 11 is selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -OP(O)(OR 1 la ) 2 , and -C(0)0R llb ;
  • R lla is selected from the group consisting of H (hydrogen), aryl, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R llb is selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • W is O (oxygen) or S (sulfur);
  • Y is O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • O oxygen
  • S sulfur
  • -NH nitride
  • formula (II) is not In another aspect of the embodiment X 2 is O (oxygen) and X 3 is -NH.
  • R 1Oa is -CH 2 C(O)R 10b .
  • R 1Oa is -CH 2 C(O)OR 100 ; and R 1 ! is selected from the group consisting of -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R Ua ) 2 , and -C(0)0R ⁇ b .
  • R 1Oc is H (hydrogen);
  • R n is selected from the group consisting of nitro, -OP(O)(OR 1 la ) 2 , and -C(0)0R llb ;
  • R Ila is selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R Hb is H (hydrogen);
  • W is O (oxygen);
  • Y is O (oxygen).
  • Another embodiment is the compound having the formula (III):
  • R 13 is selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 is one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • G is selected from the group consisting of CH and N (nitrogen);
  • G is N
  • R 13 is selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro; and J is N + (nitrogen).
  • R 13 is selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro; and J is N + (nitrogen).
  • R 15 is selected from the group consisting of nitro, and -C(O)R 15a ;
  • R 15iI is selected from the group consisting of H (hydrogen), -SR 15b , and
  • R 15b is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • R 16 is selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R 16a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R 17 is selected from the group consisting of:
  • n is ⁇ , I, or 2;
  • R 18a is selected from the group consisting of -SR 18b , -0R 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Cj -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X_j and X 5 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • O oxygen
  • S sulfur
  • -NH nitride
  • R 17 is selected from the group consisting of , and
  • X 4 is O (oxygen) and X 5 is -NH.
  • R 18 is-(CH 2 ) n R 18a ; n is 1; and R 18a is -OR 18b .
  • R 16 is -OR 16a ; and R 18b is aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro.
  • Another embodiment is the compound having the formula (V):
  • R 20 is selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 206 ;
  • R 20a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 20d are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20c is selected from the group consisting of H (hydrogen), aryl, and C i- 6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21a ;
  • R 21a is selected from the group consisting of H (hydrogen), -SR 21b , -0R 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b is selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 is selected from the group consisting of:
  • R 23 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and C 1-6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 is -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • (n) Gi is selected from the group consisting of CH and N (nitrogen);
  • (0) G 2 is selected from the group consisting of CH and N (nitrogen). In one aspect of the embodiment the compound of formula (V) is not selected from
  • R 20 is H (hydrogen); and R 21 is H (hydrogen) or -S(O) 2 OH.
  • R 23 is H (hydrogen) or -S(O) 2 OH; R 24 is -OH; and R 25 is H (hydrogen), or -S(O) 2 OH.
  • Gi is N (nitrogen); and G 2 is N (nitrogen).
  • R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto group; and R 27a and R 27b are optionally taken together with the carbon to which they are attached to form a keto group.
  • R 30 is selected from the group consisting of H (hydrogen), -OR a , -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30a is selected from the group consisting of H (hydrogen) and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30b and R 30c are each separately selected from the group consisting of H (hydrogen) and Cj -6 alkyl, or R 30b and R 30c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 31 is selected from the group consisting of H (hydrogen), -OH, -SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 is :
  • R 33 is selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fiuoro;
  • R 34 and R 35 are each separately selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fiuoro; or R 34 and R 35 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 are each separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • X ⁇ is selected from the group consisting of O (oxygen), S (sulfur) and -NH. In one aspect of the embodiment the compound of formula (VI) is not
  • R 32 is H (hydrogen); and R 32 is .
  • X 6 is S (sulfur).
  • R 34 and R 35 are optionally taken together with the carbon to which they are attached to form a keto group; and R 36 and R 37 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group.
  • R 33 is halo.
  • R 30 is H (hydrogen); and R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • R 31 is H (hydrogen); and R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • R 32 is selected from the group consisting of:
  • Another embodiment is the compound having the formula (I):
  • R la and R lb are each separately selected from the group consisting of H (hydrogen), -C(O)NR lc R ld , -C(O)OR le , -C(S)NR lc R ld , -C(S)OR lc , - NHC(O)R le , -NHC(O)NR lc R ld , -NHC(O)OR le , -NHC(S)NR lc R ld , - NHC(S)OR lc , -OC(O)NR lc R ld , -OC(O)OR le , -OC(S)NR lc R ld , -OR lf , and -NR lc R ld ; or R la and R lb are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld
  • R 2a and R 2b are each separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(0)0R 2e , -C(S)NR 2c R 2d , -C(S)OR 2e , - NHC(0)R 2e , -NHC(O)NR 2c R 2d , -NHC(0)0R 2e , -NHC(S)NR 2c R 2d , - NHC(S)0R 2e , -OC(O)NR 2c R 2d , -OC(O)OR 2e , -OC(S)NR 2c R 2d , -OR 2f , and -NR lc R ld ; or R 2a and R 2b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d is independently selected from the group consisting of H (hydrogen), Ci
  • R 3 is selected from the group consisting of H (hydrogen), - NHC(O)R 38 , -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)0R 3d , -OC(S)NR 3b R 3c , -OR 3e , -SR 3e , -NR 3b R 3c , and C -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a is selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d is selected from the group consisting of aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e is selected from the group consisting of H (hydrogen), aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and Q -6 alkyl optionally substituted with up to 5 fluoro; each R 4a is independently selected from the group consisting of H (hydrogen), aryl, and C) -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b is selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R 3a is independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • T is selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • R 6 is H (hydrogen) or Ci -6 alkyl.
  • R 1 is selected from the group consisting of-(CH 2 ) n R 10a ;
  • R 1Oa is selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 1Ob ;
  • R 1Ob is selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and Ci. 6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • n 0, 1, or 2;
  • R 11 is selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -OP(O)(OR 1 la ) 2 , and -C(O)OR llb ;
  • R I la is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • W is O (oxygen) or S (sulfur);
  • Y is O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • O oxygen
  • S sulfur
  • -NH nitride
  • R 13 is selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 is one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • G is selected from the group consisting of CH and N (nitrogen);
  • (d) J is selected from the group consisting of N + (nitrogen) and P + (phosphorous).
  • R 15 is selected from the group consisting of nitro, and -C(O)R 15a ;
  • R 15a is selected from the group consisting of H (hydrogen), -SR 15b , and -OR 15b ;
  • R 15b is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • R 16 is selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R 16a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R 17 is selected from the group consisting of:
  • n 0, 1 , or 2;
  • R 18a is selected from the group consisting of -SR 18b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Cj -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • R 20 is selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 20a is selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 20d are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21a ;
  • R 21a is selected from the group consisting of H (hydrogen), -SR 2Ib , -OR 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b is selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 is selected from the group consisting of:
  • R 23 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 is -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Cj -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • (n) Gi is selected from the group consisting of CH and N (nitrogen);
  • G 2 is selected from the group consisting of CH and N (nitrogen).
  • Another embodiment is the compound having the formula (VI):
  • R ,30 is selected from the group consisting of H (hydrogen), -OR 30a -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and C i- 6 alkyl optionally substituted with up to 5 fluoro;
  • R 30a is selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30b and R 30c are each separately selected from the group consisting of H (hydrogen) and Ci -6 alkyl, or R 30b and R 30c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 31 is selected from the group consisting of H (hydrogen), -OH, -SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 is :
  • R 33 is selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 34 and R 35 are each separately selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 are each separately selected from the group consisting of H
  • R 36 and R 37 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group
  • Xe is selected from the group consisting of O (oxygen), S (sulfur) and
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (I):
  • R la and R lb are each separately selected from the group consisting of H (hydrogen), -C(O)NR lc R ld , -C(O)OR lc , -C(S)NR lc R Id , -C(S)OR le , - NHC(0)R le , -NHC(0)NR lc R ld , -NHC(O)OR le , -NHC(S)NR lc R ld , - NHC(S)OR le , -OC(O)NR lc R ld , -OC(O)OR 16 , -OC(S)NR lc R ld , -OR lf , and -NR lc R ld ; or R la and R lb are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R Id is independently selected from the group consisting
  • R 3 is selected from the group consisting of H (hydrogen), - NHC(O)R 38 , -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)OR 3 ", -OC(S)NR 3b R 3c , -0R 3c , -SR 3e , -NR 3b R 3c , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a is selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d is selected from the group consisting of aryl, heteroaryl, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 3c is selected from the group consisting of H (hydrogen), aryl, heteroaryl, and C J-6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and C 1-6 alkyl optionally substituted with up to 5 fluoro; each R 4a is independently selected from the group consisting of H (hydrogen), aryl, and Q -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b is selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR Sb , and halo; each R 5a is independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R Sb is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • X 1 is selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (II):
  • R 10 is selected from the group consisting of-(CH 2 ) ⁇ R 10a ;
  • R 1Oa is selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 10 ";
  • R 1Ob is selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR IOc , and C L6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • n is O, 1, or 2;
  • R 11 is selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R lla ) 2 , and -C(0)0R llb ;
  • R l la is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R ⁇ b is selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • W is O (oxygen) or S (sulfur);
  • Y is O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (III):
  • R 13 is selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 is one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • G is selected from the group consisting of CH and N (nitrogen);
  • (d) J is selected from the group consisting of N + (nitrogen) and P + (phosphorous).
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (IV):
  • R 15 is selected from the group consisting of nitro, and -C(0)R I5a ;
  • R 15a is selected from the group consisting of H (hydrogen), -SR 15b , and
  • R ,15b is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • R 116 is selected from the group consisting of H (hydrogen) and -OR 16a.
  • R , 16a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R 17 is selected from the group consisting of:
  • n is ⁇ , I, or 2;
  • R 18a is selected from the group consisting of -SR 18b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Cj -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R is selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (V):
  • R 20 is selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20c ;
  • R 20a is selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 20d are each separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d are optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21a ;
  • R 21a is selected from the group consisting of H (hydrogen), -SR 21b , -0R 2Ib , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b is selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 is selected from the group consisting of:
  • R 23 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 is -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 is selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b are each separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • (n) Gi is selected from the group consisting of CH and N (nitrogen);
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (VI):
  • R 30 is selected from the group consisting of H (hydrogen), -OR 30a , -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30a is selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 31 is selected from the group consisting of H (hydrogen), -OH, -SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 is selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 is :
  • R 33 is selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 34 and R 35 are each separately selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 are each separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 are optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • the method further comprises docking the compounds to sialic acid cavity.
  • Another embodiment is the method of identifying compounds which bind to the neuraminidase protein of Influenza A virus subtype H5N1, comprising:
  • the method further comprises docking the compounds to sialic acid cavity. In another aspect of the embodiment the method further comprises docking the compounds to the 150-loop. In another aspect of the embodiment the method further comprises docking the compounds to the sialic acid cavity and the 150- loop.
  • Another embodiment is the method of identifying an agent that interacts with Influenza A virus subtype H5N1 neuraminidase protein comprising:
  • Another embodiment is the method of identifying a compound which binds to the an Influenza A virus subtype H5N1 neuraminidase protein with a desired affinity comprising: identifying one or more interactions between a ligand and a sub-unit of the Influenza A virus subtype H5N 1 neuraminidase protein; and changing a substituent on the ligand in order to modify the interaction between the ligand the neuraminidase protein subunit to provide said compound.
  • Another embodiment is the composition comprising an agent and a pharmaceutically-acceptable carrier wherein the agent is identified by
  • pill comprising a compound selected from the group consisting of:
  • Another embodiment is the injectable pharmaceutical composition
  • Another embodiment is the method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound identified by any of the above methods.
  • Another embodiment is the method of screening a compound library to identify compounds which bind to an Influenza A virus subtype H5N1 neuraminidase protein comprising:
  • the method further comprises docking the compounds to sialic acid cavity. In another aspect of the embodiment the method further comprises docking the compounds to the 430-loop. In another aspect of the embodiment the method further comprises docking the compounds to the sialic acid cavity and the 430-loop.
  • Another embodiment is the method of screening a compound library comprising:
  • the method further comprises docking the compounds to the sialic acid cavity. In another aspect of the embodiment the method further comprises docking the compounds to the 150-loop. In another aspect of the embodiment the method further comprises docking the compounds to the sialic acid cavity and the 150-loop.
  • Another embodiment is the method of identifying compounds which bind to a target protein, comprising:
  • Another embodiment is the injection device comprising the pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent is a compound having the formulae (I), (II), (III), (IV), (V), or (VI).
  • the injection device is a syringe.
  • Figure 1 The three central member structures for the most dominant clusters from the apo and holo simulations are represented above in (a) and (b), respectively, each shown in comparison to the open and closed 150-loop crystal structure.
  • FIG. 1 Selected compounds are shown clustered in apo protein binding sites.
  • FIG. 1 Selected compounds are shown clustered in holo protein binding sites.
  • FIG 4A The open 150-loop crystal structure (2HTY) is shown with compounds NSC46080 and NSC 109836.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • carrier defines a chemical compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the uptake of many organic compounds into the cells or tissues of an organism.
  • diot defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art.
  • One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • halo refers to fluoro, chloro, bromo, or iodo.
  • the thioketo moiety has a sulfur in place of where an oxygen is present in a keto group.
  • the thioketo moiety is covalently bonded to the parent molecule through the carbon atom.
  • cyano refers to a -CN group.
  • nitro refers to a -NO 2 group.
  • alkyl means any unbranched or branched, saturated hydrocarbon.
  • the alkyl moiety may be branched or straight chain.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group may be designated as "Ci- C 6 alkyl” or similar designations.
  • “Ci-C 6 alkyl” indicates that there are one to six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t- butyl, pentyl, and hexyl.
  • alkoxy refers to straight or branched chain alkyl radical covalently bonded to the parent molecule through an ⁇ O ⁇ linkage.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, n-butoxy, sec-butoxy, t-butoxy and the like.
  • C i-6 alkoxy indicates that there are one to six carbon atoms in the alkyl chain and the alkyl radical is covalently bonded to the parent molecule through an — O — linkage.
  • aryl used herein refers to homocyclic aromatic radical whether one ring or multiple fused rings.
  • aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.
  • the aryl group can be optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, Ci-6 alkyl, Ci-6 alkoxy, Ci-6 alkyl optionally substituted with up to 5 fluoro, and C i-6 alkoxy optionally substituted with up to 5 fluoro.
  • heteroaryl refers to an aromatic heterocyclic group, whether one ring or multiple fused rings. In fused ring systems, the one or more heteroatoms may be present in only one of the rings.
  • heteroaryl groups include, but are not limited to, benzothiazyl, benzoxazyl, quinazolinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, pyrrolyl, oxazolyl, indolyl, imidazolyl, tetrazolyl and the like.
  • the heteroaryl group can be optionally substituted with one or more substituents each independently selected from the group consisting of halo, cyano, nitro, hydroxy, carboxy, Ci-6 alkyl, Ci-6 alkoxy, C i -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro.
  • salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid.
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 - C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine, lysine, and the like.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 - C 7 alkylamine, cycl
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse affect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • the terms "individual,” “host,” “subject,” and “patient” are used interchangeably herein, and refer to a mammal, including, but not limited to, primates, including simians and humans.
  • compositions comprising an agent and a pharmaceutically acceptable carrier, wherein the agent can be a compound having the formula (I):
  • R la and R lb can each be separately selected from the group consisting of H (hydrogen), -C(O)NR lc R ld , -C(O)OR le , -C(S)NR lc R ld , -C(S)OR le , - NHC(O)R le , -NHC(O)NR lc R ld , -NHC(O)OR le , -NHC(S)NR lc R ld , - NHC(S)OR le , -OC(O)NR lc R ld , -OC(O)OR le , -OC(S)NR lc R ld , -OR lf , and -NR lc R ld ; or R la and R lb can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld can be
  • R 2a and R 2b can each be separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(O)OR 2e , -C(S)NR 2c R 2d , -C(S)OR 2e , - NHC(0)R 2c , -NHC(O)NR 2c R 2d , -NHC(0)0R 2e , -NHC(S)NR 2c R 2d , - NHC(S)OR 2e , -OC(O)NR 2c R 2d , -OC(O)OR 2e , -OC(S)NR 2c R 2d , -OR 2f , and -NR lc R ld ; or R 2a and R 2b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d can be independently selected from the group consisting of H (hydrogen),
  • R 3 can be selected from the group consisting of H (hydrogen), - NHC(O)R 38 , -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)OR 3d , -OC(S)NR 3b R 3c , -OR 3e , -SR 3e , -NR 3b R 3c , and C -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a can be selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c can each be separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c optionally can be taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d can be selected from the group consisting of aryl, heteroaryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro
  • R 3e can be selected from the group consisting of H (hydrogen), aryl, heteroaryl, and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and C 1-6 alkyl optionally substituted with up to 5 fluoro; each R 4a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b can be selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R 5a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X 1 can be selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • R la and R lb can be taken together with the carbon to which they are attached to form keto; and R 2a and R 2b can be taken together with the carbon to which they are attached to form keto.
  • R 3 can be -NH 2 ; and R 4 can be -S(O) 2 OH.
  • R 5 can be selected from the group consisting of -S(O) 2 OH, and -S(O) 2 NH 2 ; and Xi can be -NR 6 ; where R 6 can be H (hydrogen) or C !-6 alkyl.
  • Some embodiments provide a pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent canbe a compound having the formula (II):
  • R 10 is selected from the group consisting of -(CH 2 ) n R 10a ;
  • R 1Oa is selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 1Ob ;
  • R 1Ob is selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc is selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • n 0, 1, or 2;
  • R 11 is selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -OP(O)(OR Ha ) 2 , and -C(0)0R ⁇ b ;
  • R Ha is selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R llb is selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • W is O (oxygen) or S (sulfur);
  • Y is O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • X 2 can be O (oxygen) and X3 can be -NH.
  • R 1Oa can be -CH 2 C(O)R 10b .
  • R 1Oa can be -CH 2 C(O)OR 100 ; and R 11 can be selected from the group consisting Of -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R Ua ) 2 , and -C(0)0R llb .
  • R 1Oc can be H (hydrogen);
  • R 11 can be selected from the group consisting of nitro, -OP(O)(OR Ha ) 2 , and -C(O)OR 11 ";
  • R l la can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R l lb can be H (hydrogen);
  • W can be O (oxygen); and
  • Y can be O (oxygen).
  • Some embodiments provide a pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent can be a compound having the formula (III):
  • R 13 can be selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 can be one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • G can be selected from the group consisting of CH and N (nitrogen);
  • J can be selected from the group consisting of N + (nitrogen) and P + (phosphorous).
  • G can be N (nitrogen).
  • R 13 can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro; and J can be N + (nitrogen).
  • R 15 can be selected from the group consisting of nitro, and -C(O)R 5a ;
  • R 15a can be selected from the group consisting of H (hydrogen), -SR 15b , and -OR 15b ;
  • R 15b can be selected from the group consisting of H (hydrogen) and C, -6 alkyl;
  • R 16 can be selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R 16a can be selected from the group consisting of H (hydrogen), and C, -6 alkyl;
  • R » 17 can be selected from the group consisting of:
  • n can be 0, 1, or 2;
  • R 18a can be selected from the group consisting of -SR 18b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b can be selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X 4 and X 5 can each be individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • R 17 can be selected from the group consisting of:
  • X 4 can be O (oxygen) and X 5 can be -NH.
  • R 18 can be -(CH 2 )HR 1 a ; n can be 1 ; and R 18a can be -0R 18b .
  • R 16 can be -0R 16a ; and R 18b can be aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro.
  • Some embodiments provide a pharmaceutical composition
  • a pharmaceutical composition comprising an agent and a pharmaceutically acceptable carrier, wherein the agent can be a compound having the formula (V):
  • R 20 can be selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 2Oa can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 2Oc and R 20d can each be separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 2 c and R 20d can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e can be selected from the group consisting of H (hydrogen), aryl, and C J -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(O)R 21a , and -C(S)R 21a ;
  • R 21a can be selected from the group consisting of H (hydrogen), -SR 21b , -0R 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R lb can be selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 can be selected from the group consisting of:
  • R 23 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and C !-6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 can be -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Cj -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b are optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • (n) Gi can be selected from the group consisting of CH and N (nitrogen);
  • G 2 can be selected from the group consisting of CH and N (nitrogen).
  • R 20 can be H (hydrogen); and R 21 can be H (hydrogen) or -S(O) 2 OH.
  • R 23 can be H (hydrogen) or -S(O) 2 OH; R 24 can be -OH; and R 25 can be H (hydrogen), or -S(O) 2 OH.
  • Gi can be N (nitrogen); and G 2 can be N (nitrogen).
  • R 26a and R 2 b can be optionally taken together with the carbon to which they are attached to form a keto group; and R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto group.
  • R 30 can be selected from the group consisting of H (hydrogen), -OR 30a , -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30il can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30b and R 30c can each be separately selected from the group consisting of H (hydrogen) and Cj -6 alkyl, or R 30b and R 30c can be optionally are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 31 can be selected from the group consisting of H (hydrogen), -OH, - SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 can be:
  • R 33 can be selected from the group consisting of H (hydrogen), -OH, halo, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 34 and R 35 can each be separately selected from the group consisting of H (hydrogen), -OH, halo, and Cj -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R and R can each be separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • X 6 can be selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • R 30 and R 31 can be H (hydrogen); and R 32 can be
  • X ⁇ can be S (sulfur).
  • R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto group; and R and R can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group.
  • R 33 can be halo.
  • R 30 can be H (hydrogen); and R 32 can be selected from the group consisting Of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • R 31 can be H (hydrogen); and R 32 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • compositions comprising an agent and a pharmaceutically acceptable carrier, wherein the agent can be selected from the group consisting of:
  • the pharmaceutical composition can comprise physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound disclosed herein.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety.
  • Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition.
  • sodium benzoate, ascorbic acid and esters of p-hydroxy benzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate- meth
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include butylene glycol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, s thereof.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • parenteral delivery including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • the compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • Physiologically compatible buffers include, but are not limited to, Hanks's solution, Ringer's solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.
  • penetrants appropriate to the barrier to be permeated may be used in the formulation.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or other organic oils such as soybean, grapefruit or almond oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • compositions well known in the pharmaceutical art for uses that include intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art.
  • Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et al., Clin.
  • compositions for intranasal delviery may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure maintenance of normal ciliary action.
  • suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers.
  • Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • Agents intended to be administered intracellular ⁇ may be administered using techniques well known to those of ordinary skill in the art.
  • such agents may be encapsulated into liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior.
  • the liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm.
  • the liposome may be coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ.
  • small hydrophobic organic molecules may be directly administered intracellularly.
  • compositions may be incorporated into the pharmaceutical compositions.
  • pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents.
  • R la and R lb can each be separately selected from the group consisting of H (hydrogen), -C(0)NR lc R ld , -C(O)OR le , -C(S)NR lc R ld , -C(S)OR le , - NHC(0)R lc , -NHC(0)NR lc R ld , -NHC(0)0R le , -NHC(S)NR lc R ld , - NHC(S)OR lc , -OC(O)NR 10 R" 1 , -0C(0)0R lc , -OC(S)NR lc R ld , -0R lf , and -NR lc R ld ; or R la and R lb can be optionally taken together with the carbon to which they are attached to form a keto or thioketo
  • R 2a and R 2b can each be separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(0)0R 2e , -C(S)NR 2c R 2d , -C(S)OR 2e , - NHC(0)R 2e , -NHC(O)NR 2c R 2d , -NHC(0)0R 2c , -NHC(S)NR 2c R 2d , - NHC(S)0R 2e , -OC(O)NR 2c R 2d , -0C(0)0R 2e , -OC(S)NR 2c R 2d , -OR 2f , and -NR lc R ld ; or R 2a and R 2b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d can be independently selected from the group consisting of H (hydrogen),
  • R 3 can be selected from the group consisting of H (hydrogen), -NHC(0)R 3a , -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)0R 3d , -OC(S)NR 3b R 3c , -0R 3e , -SR 3e , -NR 3b R 3c , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a can be selected from the group consisting ofaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c can each be separately selected from the group consisting of H (hydrogen), Cj -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d can be selected from the group consisting of aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e can be selected from the group consisting of H (hydrogen), aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; each R 4a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b can be selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R 5a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X 1 can be selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 can be H (hydrogen) or Cj -6 alkyl. In some embodiments the
  • R la and R lb can be taken together with the carbon to which they are attached to form keto; and R 2a and R 2b can be taken together with the carbon to which they are attached to form keto.
  • R 3 can be -NH 2 ; and R 4 can be -S(O) 2 OH.
  • R 5 can be selected from the group consisting Of -S(O) 2 OH, and -S(O) 2 NH 2 ; and Xi can be -NR 6 ; where R 6 can be H
  • the compounds of formula (I) can be synthesized by methods known in the art.
  • the compounds of formula (I) can be synthesized by condensing an appropriately substituted halo-anthraquinone, such as bromamine acid (1- amino-4-bromo anthraquinone-2-sulfonic acid), and an appropriately substituted aniline using a copper catalyst.
  • an appropriately substituted halo-anthraquinone such as bromamine acid (1- amino-4-bromo anthraquinone-2-sulfonic acid
  • an appropriately substituted aniline using a copper catalyst.
  • certain compounds of formula (I) can be synthesized using an Ullmann Condensation in a manner similar to that disclosed in Tuong et al. "Mechanism of the Ullmann Condensation. I. Kinetic and Thermodynamic Studies," Bulletin of the Chemical Society of Japan; 43; 1970; pp.
  • the compounds of formula (I) can be synthesized by condensing an appropriately substituted diazoanthraquinone with an appropriately substituted aniline in a manner similar to that disclosed in Lynas-Gray et al., "The Action of Bases on 1 -Diazoanthraquinone-2- sulphonate and its Derivatives," Journal of the Chemical Society; 1943; 45, incorporated herein in its entirety.
  • R 10 can be selected from the group consisting Of-(CHi) n R 1 a ;
  • R 1Oa can be selected from the group consisting of tetrazole, -C(O)R 1 and -C(S)R lOb.
  • R 1Ob can be selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • n can be 0, 1, or 2;
  • R 11 can be selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R lla ) 2 , and -C(O)OR 11 ";
  • R lla can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R llb can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • W is O (oxygen) or S (sulfur);
  • Y can be O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • O oxygen
  • S sulfur
  • -NH nitride
  • (H) may not be .
  • X 2 can be O
  • R 1Oa can be -CH 2 C(O)R 10b .
  • R 1Oa can be -CH 2 C(O)OR 10c ; and R 11 can be selected from the group consisting of -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R lla ) 2 , and
  • R 1Oc can be H (hydrogen);
  • R 11 can be selected from the group consisting of nitro, -0P(0)(0R lla ) 2 , and -C(0)0R llb ;
  • R lla can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R llb can be H
  • the compounds of formula (II) can be synthesized by methods known in the art.
  • the compounds of formula (II) can be synthesized derivatization of brucine.
  • certain compounds of formula (II) can be synthesized by nitration of brucine in a manner similar to that disclosed in Leuchs et al., "Uber unusede isomere Sauretagenen der Base des Kakothelins," Ber. 43, 1042 (1910), incorporated herein in its entirety.
  • R 13 can be selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 can be one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • G can be selected from the group consisting of CH and N (nitrogen);
  • (d) J can be selected from the group consisting of N + (nitrogen) and P + (phosphorous). In some embodiments the compound of formula (HI) may not be
  • G can be N (nitrogen).
  • R 13 can be selected from the group consisting of H (hydrogen) and C] -6 alkyl optionally substituted with up to 5 fluoro; and J can be N + (nitrogen).
  • R 15 can be selected from the group consisting of nitro, and -C(0)R 15a ;
  • R 15a can be selected from the group consisting of H (hydrogen), -SR 15b , and -OR 15b ;
  • R 15b can be selected from the group consisting of H (hydrogen) and C, -6 alkyl;
  • R 16 can be selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R 16a can be selected from the group consisting of H (hydrogen), and C 1-6 alkyl;
  • R 17 can be selected from the group consisting of:
  • n can be 0, 1, or 2;
  • R 18a can be selected from the group consisting of -SR 18b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, C 1-6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b can be selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X 4 and X 5 can each be individually selected from the group consisting of O (oxygen), S (sulfur) and -NH. In some embodiments the compound of formula (IV) may not be In some embodiments R 17
  • X 4 can be O (oxygen) and X 5 can be -NH.
  • R , 1 1 8 8 can be -(CH 2 ) n R , l 18 ⁇ a a ; n can be 1; and R 1 l 8 s a a can be -OR , 18b
  • R 16 can be -OR 1 a ; and R I8b can be aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro.
  • R 20 can be selected from the group consisting of H (hydrogen), -OR 20 ⁇ -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 20a can be selected from the group consisting of H (hydrogen), and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 20d can each be separately selected from the group consisting of H (hydrogen), Cj -6 alkyl, heteroaryl, and aryl, or R 20c and R 2 can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e can be selected from the group consisting of H (hydrogen), aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21a ;
  • R 21a can be selected from the group consisting of H (hydrogen), -SR 21b , -0R 21b , and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 can be selected from the group consisting of:
  • R 23 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 can be -OH or Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH 5 -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and C, -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • (n) Gi can be selected from the group consisting of CH and N (nitrogen);
  • G 2 can be selected from the group consisting of CH and N (nitrogen). In some embodiments the compound of formula (V) may not be selected from the
  • R 20 can be H (hydrogen); and R 21 can be H (hydrogen) or -S(O) 2 OH.
  • R 23 can be H (hydrogen) or -S(O) 2 OH; R 24 can be -OH; and R 25 can be H (hydrogen), or -S(O) 2 OH.
  • Gi can be N (nitrogen); and G 2 can be N (nitrogen).
  • R 26a and R 26b can be optionally taken together with the carbon to which they are attached to form a keto group; and R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto group.
  • R 30 can be selected from the group consisting of H (hydrogen), -OR 30a , -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30a can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30b and R 30c can each be separately selected from the group consisting of H (hydrogen) and Ci -6 alkyl, or R 30b and R 30c can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R ! can be selected from the group consisting of H (hydrogen), -OH, - SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 can be selected from the group consisting Of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 is :
  • R 33 can be selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 and R 35 can each be separately selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 can each be separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • X ⁇ can be selected from the group consisting of O (oxygen), S (sulfur) and -NH. In some embodiments the compound of formula (VI) may not be selected from the group consisting of and In
  • R 30 and R 31 can be H (hydrogen); and R 32 can be R ⁇ R ⁇
  • X 6 can be S (sulfur).
  • R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto group; and R 36 and R 37 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group.
  • R 33 can be halo.
  • R 30 can be H (hydrogen); and R 32 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • R 31 can be H (hydrogen); and R 32 can be selected from the group consisting Of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH.
  • the compounds disclosed herein can be used alone, in combination with other compounds disclosed herein, or in combination with one or more other agents active in the therapeutic areas described herein.
  • Some embodiments provide a compound selected from the group consisting of:
  • Some embodiments provide a compound having the formula (I):
  • R la and R Ib can each be separately selected from the group consisting of H (hydrogen), -C(O)NR lc R ld , -C(O)OR le , -C(S)NR lc R ld , -C(S)OR le , - NHC(O)R lc , -NHC(0)NR lc R ld , -NHC(O)OR 1 *, -NHC(S)NR lc R ld , - NHC(S)OR le , -0C(0)NR lc R ld , -0C(0)0R lc , -OC(S)NR lc R ld , -OR lf , and -NR lc R ld ; or R la and R lb can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld can be
  • R 3 can be selected from the group consisting of H (hydrogen), -NHC(0)R 3a , -NHC(O)NR 3b R 3c , -NHC(O)OR 3d , -NHC(S)NR 3b R 3e , - NHC(S)OR 3d , -OC(S)NR 3b R 3e , -OR 3e , -SR 3e , -NR 3b R 3c , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a can be selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e can be selected from the group consisting of H (hydrogen), aryl, heteroaryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; R 5b can be selected from the group consisting of H (hydrogen), aryl, and Ci- 6 alkyl optionally substituted with up to 5 fluoro; and
  • Xi can be selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Cj -6 alkyl.
  • R 10 can be selected from the group consisting Of-(CH 2 )HR 1 a ;
  • R 1Oa can be selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 1Ob ;
  • R 1Ob can be selected from the group consisting of H (hydrogen), -SR 1Oe , -OR 10c , -NHR 1Oc , and C 1-6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc can be selected from the group consisting of H (hydrogen) and C !-6 alkyl;
  • n can be 0, 1, or 2;
  • R 11 can be selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -OP(O)(OR 1 la ) 2 , and -C(O)OR llb ;
  • R lla can be selected from the group consisting of H (hydrogen), aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R l lb can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • W can be O (oxygen) or S (sulfur);
  • Y can be O (oxygen) or S (sulfur); and
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • R 13 can be selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • G can be selected from the group consisting of CH and N (nitrogen);
  • R 15 can be selected from the group consisting of nitro, and -C(O)R 15a ;
  • R 15a can be selected from the group consisting of H (hydrogen), -SR !5b , and -OR 15b ;
  • R I5b can be selected from the group consisting of H (hydrogen) and C 1-6 alkyl;
  • R 116 can be selected from the group consisting of H (hydrogen) and
  • R , 16a can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl;
  • R 17 can be selected from the group consisting of:
  • n can be 0, 1, or 2;
  • R 18a can be selected from the group consisting of -SR I8b , -OR 18b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b can be selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • (k) X4 and X 5 can each be individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • Some embodiments provide a compound having the formula (V): or tautomer thereof, or their pharmaceutically acceptable salts or prodrugs, for use in the treatment of an avian influenza infection in an individual, wherein:
  • R 20 can be selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 20a can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 2 d can each be separately selected from the group consisting of H (hydrogen), Cj -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 21a ;
  • R 21a can be selected from the group consisting of H (hydrogen), -SR , -0R 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 can be selected from the group consisting of:
  • R »2"3 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 canbe -OH or Cj -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • G 2 can be selected from the group consisting of CH and N (nitrogen). [0117] Some embodiments provide a compound having the formula (VI):
  • R 30 can be selected from the group consisting of H (hydrogen), -OR 30a ,
  • R 30b and R 30c can each be separately selected from the group consisting of H (hydrogen) and Ci -6 alkyl, or R 30b and R 30c can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 31 can be selected from the group consisting of H (hydrogen), -OH, - SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 can be :
  • R 33 can be selected from the group consisting of H (hydrogen), -OH, halo, and C] -6 alkyl optionally substituted with up to 5 fluoro;
  • R 34 and R 35 can each be separately selected from the group consisting of H (hydrogen), -OH, halo, and Cj -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 can each be separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R 36 and R 37 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • Xe can be selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (I): or a pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R la and R lb can each be separately selected from the group consisting of H (hydrogen), -C(0)NR lc R ld , -C(0)0R le , -C(S)NR lc R Id , -C(S)OR le , - NHC(0)R le , -NHC(O)NR 10 R 1 ", -NHC(0)0R lc , -NHC(S)NR lc R ld , - NHC(S)0R le , -0C(0)NR lc R ld , -0C(0)0R le , -OC(S)NR lc R ld , -OR lf , and -NR lc R ld ; or R la and R lb can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R lc and R ld can be independently selected from the group consisting of H (hydr
  • R 2a and R 2b can each be separately selected from the group consisting of H (hydrogen), -C(O)NR 2c R 2d , -C(0)0R 2e , -C(S)NR 2e R 2d , -C(S)OR 2e , -
  • NHC(0)R 2e -NHC(0)NR ,2 z c c ⁇ R>2 z d ⁇ , -NHC(0)0R i2 z e t , -NHC(S)NR ,2'c c Rr»2 z ⁇ cl, NHC(S)OR 2c , -OC(O)NR 2c R 2d , -0C(0)0R 2e , -OC(S)NR 2c R 2d , -OR 2f , and -NR lc R ld ; or R 2a and R 2b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; each R 2c and R 2d can be independently selected from the group consisting of H (hydrogen), Ci -6 alkyl, and aryl, or R 2c and R 2d can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidiny
  • R 3 can be selected from the group consisting of H (hydrogen), - NHC(O)R 3 ", -NHC(O)NR 3b R 3c , -NHC(0)0R 3d , -NHC(S)NR 3b R 3c , - NHC(S)OR 3 ", -OC(S)NR 3b R 3c , -OR 3e , -SR 3e , -NR 3b R 3c , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3a can be selected from the group consisting of aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3b and R 3c can each be separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 3b and R 3c can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 3d can be selected from the group consisting of aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 3e can be selected from the group consisting of H (hydrogen), aryl, heteroaryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 4a ) 2 , -SR 4b , halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; each R 4a can be independently selected from the group consisting of H (hydrogen), aryl, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 4b can be selected from the group consisting of H (hydrogen), heteroaryl, aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5 can be selected from the group consisting of -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OP(O)(OR 5a ) 2 , -SR 5b , and halo; each R 5a can be independently selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 5b can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and (f) Xi can be selected from the group consisting of O (oxygen), S (sulfur) and -NR 6 ; where R 6 is H (hydrogen) or Ci -6 alkyl.
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (II):
  • R 10 can be selected from the group consisting of-(CH 2 ) n R 10a ;
  • R 1Oa can be selected from the group consisting of tetrazole, -C(O)R 10b , and -C(S)R 1Ob ;
  • R IOb can be selected from the group consisting of H (hydrogen), -SR 1Oc , -OR 10c , -NHR 1Oc , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 1Oc can be selected from the group consisting of H (hydrogen) and C 1-6 alkyl;
  • n can be 0, 1, or 2;
  • R 11 can be selected from the group consisting of tetrazole, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , nitro, -0P(0)(0R lla ) 2 , and -C(0)0R llb ;
  • R l la can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R llb can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • W can be O (oxygen) or S (sulfur);
  • Y can be O (oxygen) or S (sulfur);
  • X 2 and X 3 are each individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (III):
  • R 13 can be selected from the group consisting of H (hydrogen), Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 14 can be one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • G can be selected from the group consisting of CH and N (nitrogen);
  • (d) J can be selected from the group consisting of N + (nitrogen) and P + (phosphorous).
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (IV):
  • R 15 can be selected from the group consisting of nitro, and -C(O)R 15a ;
  • R 15a can be selected from the group consisting of H (hydrogen), -SR 15b , and -OR 15b ;
  • R 15b can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl;
  • R 16 can be selected from the group consisting of H (hydrogen) and -OR 16a ;
  • R 17 can be selected from the group consisting of:
  • n can be 0, 1, or 2;
  • R 18a can be selected from the group consisting of -SR 18b , -OR I8b , aryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro, and heteroaryl optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 18b can be selected from the group consisting of aryl and heteroaryl, each optionally substituted with one or more substituents each individually selected from the group consisting of OH, halo, cyano, nitro, aryl, heteroaryl, Ci -6 alkoxy optionally substituted with up to 5 fluoro, and Ci -6 alkyl optionally substituted with up to 5 fluoro; and
  • X 4 and X 5 can each be individually selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (V): or tautomer thereof, or their pharmaceutically acceptable salts or prodrugs, wherein:
  • R ,20 can be selected from the group consisting of H (hydrogen), -OR 20a , -SR 20a , -C(O)NR 20c R 20d , -NHC(O)R 20e ;
  • R 20a can be selected from the group consisting of H (hydrogen), and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 20c and R 20d can each be separately selected from the group consisting of H (hydrogen), Ci -6 alkyl, heteroaryl, and aryl, or R 20c and R 20d can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 20e can be selected from the group consisting of H (hydrogen), aryl, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , halo, -C(0)R 21a , and -C(S)R 2Ia ;
  • R 21a can be selected from the group consisting of H (hydrogen), -SR 21b , -0R 21b , and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 21b can be selected from the group consisting of H (hydrogen), and C J-6 alkyl optionally substituted with up to 5 fluoro;
  • R 22 can be selected from the group consisting of:
  • R 23 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Cj -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 24 can be -OH or C] -6 alkoxy optionally substituted with up to 5 fluoro;
  • (k) R 25 can be selected from the group consisting of H (hydrogen), -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -OH and Ci -6 alkoxy optionally substituted with up to 5 fluoro;
  • R 26a and R 26b can each be separately selected from the group consisting of H (hydrogen), -OH, Cj -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 26a and R 26b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 27a and R 27b can each be separately selected from the group consisting of H (hydrogen), -OH, Ci -6 alkyl optionally substituted with up to 5 fluoro, and Ci -6 alkoxy optionally substituted with up to 5 fluoro; or R 27a and R 27b can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • (n) Gi can be selected from the group consisting of CH and N (nitrogen);
  • G 2 can be selected from the group consisting of CH and N (nitrogen).
  • Some embodiments provide a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound having the formula (VI):
  • R 30 can be selected from the group consisting of H (hydrogen), -OR 30a , -SR 30a , -NR 30b R 30c , -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30a can be selected from the group consisting of H (hydrogen) and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 30b and R 3Oc can each be separately selected from the group consisting of H (hydrogen) and Ci -6 alkyl, or R 30b and R 30c can be optionally taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
  • R 31 can be selected from the group consisting of H (hydrogen), -OH, - SH, -S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, -CH 2 C(O)OH, and Ci -6 alkyl optionally substituted with up to 5 fluoro;
  • R 32 can be selected from the group consisting Of-S(O) 2 OH, -S(O) 2 NH 2 , -P(O)(OH) 2 , -C(O)OH, and -CH 2 C(O)OH; or R 32 can be :
  • R 33 can be selected from the group consisting of H (hydrogen), -OH, halo, and Cj -6 alkyl optionally substituted with up to 5 fluoro;
  • R 34 and R 35 can each be separately selected from the group consisting of H (hydrogen), -OH, halo, and Ci -6 alkyl optionally substituted with up to 5 fluoro; or R 34 and R 35 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group;
  • R 36 and R 37 can each be separately selected from the group consisting of H (hydrogen), -OH, -SH, and halo; or R and R 37 can be optionally taken together with the carbon to which they are attached to form a keto or thioketo group; and
  • Xe can be selected from the group consisting of O (oxygen), S (sulfur) and -NH.
  • the present disclosure provides a method of ameliorating an avian influenza infection in an individual, the method comprising administering to the individual an effective amount of a compound identified by the methods described herein.
  • the compounds or pharmaceutical compositions may be administered to the patient by any suitable means.
  • methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrasternally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation; as well as (e) administration topically; as deemed appropriate by those of skill in the art
  • compositions suitable for administration include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.
  • compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et at. 1975, in "The Pharmacological Basis of Therapeutics", which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1).
  • dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient.
  • the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 5O or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g. 5 to 200 mg.
  • an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg is used.
  • dosages may be calculated as the free base.
  • the composition is administered 1 to 4 times per day.
  • compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each active ingredient up to 1000 mg per day.
  • each active ingredient up to 1000 mg per day.
  • the compounds disclosed herein in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • An oral composition described herein may be administered or prescribed in a dosage less than, for example, about 750 mg/kg, about 500 mg/kg, about 300 mg/kg, or about 150 mg/kg.
  • An intravenous composition described herein may be administered or prescribed in a dosage less than, for example, about 25 mg/kg and greater than, for example, 5 mg/kg.
  • a composition described herein can be prescribed or administered at a constant dose, or the dosage can change as a function of treatment time.
  • dosages may increase or decrease with time in a step-wise or continuous manner.
  • the dosage may vary depending on the effect of the dosage on a condition being treated and the occurrence of adverse side effects.
  • the patient may be instructed to continue to lower the dosage until a side effect is reduced to an acceptable level.
  • the patient may be instructed to continue to lower the dosage until the dosage is no longer effective and then slightly increase the dosage.
  • composition described herein can be prescribed or administered at a specific dosage per day.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compositions may, for example, comprise one or more of the above- identified compounds, in combination with a pharmaceutically acceptable carrier, excipient or diluent.
  • a pharmaceutically acceptable carrier excipient or diluent.
  • Such carriers will be nontoxic to recipients at the dosages and concentrations employed.
  • a suitable dosage may be from about 0.01 ⁇ g/kg to about 1 g/kg body weight, typically by the intraocular, intravenous, intradermal, subcutaneous, intramuscular, or by other routes.
  • a more typical dosage is about 1 ⁇ g/kg to about 500 mg/kg, with about 10 ⁇ g/kg, 100 ⁇ g/kg, 1 mg/kg, 10 mg/kg, 20 mg/kg, 50 mg/kg, 100 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg, and various ranges within these amount being still more typical for administration. It will be evident to those skilled in the art that the number and frequency of administration will be dependent upon the response of the host. "Pharmaceutically acceptable carriers" for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remingtons Pharmaceutical Sciences, Mack Publishing Co. (A.R. Gennaro edit. 1985).
  • sterile saline and phosphate-buffered saline at physiological pH may be used.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of />-hydroxybenzoic acid may be added as preservatives.
  • antioxidants and suspending agents may be used.
  • compositions as described herein can be in a unit dosage form.
  • Unit dosage form can refer to a product form in which premeasured dosages of the drug are packaged, in contrast to bulk preparations. Examples of unit dosage forms are described herein, but several non limiting examples, include, a pill, a tablet, a capsule, a gel cap, a small liquid drug, an ampoule, a fast melt formulation, and the like.
  • a composition described herein can be administered using any suitable route or method of delivery.
  • the composition may be in the form of a solid, liquid or gas (aerosol).
  • a composition described herein can be administered alone or in combination with other substances.
  • Suitable routes of administration include oral; buccal; sublingual; pulmonary; transdermal; rectal; vaginal; topical; transmucosal; intestinal administration; intraspinally; ocular; parenteral delivery (e.g.
  • the route of administration may be determined by a condition to be treated.
  • Preferred routes of administration include oral administration.
  • compositions that will be administered to a patient take the form of one or more dosage units, where for example, a tablet may be a single dosage unit, and a container of one or more compounds of the invention in aerosol form may hold a plurality of dosage units.
  • compositions may be formulated as pills, tablets, powders, granules, dragees, capsules, liquids, sprays, gels, syrups, slurries, suspensions and the like, in bulk or unit dosage forms, for oral ingestion by a patient to be treated.
  • the composition may be an oral dosage form, and the oral dosage form may be a solid oral dosage form.
  • the compositions can be formulated readily, for example, by combining the active compound with any suitable pharmaceutically acceptable carrier or excipient.
  • fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol
  • cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • sustained release materials can be found in the incorporated materials in Remington: The Science and Practice of Pharmacy (20 th ed, Lippincott Williams & Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety.
  • a variety of techniques for formulation and administration can be found in Remington: The Science and Practice of Pharmacy (20 l ed, Lippincott Williams & Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety.
  • compositions involve intimate mixing of the pharmaceutical excipients and the active ingredient in its salt form, then it may be desirable to use pharmaceutical excipients which are non-basic, that is, either acidic or neutral excipients.
  • compositions and formulations disclosed herein also can include one or more pharmaceutically acceptable carrier materials or excipients.
  • Such compositions can be prepared for storage and for subsequent administration.
  • Acceptable carriers or diluents for therapeutic use are described, for example, in the incorporated material of Remington: The Science and Practice of Pharmacy (2003).
  • carrier material or excipient herein can mean any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration.
  • Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition.
  • Acceptable excipients include lactose, sucrose, starch powder, maize starch or derivatives thereof, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.
  • dissolution or suspension of the active compound in a vehicle such as water or naturally occurring vegetable oil like sesame, peanut, or cottonseed oil or a synthetic fatty vehicle like ethyl oleate or the like may be desired.
  • Buffers, preservatives, antioxidants and the like can be incorporated according to accepted pharmaceutical practice.
  • the compound can also be made in microencapsulated form.
  • the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like.
  • compositions and formulations can include any other agents that provide improved transfer, delivery, tolerance, and the like.
  • These compositions and formulations can include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.
  • any of the foregoing mixtures may be appropriate in treatments and therapies in accordance with the present invention, provided that the at least one active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration.
  • the at least one active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration.
  • Some embodiments provide a method of identifying compounds which bind to the neuraminidase protein of Influenza A virus subtype H5N1, comprising:
  • the method further comprises docking compounds to sialic acid cavity.
  • Some embodiments provide a method of identifying compounds which bind to the neuraminidase protein of Influenza A virus subtype H5N1, comprising:
  • the method further comprises docking the compounds to sialic acid cavity. In some embodiments, the method further comprises docking the compounds to the 150-loop. In some embodiments, the method further comprises docking the compounds to the sialic acid cavity and the 150-loop.
  • Some embodiments provide a method of identifying an agent that interacts with Influenza A virus subtype H5N1 neuraminidase protein comprising:
  • the agent that interacts with Influenza A virus subtype H5N1 neuraminidase protein can be selected from the group consisting of:
  • Some embodiments provide a method of identifying a compound which binds to an Influenza A virus subtype H5N1 neuraminidase protein with a desired affinity comprising identifying one or more interactions between a ligand and a sub-unit of the Influenza A virus subtype H5N1 neuraminidase protein; and changing a substituent on the ligand in order to modify the interaction between the ligand the neuraminidase protein subunit to provide said compound.
  • the ligand can be selected from the group consisting of:
  • compositions comprising an agent and a pharmaceutically-acceptable carrier wherein the agent is identified by
  • the present disclosure provides a pill comprising a compound selected from the group consisting of:
  • the present disclosure provides an injectable pharmaceutical composition
  • the present disclosure provides a method of screening a compound library to identify compounds which bind to an Influenza A virus subtype H5N1 neuraminidase protein comprising:
  • the method further comprises docking compounds to sialic acid cavity. In some embodiments, the method further comprises docking compounds to the 430-loop. In some embodiments, the method further comprises docking compounds to sialic acid cavity and the 430-loop.
  • the present disclosure provides a method of screening a compound library comprising:
  • the library can contain in the range of from about 1000 to about 2000 individual compounds, in the range of from about 2000 to about 10,000 individual compounds, in the range of from about 10,000 to about 50,000 compounds, in the range of from about 50,000 to about 150,000, in the range of from about 150,000 to about 500,000 compounds.
  • the library can be the National Cancer Institute First Diversity Set I which contains 1990 individual compounds. In another embodiment, the library can be the National Cancer Institute Second Diversity Set II which contains 1364 individual compounds.
  • virtual screening can identify the compounds which bind to the Influenza A virus subtype H5N1 neuraminidase protein with a desired binding affinity.
  • the binding affinity can be represented by comparison of the energy of the holo protein structure with the energy of the apo protein structure.
  • in vitro screening can identify compounds which inhibit Neuramidase from H5N1 with greater than 50% inhibition from about 10 mg/mL to about 200 mg/L.
  • the amount of compound providing greater than 50% inhibition can be in the range of from about 10 mg/mL to about 50 mg/mL, from 50 mg/mL to 100 mg/mL or from 100 mg/mL to about 200 mg/mL. In one embodiment, the amount of compound providing greater than 50% inhibition can be 200 mg/mL.
  • in vitro screening can identify compounds which inhibit Neuramidase from H5N1 with greater than 5% inhibition from about 5 ⁇ g/mL to about 200 ⁇ g/L.
  • the apo system was built with the 2HTY crystal structure [7]. Protonation states for histidine residues were defined at an apparent pH 6.5 using the PDB2PQR web server [14]. All crystallographically resolved water oxygen positions were retained in the apo system, as well as Ca 2+ ions, which are required for optimal NA function [15]. In order to mimic future experimental inhibition assay conditions, a 20 mM NaCl salt bath was introduced. The simulated system contained 112,311 atoms. Additional details for the of the simulation set-up is known in the art as exemplified in Amaro, R.E., et al., Remarkable loop flexibility in avian influenza Nl and its implications or antiviral drug design. JAm Chem Soc, 2007. 129(25): p. 7764-7765 [6].
  • the 2HU0 structure used for the holo system initially had a single Tamiflu molecule bound in the active site of chain B [7].
  • chain B was aligned to chain A, C, and D by superimposition of the backbone C ⁇ -atoms and the resulting transformation matrix was applied to the Tamiflu molecule.
  • Amber9 was used to set up the Tamiflu-bound system using an identical protocol to the apo system, with the exception of the additional Tamiflu parameters. Tamiflu was parameterized as described in Ref. [6]. Full details for the holo- system setup can be found in References [8, 9].
  • the composite tetrameric Tamiflu-bound system comprising one Tamiflu molecule in each of the four active sites and calcium ions in 20 mM NaCl salt bath, contained 112,457 atoms.
  • each chain of the tetramer was extracted at 10 ps intervals over the 40 ns simulation.
  • the resulting 1.6x10 4 trajectory structures for each simulation were superimposed using all C ⁇ atoms to remove overall rotation and translation.
  • the RMSD-clustering was performed on the subset of 62 residues that line the entire binding-site area, which we define here as the binding-site residues: 117-119, 133-138, 146-152, 156, 179, 180, 196-200, 223-228, 243-247, 277, 278, 293, 295, 344-347, 368, 401, 402, and 426-441.
  • AutoDockTools version 1.4.5 [18] was used to add polar hydrogens and assign Gaminationer charges to each of the eight NA structures.
  • the PDB2PQR web server http://nbcr.net/pdb2pqr
  • AutoGrid version 4.0 was used to create affinity grids centered on the active site.
  • Each grid enclosed an area of 64 by 72 by 66 A with 0.375 A spacing and affinity grids were calculated for all of the following atom types: A (aromatic carbon), C, F, I, N, NA (hydrogen-bond-accepting N) Cl, O, OA (hydrogen-bond- accepting O), P, S, SA (hydrogen-bond-accepting S), Br, H and e (electrostatic). All NA structures from simulation were aligned with the closed 150-loop crystal structure (2HU4, chain B) to maintain consistent grid location.
  • NCIDS National Cancer Institute Diversity Set
  • NCIDS National Cancer Institute Diversity Set
  • the topological changes within the Nl binding site influence the electrostatic potential of the binding site cavity surfaces, as shown in Figures 2 and 3.
  • Figure 2a shows selected hits clustered in Apo crystal structure.
  • Figure 2b shows selected hits clustered in the Apo-1 simulation structure.
  • Figure 2c shows selected hits clustered in the Apo-2 simulation structure.
  • Figure 2d shows selected hits clustered in the Apo-3 simulation structure.
  • the central member structure of the most dominant cluster for the apo simulations, Apo-1 is significantly more open in the 150- loop region than in the open-loop crystal structure.
  • a comparison of the alpha-carbon atoms for the 62 residues lining the binding site results in an RMSD between the open crystal structure and Apo-1 of 2.05 A (Fig. 1).
  • the so-called "wide-open" structure [6] appears to be energetically and structurally stabilized by locally-formed hydrogen bonds, as noted in [7].
  • the central member configuration for the second most dominant apo cluster, Apo-2 is similar to the open-loop crystal structure, exhibiting a binding site alpha-carbon RMSD of 0.95 A.
  • the central member structure of third most dominant apo cluster, Apo-3 is similar to the closed-loop crystal structure; alignment of Apo-3 to the closed-loop crystal structure yields an alpha-carbon RMSD over the 62 binding site residues of 1.73 A.
  • the central member structure of the most dominant cluster is similar to the open-loop crystal structure, and exhibits an alpha-carbon RMSD over the binding site region of 0.95 A.
  • the central member structure of the second cluster, Holo-2 is intermediary to the open-loop crystal structure and the closed-loop crystal structure with an alpha-carbon RMSD of 1.18 A and 1.27 A, respectively.
  • the third central member cluster structure, Holo-3 is similar to the open- loop crystal structure in the 150-loop region, and the two structures exhibit an alpha- carbon RMSD of 1.54 A over the entire binding site.
  • the apo ensemble exhibits a greater degree of flexibility in the 150- and 430-loop regions than the holo ensemble.
  • the presence of Tamiflu in the active site constrained the motion of the protein during the holo trajectory, through contacts formed between Dl 51 and Rl 52 in the 150-loop and Tamiflu [6].
  • the holo ensemble was predisposed to have higher-affinity for Tamiflu than the apo-ensemble. This preference is reflected in the binding energies and relative rankings calculated in automated docking (Tables Sl, S2).
  • Table Sl shows hits sorted by lowest binding energy. Each compound is identified by its NSC classification number. Tamiflu is included for reference. Table Sl expresses the binding affinity of each ligand as the Gibbs free energy (kcal/mol) of the most populated cluster followed by the percentage of docked conformations in that energy in parenthesis. Bold font denotes that the compound is among the top 27 lowest energy hits for the given receptor. Brackets denote that the clustering of the docking did not meet the 25 percent cutoff. Ligands identified from the ensemble screens that were not identified by the crystal structure screens are underlined.
  • Table S2 shows hits sorted by lowest binding energy. Each compound is identified by its NSC classification number. The binding affinity is expressed as the Gibbs free energy (kcal/mol) of the most populated cluster followed by the percentage of docked conformations in that energy in parenthesis. Bold font denotes that the compound is among the top 27 lowest energy hits for the given receptor. The values in brackets denote that the clustering of the docking did not meet the 25 percent cutoff. Underlined hits are those identified from the ensemble screens that were not identified by the crystal structure screens.
  • the clustering of top hits in each system reveals three distinct cavities (Fig. 2, 3) within the NA active site.
  • the sialic acid cavity is the locality in which the endogenous ligand binds and it is lined with important residues that facilitate the sialidase activity of NA (Table 1).
  • Tamiflu was correctly predicted to bind within sialic acid cavity in seven of the eight structures, providing a positive control for the docking studies (Fig. Sl); the exception was the predicted binding pose of Tamiflu to the central member structure of the most dominant apo cluster.
  • the opening of the 150-loop in reveals a second cavity to which a number of docked hits clustered.
  • the 150-cavity is a variable binding region adjacent to the sialic acid cavity that opens and closes with the motion of the 150-loop (Table 1). Finally, a third cavity of high ligand affinity is uncovered by hits clustering to the region near the flexible 430-loop.
  • the 430-cavity varies in size with the motion of the 430-loop (Table 1). The existence of these high affinity regions in the 150- cavity and the 430-cavity, which are disparate from the sialic acid cavity, correlate with the location of several hot spots indicated by the CS-Map analysis of the same NA receptor-ensembles [7].
  • Tamiflu docks to both open- and closed-loop crystal structures in a manner consistent with its crystallized conformation.
  • the overall RMSD (all-atoms) of the predicted binding pose compared to the crystal structure pose is 1.8 A for the closed- loop structure and 2.1 A for the open-loop structure.
  • the differences between docked and crystal poses lie primarily in the orientation of the pentyl ether group, which interacts with the protein through variable hydrophobic interactions.
  • the negatively charged carboxylate group is anchored through electrostatic interactions to the arginine trio (Rl 18, R292 and R371) and its position does not differ significantly between the docked and crystal poses.
  • the successful re-docking of Tamiflu confirms that AutoDock 4.0.1 is able to emulate experimental binding with an excellent degree of accuracy and precision, serving as a positive control to validate the virtual screening hits.
  • the conformation of the 150-loop reveals the presence of the so-called "open" 150-cavity .
  • two of the 1 1 selected hits for this structure (selection criteria delineated in the Methods section) dock in the sialic acid cavity, three dock in the open 150-cavity and two dock in the 430-cavity (Fig. 2a).
  • Two other hits bind simultaneously to both the 150-cavity and the 430-cavity.
  • These two compounds are note- worthy for their ability to span two cavities.
  • Another notable compound docks primarily in the 430-cavity but extends a carboxylic acid functional group into the sialic acid cavity.
  • Table 2 shows the 27 identified compounds ranked by their weighted mean energy (kcal/mol) from the Relaxed Complex Scheme. Also listed in Table 2 are the predicted Ki ( ⁇ M) as calculated from the weighted mean binding energy, the chemical structure, and the predicted binding site.
  • Experimental IC 5 O values (nM/L) for Tamiflu, Relenza and peramivir are denoted with parenthesis [38]. For comparison, the last two columns indicate the compounds' relative rank (among all 1883 NCI Diversity Set I compounds and the four control compounds screened) in the crystal structure screenings. Underlined hits are those identified from the ensemble screens that were not identified by the crystal structure screens.
  • Apo-1 is characterized by the wide-open conformations of both the 150-loop and the 430-loop (Fig. Ia), revealing the presence of the so-called “wide-open” 150-cavity and “wide-open” 430-cavity, respectively. This degree of loop flexibility is not observed in the crystal structures and the large outward shift of the 150-loop in particular has a profound effect on ligand binding.
  • Six out of seven selected hits for this structure — and Tamiflu, notably — dock in the wide-open 150-cavity (Fig. 2b). Only one of the selected hits docks in the sialic acid cavity and none in the wide-open 430-cavity (Fig. 2b).
  • the wide-open 150-loop conformation may cause Tamiflu to dock irregularly in this structure.
  • Apo-2 is structurally similar to the open-loop crystal structure with the notable exception of a more open 430-loop conformation, which is still less open than the wide-open 430-loop conformation in Apo-1 (Fig. Ia).
  • the open 430-loop conformation defines the presence of a corresponding "open" 430-cavity.
  • Four of the six selected hits for this structure dock in the open 430-cavity and two hits dock in the sialic acid cavity (Fig. 2c).
  • One potential butterfly compound docks primarily in the open 430-cavity, but also extends into the sialic acid cavity with a primary amide functional group.
  • Apo-3 is structurally similar to the closed-loop crystal structure in the 150-loop region, but differs in the open conformation of the 430-loop and the subsequent presence of the open 430-cavity (Fig. Ia). Two of the three selected hits for this structure dock in the open 430-cavity and one hit docks in the sialic acid cavity (Fig. 2d). As the 150-loop is in the closed conformation, the 150-cavity is absent in Apo-3. Fewer hits were selected from the virtual screen of Apo-3 than from other apo-ensemble screens because fewer compounds met the clustering and druglikeness selection criteria. This may be due to the binding opportunities excluded by the closed 150-cavity and may suggest that the opening of the 150-loop has an allosteric affect on ligand-receptor interactions in the sialic acid cavity and 430-cavity.
  • HoIo-I is structurally similar to the open-loop crystal structure (Fig. Ib). HoIo-I possesses an open 150-loop conformation and an open 430-loop conformation that corresponds to an open 150 cavity and an open 430-cavity, respectively. Three of the four selected hits for this structure dock in the sialic acid cavity. One hit docks primarily in the 430-cavity but extends into the sialic acid cavity with a sulfate functional group (Fig. 3b). This latter compound is notable for its possible bridging interactions. No hits dock to the open 150-cavity.
  • the conformation of the 150-loop is in-between the open and closed positions seen in the two crystal structures (Fig. Ib).
  • This so-called "half-open” 150-loop conformation and the subsequent "half-open” 150-cavity represent a distinct conformation not observed in the crystal structures or in the apo-ensemble.
  • the conformation of the 430-loop in Holo-2 is open, corresponding to an open 430-cavity.
  • One of the four selected hits for this structure docks to the sialic acid cavity and two hits dock to the 430-cavity (Fig. 3b).
  • Holo-3 possesses another unique intermediary conformation in which the 150-loop is more open in comparison to the open-loop crystal structure but less open in comparison to the wide-open 150-loop conformation seen in Apo-1 (Fig. Ib).
  • the conformation the 430-loop in Holo-2 is open, corresponding to an open 430-cavity (Fig 3d).
  • All of the three selected for this structure hits dock in the active site.
  • One of these hits extends into the 150-cavity with a methyl-chlorobenzene functional group. This latter compound possesses bridging potential.
  • no hits dock into the open 430-loop in Holo-3.
  • fewer hits were selected from the Holo-3 screen due to the fact that they did not meet the clustering and druglikeness criteria.
  • the average ligand-binding affinity for Holo-3 is also reduced in comparison to the other seven structures (Table S2, S3).
  • Table S3 shows 27 hits, the hits are re-ranked by their weighted RC mean.
  • the weighted RC mean is the mean energy (kcal/mol) of each ligand to each of the 27 clusters of the non-redundant set, weighted by the percentage of time the receptor spends in each cluster. This value is shown in comparison to the energy predicted from the holo crystal structure alone, the average predicted energy from the three most dominant holo clusters, and the unweighted RC mean.
  • binding spectra provides clear statistical support and justification for the RC virtual screening approach in terms of employing the dominant holo- and apo- ensembles.
  • a small number of representative structures as determined by the RMSD- based clustering technique the majority of the sampled conformational space is captured.
  • the subsequent screening of large compound libraries against the reduced set of receptor structures is then possible without sacrificing binding energy accuracy.
  • the mean weighted binding free energy is used to provide the final ranking for the top 27 hits and four control compounds presented in Table 2.
  • the RCS combines the advantages of docking algorithms with dynamic structural information provided by MD simulations, explicitly accounting for the flexibility of both the receptor and docked ligands.
  • the development of computational tools for computer-aided drug design depends on the critical compromise between accuracy and computational costs. Ideally, the most reliable prediction of molecular affinity can be obtained through rigorous free energy calculations of the ligand-binding process [23-34].
  • the goal of the RCS has been to account for receptor flexibility in a relatively computationally inexpensive manner.
  • the top compounds were redocked into the entire, non-redundant holo- ensemble.
  • the rationale for using the holo-ensemble for the re-dockings is two-fold.
  • the neuraminidase receptor may be interacting with its natural sialic acid substrate before any other ligand gains access to the active site. Therefore the Tamiflu-bound holo-ensemble may be considered a better approximation to the receptor structures in vivo because of the ligand-induced effect on the binding site.
  • NSC 109836 consistently binds in the sialic acid cavity and may not be affected by the motion of the 150- and 430-loops (Fig. 4a).
  • the diimino-triazinane functional group forms hydrogen bonds to framework residues El 19 and S 179 and the hydoxy(oxido)amino functional group forms hydrogen bonds to the catalytic arginine trio (Rl 18, R292 and R371) in the same manner as the carboxylate functional group of Tamiflu [36].
  • residues Rl 18, S179, and R371 were also identified as important hydrogen-bond mediators by CS-Map analysis [7].
  • NSC 109836 also forms non- hydrogen-bonding interactions with known catalytic residues D151, R224, E276, and Y406 and framework residues Rl 56, Wl 78, E227 and E277 [36]. Of these residues, all except E276 and Y406 are also predicted to mediate non-bonded interactions by the CS- Map analysis [7].
  • NSC211332 also binds consistently in the sialic acid cavity regardless of 150- or 430-loop motion. It is a diaminohexahydro-carbonitrile that in its lowest energy pose, docking to Apo-3, forms hydrogen bonds to framework residues El 19 and E227 [36]. NSC211332 also forms non-hydrogen bonding interactions with catalytic residues Dl 51, Rl 52 and Y406 and with framework residue Wl 78 [36]. Residue E227 is predicted to be an important hydrogen-bond mediator by the CS-Map analysis and Dl 51, Rl 52 and Wl 78 are recognized as important non-bonded interaction mediators [7].
  • the 150-cavity may be a promising target for novel, selective inhibitors against the pandemic strain.
  • Compounds may inhibit Nl by binding to this area alone or when bridged to active site binders.
  • Ten compounds exhibit high affinity for open or wide-open 150-cavity in one or more of the eight Nl structures (Table 2).
  • Six compounds exhibit high affinity the wide-open 150-cavity in Apo-1 (Table S2), these compounds were identified using the receptor-ensemble as described herein.
  • NSCl 6163 is one of the six compounds that bind the wide-open 150- cavity in Apo-1 (Fig. 4b). NSCl 6163 surprisingly binds with high affinity in the wide- open 150-cavity and does not bind favorably in the open 150-cavity, which may explain its relatively low ranking despite its many strong interactions with the protein. It is an acidic naphthalene-based structure that forms hydrogen bonds with Q 136, L 134, Dl 51, Rl 56 and R430; all except L 134 are also predicted to be important hydrogen-bond mediators by CS-Map analysis [7]. NSC16163 also interacts with V149 and T439 through non-hydrogen-bonding interactions in agreement with the CS-Map analysis. Though NSC16163 does not bind directly in the sialic acid cavity, it interacts with catalytic residue Dl 51 and framework residue Rl 56, suggesting that it may inhibit NA activity [36].
  • naphthalene-based compounds also bind with high affinity in the 150-cavity, interacting through hydrophobic interactions to the hydrophobic naphthalene group and through hydrogen-bonding interactions to polar functional groups on the naphthalene base (Table 2). These compounds include NSC45576, NSC45583, NSC37245 and NSC327705.
  • Some of the highest affinity hits to the open and wide-open 150-cavity are steroids such as NSC 17245, NSC 18312 and NSC59620. These compounds interact with the 150-cavity primarily through hydrophobic interactions, specifically to hydrophobic residues Vl 16, 1117, L134, T135, S145, T148, V149, P431, 1437, W438 and T439. Of these residues, Vl 16, V149, P431 and T439 are also predicted to be important non-bonded interaction mediators by CS-Map analysis [7]. These compounds also interact with catalytic and framework residues — most notably Rl 18, Dl 51 and Rl 56 — known to be important in cleaving sialic acid [36].
  • the 430-cavity may favor naphthalene-based compounds, namely NSC148354, NSC45582, NSC37245 and NSC327705. These compounds interact through hydrophobic interactions to hydrophobic residues P326, Y347, S370, W403, S404, Y406, 1427, G429, P431, 1437, W438 and T439 in the 430- cavity. Residues S404, Y406, 1427, P431 and T439 are also indicted by CS-Map analysis to be important in mediating non-bonded interactions [7].
  • NSC 148354 is one example of a naphthalene-based compound that binds with high affinity to the open 430-cavity seen only in MD simulations. In its lowest energy conformation, docking to Holo-2, NSC148354 forms hydrogen bonds to residues N369 and R371 ; R371 is predicted by CS-Map analysis to be a hydrogen bond mediator [7]. NSC148354 also interacts through non-bonded interactions to Y347, S370, W403, S404, 1427, R428, P431 and K432; S404, 1427, R428, P431 and K432 are predicted to mediate non-bonded interactions by CS-Map analysis [7]. Of these residues, R371 is identified as a catalytic residue [36]; though NSC148354 does not bind in the sialic acid cavity, it may still inhibit NA sialidase activity through hydrogen bonding with R371.
  • NSC90630, NSC106920, NSC327704, NSC371688, NSC372294 and NSC46080 all bind in the 430- cavity with strong interactions to the same hydrophobic residues listed previously.
  • NSC46080 is an interesting benzodiazepine that is highly ranked in the crystal structure screens but poorly ranked in the apo- and holo-ensemble screens and the RCS redocking (Table 2).
  • Figure 4a shows the open 150-loop crystal structure (2HTY) with NSC46080 and NSC 109836 bound.
  • NSC46080 docks similarly in both crystal structures, its overlapping position is shown in Fig. 4a.
  • NSC 109836 also docks similarly in both crystal structures, and its overlapping position is shown in Fig. 4a.
  • NSC45583, NSC327704 and NSCl 17079- dock primarily with hydrophobic interactions in the 430-cavity and extend a polar function group into the sialic acid cavity.
  • NSC327704 and NSCl 17079 may be candidates for bridging to Tamiflu with a distance of 1.47 A and 2.19 A, respectively, between the carboxylate group of Tamiflu and the closest possible linker atom.
  • NSC45583 has a distance of 5.20 between the carboxylate group and the closest linker atom. Though NSC45583 binds with high affinity to four out of eight Nl structures, it binds very differently to each structure.
  • NSC 16460 may be a promising cavity-bridging compound. NSC 16460 finds its lowest energy pose when docking to Holo-3. NSC 16460 contains a diamino- triazine group that binds in the sialic acid cavity and forms hydrogen bonds to catalytic residue Rl 18 and to framework residues S 179 and E277 [36]. Of these three residues, S 179 and E277 are also predicted to mediate hydrogen-bonding by the CS-Map analysis [7]. NSC 16460 also interacts through non-bonded interactions to catalytic residues Dl 51 and Y406 and framework residues El 19, R156, W178 and E227 [36].
  • NSC 16460 binds simultaneously to the open 150-cavity through hydrophobic contacts to residues 11 17, T135, Q136 and T439, which are mediated by a methyl- chlorobenzene group on the ligand.
  • the CS-Map analysis predicted that Q 136 and T439 are important mediators of non-bonded interactions [7].
  • NSC 16460 may not need to be linked to sialic acid. NSC 16460 may naturally bridge the catalytic residues in the sialic acid cavity to the high- affinity open 150-cavity.
  • the compounds of interest are validated and ranked through re-docking experiments into a set of structures representing the holo ensemble within the RCS framework.
  • the method described herein identified 27 drug-like compounds available from the NCI diversity set that may yield viable new compounds and scaffolds for future antiviral development against Nl .
  • Fluorescence based neuraminidase assay was determined as previously described (Potier et al., "Fluorometric assay of neuraminidase with a sodium (4- methylumbelliferyl-alpha-D-N-acetylneuraminate) substrate," Anal. Biochem., 1979, 94:287-96). Recombinant Nl influenza enzyme was incubated in a reaction buffer containing 33 mM MES, pH 6.5, and 4 mM calcium chloride, with or without inhibitors. Two inhibitor concentrations were used: 200 mM in the first round and 20 ⁇ M in the second round.
  • the fluorescent substrate 4-Methylumbeliferyl-iV- acetyl-a-D-neuramininic acid ammonium salt (4MU-NANA) was added to a final concentration of 50 ⁇ M. Reactions were stopped after 1, 15, and 30 minutes at 37 °C with the addition of 0.014 mM sodium hydroxide in 83% ethanol. Fluorescence was quantified with a Spectrofluorometric detector (RF-551), using an excitation wavelength of 362 nm and emission wavelength of 448 nm.
  • RF-551 Spectrofluorometric detector
  • Table 3 shows the in vitro results from testing 26 ligands with one reference compound.
  • the reference compound was oseltamivir and was purified from Tamiflu by using HPLC. Two kinds of concentration were used: 200 mg/L for 26 compounds; and then 20 ⁇ ig/L for the 6 compounds with the highest inhibition.
  • the MW of the 26 ligands were considered to all be similar and the in vitro testing was blinded. Thus, the same concentration for each compound was used in the assay, about 400 ⁇ M and about 40 nM), respectively.
  • the percent inhibition for each ligand was compared at different reaction times. After 30 min 23 compounds from among 26 compounds showed some inhibition at 200 mg/L. The inhibition ranged from 6.3% to 89.8% at 200 mg/L.
  • the oseltamivir (reference compound) showed 62% inhibition at 200 mg/L.
  • Oseltamivir showed very low inhibition at this concentration.
  • Table 4 shows that by screening only 26 compounds out of the NCI diversity set I, six compounds were identified that showed inhibition ranging from about 6% to about 21% at 20 ⁇ g/L.

Abstract

La présente invention concerne, d'une part un composé pouvant se lier à une protéine, en l'occurrence la neuraminidase du sous-type H5N1 du virus de la grippe aviaire, et d'autre part des compositions, notamment des compositions comprenant un composé de l'invention. Les modes de réalisation de l'invention concernent en outre des procédés thérapeutiques, notamment des procédés thérapeutiques dirigés contre la grippe aviaire.
PCT/US2009/031732 2008-01-23 2009-01-22 Recherche systématique virtuelle utilisant des ensembles pour mettre en évidence de nouveaux composés antiviraux dirigés contre la neuraminidase de la grippe aviaire WO2009128964A2 (fr)

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US20130090355A1 (en) * 2010-05-21 2013-04-11 Albert Einstein College Of Medicine Of Yeshiva University Chemical agents for the prevention of inhibition or tumor metastasis
CN103044338A (zh) * 2012-12-12 2013-04-17 天津医科大学总医院 miR-21小分子抑制剂及应用
EP2599480A1 (fr) 2011-12-03 2013-06-05 Universität Innsbruck Compositions pour le traitement de la grippe

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130090355A1 (en) * 2010-05-21 2013-04-11 Albert Einstein College Of Medicine Of Yeshiva University Chemical agents for the prevention of inhibition or tumor metastasis
EP2599480A1 (fr) 2011-12-03 2013-06-05 Universität Innsbruck Compositions pour le traitement de la grippe
CN103044338A (zh) * 2012-12-12 2013-04-17 天津医科大学总医院 miR-21小分子抑制剂及应用

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