EP2619206A1 - Analogues carbanucléosidiques 2'-fluoro-substitués pour traitement antiviral - Google Patents

Analogues carbanucléosidiques 2'-fluoro-substitués pour traitement antiviral

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Publication number
EP2619206A1
EP2619206A1 EP11715792.5A EP11715792A EP2619206A1 EP 2619206 A1 EP2619206 A1 EP 2619206A1 EP 11715792 A EP11715792 A EP 11715792A EP 2619206 A1 EP2619206 A1 EP 2619206A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
independently
another aspect
compound
cipf2
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP11715792.5A
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German (de)
English (en)
Inventor
Aesop Cho
Choung Kim
Adrian Ray
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gilead Sciences Inc
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Gilead Sciences Inc
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=47748238&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP2619206(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from US12/885,917 external-priority patent/US7973013B2/en
Priority claimed from US13/050,820 external-priority patent/US8455451B2/en
Application filed by Gilead Sciences Inc filed Critical Gilead Sciences Inc
Publication of EP2619206A1 publication Critical patent/EP2619206A1/fr
Withdrawn legal-status Critical Current

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    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates generally to compounds with antiviral activity, more particularly nucleosides active against Flaviviridae infections and most particularly to inhibitors of hepatitis C virus RNA-dependent RNA polymerase.
  • Viruses comprising the Flaviviridae family comprise at least three
  • BVDV bovine viral diarrhea virus
  • CSFV classical swine fever virus
  • BDV border disease of sheep
  • Flaviviruses are responsible for important human diseases such as dengue fever and yellow fever while hepaciviruses cause hepatitis C vims infections in humans.
  • Flaviviridae family Other important viral infections caused by the Flaviviridae family include West Nile virus (WNV) Japanese encephalitis virus (JEV), tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hemorrhagic fever virus and Zika virus. Combined, infections from the Flaviviridae virus family cause significant mortality, morbidity and economic losses throughout the world. Therefore, there is a need to develop effective treatments for Flaviviridae virus infections. 802.CIPF2 The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol.
  • HCV hepatitis C virus
  • RNA-dependent RNA polymerase is one of the best studied targets for the development of novel HCV therapeutic agents.
  • the NS5B polymerase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2, US 2004/0006002 Al). These enzymes have been extensively characterized at the biochemical and structural level, with screening assays for identifying selective inhibitors (De Clercq, E. (2001) J. Pharmacol. Exp.Ther. 297:1-10; De Clercq, E. (2001) J. Clin. Virol. 22:73-89).
  • Biochemical targets such as NS5B are important in developing HCV therapies since HCV does not replicate in the laboratory and there are difficulties in developing cell-based assays and preclinical animal systems.
  • ribavirin a nucleoside analog
  • interferon-alpha (a) (1FN) interferon-alpha
  • Ribavirin alone is not effective in reducing viral RNA levels, has significant toxicity, and is known to induce anemia.
  • the combination of IFN and ribavirin has been reported to be effective in the management of chronic hepatitis C (Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half the patients infected with some genotypes show a persistent benefit when given this treatment.
  • Other patent applications disclosing the use of nucleoside analogs to treat hepatitis C virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO
  • Certain ribosides of the nucleobases pyrrolo[l ,2-f][l ,2,4]triazine, imidazo[l,5- fj[l ,2,4]triazine, imidazo[l ,2-f][l,2,4]triazine, and [l ,2,4]triazolo[4,3-f][l ,2,4]triazine have been disclosed in Carbohydrate Research 2001, 331(1), 77-82; Nucleosides & Nucleotides (1996), 15(1 -3), 793-807; Tetrahedron Letters (1994), 35(30), 5339-42; Heterocycles (1992), 34(3), 569-74; J.
  • Ribosides of pyrrolo[l ,2-fj[l,2,4]triazinyl, imidazo[l,5-f][l,2,4]triazinyl, imidazo[l,2-f][l ,2,4]triazinyl, and [l ,2,4]triazolo[4,3-f][l,2,4]triazinyl nucleobases with antiviral, anti-HCV, and anti-RdRp activity have been disclosed by Babu, Y. S., WO2008/089105 and WO2008/141079; Cho, et al., WO2009/132123 and Francom, et al. WO2010/002877.
  • the invention also comprises compounds of Fonnula I or Formula IV-VI that inhibit viral nucleic acid polymerases, particularly HCV RNA-dependent RNA polymerase (RdRp), rather than cellular nucleic acid polymerases.
  • RdRp HCV RNA-dependent RNA polymerase
  • the compounds of Formula 1 or Formula IV-VI have been discovered to be efficacious against both wild type and S282T mutant strains of HCV virus. Therefore, a compound of Formula I or Formula IV-VI are useful for treating Flaviviridae infections in humans and other animals.
  • R 1 is (Ci-Q)alkyl, (C 4 -C 8 )carbocyclylalkyl, (Q-C ⁇ substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C2-Cg)substituted alkynyl, or aryl(C 1 -C 8 )alkyl;
  • R 2 is halogen
  • each R 3 , R 4 , or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, N0 2 , S(0) n R a , halogen, (Ci-Cg)alkyl, (C4-C 8 )carbocyclylalkyl, (Ci-C 8 ) substituted alkyl,
  • each n is independently 0, 1 , or 2;
  • each Y or Y 1 is, independently, O, S, NR, + N(0)(R), N(OR), + N(0)(OR), or N-NR 2 ;
  • W 1 and W 2 when taken together, are -Y 3 (C(R y ) 2 ) 3 Y 3 -; or one of W 1 or W 2 together with either R or R is -Y - and the other of W or W is Formula la; or W and W 2 are each, independently, a group of the Formula la:
  • each Y z is independently a bond, O, CR 2 , NR, N(0)(R), N(OR), ⁇ N(0)(OR), N-NR 2 , S, S-S, S(O), or S(0) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is inde endently R y or the formula:
  • each Mia, Ml c, and Ml d is independently 0 or 1 ;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
  • each R is independently H, (Cj-Cs) alkyl, (Ci-Cg) substituted alkyl, (C 2 - Cs)alkenyl, (C2-Cg) substituted alkenyl, (C 2 -Cg) alkjnyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 2 o aryl, C6-C 2 o substituted aryl, C 2 -C 2 o heterocyclyl, C 2 -C 2 o substituted heterocyclyl, arylalkyl or substituted arylalkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, -C(Y')R Y , -C(Y')W 5 , -S0 2 R Y , or -S0 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R Y groups;
  • each X 1 or X 2 is independently C-R 10 or N; 802.CIPF2 each R 8 is halogen, NR n R 12 , N(R )OR n , R'WR 12 , N 3 , NO, N0 2 , CHO,
  • each R 9 or R 10 is independently H, halogen, NR U R 12 , N(R ! 1 )OR u ,
  • each (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci-C 8 )alkyl of each R 1 , R 3 , R 4 , R 5 , R 6 , R 1 1 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a ; and wherein one or more of the nonterminal carbon atoms of each said (Ci-C 8 )alkyl may be optionally replaced with -0-, -S- or -NR a -.
  • novel compounds of Formula I or Formula IV- VI with activity against infectious Flaviviridae viruses are provided.
  • the compounds of the invention may inhibit viral RNA- dependent RNA polymerase and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human virus such as hepatitis C. 802.CIPF2
  • pharmaceutical compositions comprising an effective amount of a Formula I or a Formula IV-VI compound, or a
  • the present application provides for combination pharmaceutical agent comprising:
  • a) a first pharmaceutical composition comprising a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable salt, solvate, or ester thereof;
  • a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha- glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non- nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.
  • additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitor
  • the present application provides for a method of inhibiting HCV polymerase, comprising contacting a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; or a
  • the present application provides for a method of inhibiting HCV polymerase, comprising contacting a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; or a
  • the present application provides for a method of treating and/or preventing a disease caused by a viral infection wherein the viral infection is caused by a virus selected from the group consisting of dengue virus, 802.CIPF2 yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis virus, St Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and Hepatitis C virus; by administering to a subject in need thereof a virus selected from the group consisting of dengue virus, 802.CIPF2 yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-borne encephalitis virus, Junjin virus, Murray Valley encephalitis virus, St Louis encephalitis virus, Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virus and Hepatitis C virus; by administering to a subject in need thereof a virus selected from the group consisting of dengue virus,
  • the present application provides for a method of treating HCV in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I or Formula IV- VI; or a
  • the present application provides for a method of treating HCV in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I or Formula IV -VI; or a
  • Another aspect of the invention provides a method for the treatment or prevention of the symptoms or effects of an HCV infection in an infected animal which comprises administering to, i.e. treating, said animal with a pharmaceutical combination composition or fonnulation comprising an effective amount of a Formula I compound or Formula IV- VI, and a second compound having anti-HCV properties.
  • the invention also provides a method of inhibiting HCV, comprising administering to a mammal infected with HCV an amount of a Formula I or Formula IV-VI compound, effective to inhibit the replication of HCV in infected cells in said mammal.
  • a compound of Formula I or Formula IV-VI for the manufacture of a medicament for the treatment of Flaviviridae viral infections.
  • a compound of Formula I or Formula IV-VI for use in treating a Flaviviridae viral infection.
  • the Flaviviridae viral infection is acute or chronic HCV infection.
  • the treatment results in the reduction of one or more of the viral loads or clearance of NA in the patient.
  • the invention also provides processes and novel
  • novel methods for synthesis, analysis, separation, isolation, purification, characterization, and testing of the compounds of this invention are provided.
  • R 1 is (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (Ci-Cg)substituted alkyl,
  • each R 3 , R 4 , or R 5 is independently H, OR a , N(R a ) 2 , N 3 , CN, N0 2 , S(0) N R A , halogen, (C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, (C]-C 8 )substituted alkyl,
  • each n is independently 0, 1 , or 2;
  • each Y or Y is, independently, O, S, NR, N(0)(R), N(OR), + N(0)(OR), or
  • N-NR 2 802.CIPF2
  • W 1 and W 2 when taken together, are - ⁇ Y (C(R y ) 2 ) 3 Y 3 -; or one of W 1 or W 2 together with either R 3 or R 4 is -Y 3 - and the other of W 1 or W 2 is Formula la; or W 1 and W 2 are each, independently, a group of the Formula la:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR), N-NR 2 , S, S-S, S(O), or S(0) 2 ;
  • each Y is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R is inde endently R y or the formula:
  • each Mia, Ml c, and Mid is independently 0 or 1 ;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • each R is independently H, (Ci-C 8 ) alkyl, (C]-C 8 ) substituted alkyl, (C 2 - Q)alkenyl, (C 2 -C 8 ) substituted alkenyl, (C2-C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C6-C20 aryl, C 6 -C 2 o substituted aryl, C 2 -C 2 o heterocyclyl, C 2 -C 2 o substituted heterocyclyl, arylalkyl or substituted aryl alkyl;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, -C(Y')R y , -C(Y')W 5 , -S0 2 R y , or -S0 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups;
  • each X 1 or X 2 is independently C-R 10 or N;
  • each R 8 is halogen, NR n R 12 , N(R n )OR n , NR"NR" R 12 , N 3 , NO, N0 2 , CHO,
  • each R 9 or R 10 is independently H, halogen, NR 1 V 2 , N(R u )OR n ,
  • each R 1 1 or R 12 is independently H, (C C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 - C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -S(0) n (Ci-C 8 )alkyl or aryl(C C 8 )alkyl; or
  • R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S- or -NR a -;
  • each (C]-C 8 )alkyl, (C2-C 8 )alkenyl, (C2-C )alkynyl or aryl(Ci-C 8 )alkyl of each R 1 , R 3 , R 4 , R 5 , R 6 , R 1 1 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR A ; and wherein one or more of the nonterminal carbon atoms of each said (C)-C 8 )alkyl may be optionally replaced with -0-, -S- or -NR a -.
  • R 1 is (C 1 -C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C )alkynyl. In another aspect of this embodiment, R 1 is (Cj-C 8 )alkyl. In another aspect of this embodiment, R 1 is methyl, CH 2 F, or ethynyl. In another aspect of this embodiment, R 1 is methyl. In another aspect of this embodiment, R 1 is (Ci-Cg)alkyl and R 6 is H. In another aspect of this embodiment, R 1 is (C]-C 8 )alkyl and at least one of X 1 or X2 is N. In another aspect of this embodiment, R 1 is
  • (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3 .
  • R 3 is H, OR a , N(R a ) 2 , N 3 , CN, SR a , halogen, (C 1 -C 8 )alkyl, (C 2 -C8)alkenyl or (C 2 -C 8 )alkynyl.
  • R 3 is H.
  • R 3 is H and R 1 is (C]-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alkynyl.
  • R " is H
  • R is (Ci-Cg)alkyl.
  • R is H and R methyl, CH 2 F, or ethynyl.
  • R 3 is H and R 1 is methyl.
  • R 3 is H, R 1 is (Cj-C 8 )alkyl and at least one of X 1 or X 2 is N.
  • R 3 is H, R 1 is methyl and at least one of X 1 or X2 is N.
  • R 3 is H, R 1 is
  • R 6 is CN, OH, or CH 3 .
  • R 3 is H, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 3 is H, R 1 is methyl and R 6 is H.
  • R 4 is H, OR a , N(R a ) 2 , N 3 , CN, SR a , halogen, (Ci-Cg)alkyl, (C 2 -C8)alkenyl or (C2-C 8 )alkynyl.
  • R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is (C 1 -C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C )alkynyl. In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alkynyl. In another aspect of this embodiment, R 4 is OR a and R 1 is (Cj-C 8 )alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Ci-C 8 )alkyl and R 6 is CN, OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Ci-Cs)alkyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R is OH, R is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-Cs)alkyl and R 6 is CN, OH, or C3 ⁇ 4. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • R 5 is H, OR a , N(R a ) 2 , N 3 , CN, SR a , halogen,
  • R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-C8)alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C )alkynyl. In another aspect of this embodiment, R 4 is OR a and R 1 is
  • R 4 is OR a and R 1 is (Ci-C 8 )alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (C)-C 8 )alkyl and R 6 is CN, OH, or CH 3 In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 802.CIPF2 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H. In another aspect of this embodiment, R 5 is N 3 .
  • R 5 is H.
  • R 4 is H or OR a .
  • R 4 is OR a .
  • R 4 is OR d and R 1 is (Ci-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C2-Cs)alkynyl.
  • R 4 is OR a and R 1 is
  • R 4 is OR a and R 1 is (Ci-C 8 )alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (C l -C 8 )alkyl and R 6 is CN, OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is CN , OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (C 1 -C 8 )alkyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • R 6 is H, CN, OR a or CH 3 .
  • R 6 is H.
  • R 6 is CN.
  • R 6 is OR a .
  • R 6 is OH.
  • R 6 is CH 3 .
  • R 4 is H or OR a .
  • R 4 is OR d .
  • R 4 is OR a and R 1 is (Q— C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C )alkynyl.
  • R 4 is OR a and R 1 is
  • R 4 is OR a and R ! is (Ci-C8)alkyl.
  • R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is (Ci-Ca)alkyl and at least one of X or X " is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Ci-C 8 )alkyl and R 6 is CN, OH, or CH 3 In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is H. In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this embodiment, R 4 is OH, R 1 is (C 1 -C 8 )alkyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (C]-C 8 )alkyl and R 6 is
  • R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • R 6 is CN, OR a or CH 3 . In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is (C]-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alkynyl.
  • R 4 is OR a and R 1 is (d-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alk nyl. In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-C 8 )alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is (C[-C 8 )alkyl and at least one of X' or X 2 is . In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3 In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-Cg)alkyl and at least one of 802.CIPF2 X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3 In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R is H.
  • R is
  • R 6 is H. In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-C8)alkyl, (Cr-Cg) alkenyl or (C 2 -Cg)alkynyl. In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-Cg)alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Ci-Cg)alkyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is (C]-C 8 )alkyl and R 6 is CN, OH, or CH 3
  • R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OH, R 1 is methyl and R 6 is H.
  • X 1 is N or C-R 10 . In another aspect of this embodiment, X 1 is N. In another aspect of this embodiment, X 1 is C-R 10 . In another aspect of this embodiment, X 2 is C-H. In another aspect of this embodiment, X 1 is N and X 2 is C-H. In another aspect of this embodiment, X 1 is C-R 10 and X" ⁇ is CH. In another aspect of this embodiment R 6 is H. In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a .
  • R 4 is OR a .
  • R 4 is OR a and R 1 is (Ci-C 8 )alkyl, (C2 ⁇ Cg) alkenyl or (C 2 -C )alkynyl.
  • R 4 is OR a and R 1 is (Cj-C 8 )alkyl.
  • R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (C,-C 8 )alkyl and R 6 is CN, OH, or CH 3
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Q-C 8 )alkyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-C 8 )alkyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • each R is independently halogen, NR l l R ,2 , N(R 1 1 )OR 1 1 , NR 1 1 NR l l R 12 , OR H or SR 1 1 .
  • R 1 is methyl, C3 ⁇ 4F or ethynyl.
  • 802.CIPF2 R 1 is methyl.
  • R 9 is H, halogen, or NR U R 12 .
  • R is H, halogen, or NR n R 12 and R' is methyl, CH 2 F, or ethynyl.
  • R 9 is H, halogen, or NR" R' 2 and R 1 is methyl.
  • R 8 is NH 2 and R 9 is H or halogen.
  • R 8 is NH 2 and R 9 is H or halogen and R 1 is methyl, CH 2 F, or ethynyl.
  • R 8 is NH 2 and R 9 is H or halogen and R 1 is methyl.
  • R 8 and R 9 are each NH 2 .
  • R 8 and R 9 are each NH 2 and R 1 is methyl.
  • R 8 and R 9 are each NH 2 and R 1 is methyl, CH 2 F or ethynyl. In another aspect of this embodiment, R 8 is OH and R 9 is NH 2 . In another aspect of this embodiment, R 8 is OH, R 9 is NH 2 and R 1 is methyl. In another aspect of this embodiment, R 8 is OH, R 9 is NH 2 and R 1 is methyl, CH 2 F, or ethynyl. In another aspect of this embodiment R 6 is H. In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 .
  • R 4 is H or OR . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-C 8 )alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alkynyl. In another aspect of this embodiment, R 4 is OR a and R 1 is (Ci-Cg)alkyl. In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is (Q-C 8 )alkyl and at least one of X ! or X 2 is N.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (C,-C 8 )alkyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-C 8 )alkyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 802.CIPF2 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • each R 10 is, independently, H, halogen, CN or optionally substituted heteroaryl.
  • R 1 is methyl.
  • R 1 is methyl, CH 2 F or ethynyl.
  • R 9 is H, halogen, or NR 1 'R 12 .
  • R 9 is H, halogen, or NR n R 12 and R ! is methyl.
  • R 9 is H, halogen, or NR 1 ] R and R 1 is methyl, C3 ⁇ 4F, or ethynyl.
  • R 8 is NH 2 and R 9 is H or halogen. In another aspect of this embodiment, R 8 is NH 2 and R 9 is H or halogen and R 1 is methyl. In another aspect of this embodiment, R 8 is NH 2 and R 9 is H or halogen and R 1 is methyl,
  • R and R are each NH 2 .
  • R 8 and R 9 are each NH 2 and R 1 is methyl.
  • R 8 and R 9 are each NH 2 and R 1 is methyl, CH 2 F or g 9
  • R is OH and R is NH 2 .
  • R 8 is OH, R 9 is NH 2 and R 1 is methyl.
  • R 8 is OH, R 9 is NH 2 and R 1 is methyl, CH 2 F, or ethynyl.
  • R 6 is H.
  • R 6 is CN.
  • R 6 is OR a .
  • R 6 is OH.
  • R 6 is CH 3 .
  • R 4 is H or OR a .
  • R 4 is OR a .
  • R 4 is OR and R 1 is (Ci-Cg)alkyl, (C 2 -C 8 ) alkenyl or (C 2 -C 8 )alkynyl.
  • R 4 is OR d and R 1 is
  • R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N.
  • R 4 is OR d , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is (Cj-C 8 )alkyl and R 6 is CN, OH, or CH .
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H. In another aspect of this embodiment, R 4 is OH 802.CIPF2 and R 1 is methyl. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-C 8 )alkyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is (Ci-Cg)alkyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • R 1 is CH 3 , CH 2 F, or ethynyl and all remaining variables are defined as for Formula I.
  • R 4 is H, OR a , N(R a ) 2 , N 3 , CN, SR a , halogen, (Ci-C 8 )alkyl, (C2-Cg)alkenyl or (C 2 -C 8 )alkynyl.
  • R 4 is H or OR a .
  • R 4 is OR a .
  • R 4 is OR a and R 1 is CH 3 , CH 2 F, or ethynyl.
  • R 4 is OR' 1 and R 1 is methyl.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is H. In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this 802.CIPF2 embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • R 6 is H, CN, OR a or CH 3 .
  • R 6 is H.
  • R 6 is CN.
  • R 6 is OR a .
  • R 6 is OH.
  • R 6 is CH 3 .
  • R 4 is H or OR a .
  • R 4 is OR a .
  • R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OH, R 1 is methyl and R 6 is H.
  • R 6 is CN, OR a or CH 3 . In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 6 is H. In another aspect of this embodiment R is CN. In another aspect of this embodiment R' is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OR d , R 1 is methyl and R 6 is H. In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this embodiment, R 4 is
  • R is methyl and at least one of X or X is N.
  • R 4 is OH, R 1 is methyl and R 6 is CCNN, OH, or CH 3 .
  • R 4 is OH, R 1 is methyl and R 6 is H.
  • X 1 is N or C-R 10 . In another aspect of this embodiment, X 1 is N. In another aspect of this embodiment, X 1 is C-R 10 . In another aspect of this embodiment, X " is C-H. In another aspect of this embodiment, X is N
  • R 6 is H. In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR a . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is CH 3 . In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is methyl. In another aspect of this embodiment, R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR , R 1 is methyl and R 6 is CN, OH, or C3 ⁇ 4. In another aspect of this embodiment, R 4 is OH and R 1 is methyl. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N. In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 . In another aspect of this embodiment, R 4 is OH, R 1 is methyl and R 6 is H.
  • each R is independently halogen
  • R 1 is methyl, CH 2 F or ethynyl. In another aspect of this embodiment, R 1 is methyl.
  • R 9 is H, halogen, or NR n R 12 . In another aspect of this embodiment, R 9 is H, halogen, or NR 1 ! R 12 and R 1 is methyl, CH 2 F, or ethynyl. In another aspect of this embodiment, R is H, halogen, or NR n R 12 and R 1 is methyl.
  • R 8 is NH 2 and R 9 is H or halogen. In another aspect of this embodiment, R 8 is NH 2 and R 9 is H or halogen and
  • R is methyl, CH 2 F, or ethynyl.
  • R is NH 2 and R 9 is H or halogen and R 1 is methyl.
  • R 8 and R 9 are each NH 2 .
  • R 8 and R 9 are each NH 2 and R 1 is methyl, CH 2 F or ethynyl.
  • R 8 and R 9 are each
  • R is methyl.
  • R is OH and R is NH 2 .
  • R 8 is OH, R 9 is NH 2 and R 1 is methyl, CH 2 F, or ethynyl. In another aspect of this embodiment, R 8 is OH, R 9 is NH 2 and R 1 is methyl.
  • R 6 is H. In another aspect of this embodiment R 6 is CN. In another aspect of this embodiment R 6 is OR d . In another aspect of this embodiment R 6 is OH. In another aspect of this embodiment R 6 is C3 ⁇ 4. In another aspect of this embodiment, R 4 is H or OR a . In another aspect of this embodiment, R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is 802.CIPF2 methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OH, R 1 is methyl and R 6 is H.
  • each R 10 is, independently, H, halogen, CN or optionally substituted heteroaryl.
  • R 1 is methyl.
  • R 9 is H, halogen, or NR 1 'R 12 .
  • R 9 is H, halogen, or NR n R 12 and R 1 is methyl.
  • R 8 is 9
  • R is H or halogen.
  • R 8 is 9 halogen and R 1
  • R 8 and R 9 are each N3 ⁇ 4. In another aspect of this embodiment, R 8 and R 9 are each N3 ⁇ 4 and R 1 is methyl. In another aspect of this embodiment, R 8 is OH and R 9 is ct of this embodiment, R 8
  • R 9 is NH 2 and R 1 is methyl.
  • R 6 is H.
  • R 6 is CN.
  • R 6 is OR a .
  • R 6 is OH.
  • R 6 is CH 3 .
  • R 4 is H or OR a .
  • R 4 is OR a and R 1 is methyl.
  • R 4 is OR a , R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OR a , R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OR a , R 1 is methyl and R 6 is H.
  • R 4 is OH and R 1 is methyl.
  • R 4 is OH, R 1 is methyl and at least one of X 1 or X 2 is N.
  • R 4 is OH, R 1 is methyl and R 6 is CN, OH, or CH 3 .
  • R 4 is OH, R 1 is methyl and R 6 is H.
  • R 1 is (Ci-Cg)alkyl, (C 4 -C 8 )carbocyclylalkyl, (C]-C 8 )substituted alkyl, (C 2 -Cg)alkenyl, (C 2 -C 8 )substituted alkenyl, (C 2 -C 8 )alkynyl, (C 2 -C 8 )substituted alkynyl, or aryl(Ci-C 8 )alkyl;
  • R 2 is halogen
  • R 3 , R 4 , and R 5 are each independently H, halogen, OR a , N(R a ) 2 , N 3 , CN, N0 2 , S(0) n R a , (Ci-Cg)alkyl, (C 4 -C 8 )carbocyclylalkyl, (C,-C 8 )substituted alkyl,
  • R 3 , R 4 or R 5 on adjacent carbon atoms when taken together are - 0(CO)0- or when taken together with the ring carbon atoms to which they are attached form a double bond;
  • each n is independently 0, 1, or 2;
  • Y is ⁇ , S, NR, + N(0)(R), N(OR), N(0)(OR), or N-NR 2 ;
  • W and W when taken together, are -Y 3 (C(R y ) 2 ) 3 Y -; or
  • W 1 and W 2 are each, independently, a group of Formula IVa:
  • each Y 1 is, independently, O, S, NR, + N(0)(R), N(OR), + N(0)(OR), or N-NR 2 ;
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR), N-NR 2 , S, S-S, S(0), or S(0) 2 ;
  • each Y 3 is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is a group of Formula IVb: 802.CIPF2
  • each Mi a, Ml c, and Mid is independently 0 or 1 ;
  • M12c is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
  • C 3 -C 20 carbocyclyl, C 2 -C 2 o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R 20 groups;
  • each R is independently H, (C]-C 8 ) alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) alkynyl, C 6 -C 2 o aryl, C 3 -C 20 carbocyclyl, C 2 -C 2 o heterocyclyl, or arylalkyl;
  • each R 8 is halogen, NR n R 12 , N(R u )OR n , NR H NR U R !2 , N 3 , NO, N0 2 , OR 11 or S(0) n R u ;
  • each R is independently a carbocycle or heterocycle optionally substituted with 1-3 R 20 groups;
  • each (Ci-Cg)alkyl, (C2-C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci ⁇ C 8 )alkyl of each R 1 , R 3 , R 4 , R 5 , R 6 , R 1 ! or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R b ) 2 or OR b ; and wherein one or more of the nonterminal carbon atoms of each said (Ci-C 8 )alkyl may be optionally replaced with -0-, -S- or -NR b ;
  • Y and Y 1 is O.
  • R 8 is halogen, NR n R 12 , N(R n )OR n , NR' WR 12 , OR 1 1 or S(0) n R n .
  • R 9 is H, halogen, S(0) pharmaceuticalR' 1 or NR 1 'R' 2 .
  • R 4 is OR a .
  • R 1 is CH 3 .
  • R 2 is F.
  • R is 802.CIPF2
  • R 1 is methyl or ethynyl
  • R 4 is OR a
  • R 7 is H or
  • compound of Formula V are represented the following structures: 802.CIPF2
  • R 4 is OR a ;
  • each n is independently 0, 1 , or 2;
  • Y is O, S, NR, N(0)(R), N(OR), + N(0)(OR), or N-NR 2 ;
  • W 1 and W 2 when taken together, are -Y 3 (C(R y ) 2 ) 3 Y 3 -; or
  • W 1 or W 2 together with R 4 is -Y 3 - and the other of W ] or W 2 is Formula la;
  • W 1 and W 2 are each, independently, a group of Fonnula Via: 802.CIPF2
  • each Y 1 is, independently, O, S, NR, + N(0)(R), N(OR), + N(0)(OR), or N-NR 2 ;
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR),
  • each Y is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is a roup of Formula VIb:
  • each Mi a, Ml c, and Mi d is independently 0 or 1 ;
  • M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
  • C 3 -C 2 o carbocyclyl, C 2 -C 2 o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R 20 groups;
  • each R is independently H, (Ci-C 8 ) alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) alkynyl,
  • a is the point of attachment to R ;
  • Ar is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1 -3 R 20 groups;
  • each R y is independently (Ci-C 8 ) alkyl or C5-C6 carbocyclyl, wherein the alkyl and carbocyclyl are optionally substituted with 1 -3 R 20 groups;
  • each R is independently H, (Ci-C 6 ) alkyl, or aryl alkyl;
  • compounds of Fomiula IV- VI are represented by compounds having a structure:
  • R 1 1 or R 1 ⁇ " is independently H, (Ci-Q)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl,
  • R 1 1 and R 12 taken together with a nitrogen to which they are both attached, form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S- or -NR a -. Therefore, by way of example and not lim
  • R 6 , R" or R 12 is, independently, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci-C 8 )alkyl, wherein said (Ci-C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(Ci-C 8 )alkyl are, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 or OR a . Therefore, by way of example and not limitation, R 3 , R 4 , R 5 , R 6 , R 1 1 or R 12 could represent moieties such as -CH(NH 2 )CH 3 , - 802.CIPF2
  • R 3 , R 4 , R 5 , R 6 , R 1 1 or R i2 is (Ci-Cg)alkyl wherein one or more of the non-tenninal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -0-, -S- or -NR a -.
  • R 3 , R 4 , R 5 , R 6 , R 1 1 or R 12 could represent moieties such as -CH 2 OCH 3 , -CH 2 OC3 ⁇ 4CH 3 , -CH 2 OCH(CH 3 ) 2 , -CH 2 SCH 3 , - (CH 2 ) 6 OCH 3 , -(CH 2 ) 6 N(CH 3 ) 2 and the like.
  • Formulas I-III is a compound selected from the group consisting of
  • a compound useful for the synthesis of the compounds of Formula I selected from the group consisting of
  • a compound of the invention or "a compound of Formula I” means a compound of Formula 1 or a pharmaceutically acceptable salt, thereof.
  • a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, thereof.
  • Alkyl is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.
  • an alkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 alkyl), 1 to 8 carbon atoms (i.e., Ci-C 8 alkyl), or 1 to 6 carbon atoms (i.e., C] -C 6 alkyl).
  • alkyl groups include, but are not limited to, methyl (Me, - CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, 802.CIPF2 i-propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-methyl-methyl (Me, - CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2
  • Alkoxy means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom.
  • the alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms(/ ' .e., Q-C 12 alkoxy), or 1 to 6 carbon atoms(z ' .e., Ci-C 6 alkoxy).
  • alkoxy groups include, but are not limited to, methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2 CH 3 or -OEt), t-butoxy (-0-C(CH 3 ) 3 or -OtBu) and the like.
  • Haloalkyl is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom.
  • the alkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e., C 1 -C 20 haloalkyl), 1 to 12 carbon atoms(z ' .e., C 1 -C 12 haloalkyl), or 1 to 6 carbon atoms( .e., Ci-C 6 alkyl).
  • Suitable haloalkyl groups include, but are not limited to, -CF 3 , -CHF 2 , -CFH 2 , -CH 2 CF 3 , and the like.
  • Alkenyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp 2 double bond.
  • an alkenyl group can have 2 to 20 carbon atoms (i.e., C 2 -C 2 o alkenyl), 2 to 8 carbon atoms (i.e., C 2 -Cg alkenyl), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkenyl).
  • Alkynyl is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond.
  • an alkynyl group can have 2 to 20 carbon atoms ⁇ i.e., C 2 -C 2 o alkynyl), 2 to 8 carbon atoms (i.e., C 2 -Cs alkyne,), or 2 to 6 carbon atoms (i.e., C 2 -C 6 alkynyl).
  • suitable alkynyl groups include, but are not limited to, acetylenic (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • Alkylene refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane.
  • an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkylene radicals include, but are not limited to, methylene (-CH 2 -), 1 ,1 -ethyl (-CH(CH 3 )-), 1 ,2-ethyl (-CH 2 CH 2 -), 1,1 -propyl (-CH(CH 2 CH 3 )-), 1,2-propyl (-CH 2 CH(CH 3 )-), 1,3-propyl (-CH 2 CH 2 CH 2 -), 1,4-butyl (-CH 2 CH 2 CH 2 CH 2 -), and the like.
  • alkenylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene.
  • alkenylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Alkynylene refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.
  • an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • Typical alkynylene radicals include, but are not limited to, acetylene (-C ⁇ C-), propargyl (-CH 2 C ⁇ C-), and 4-pentynyl (-CH 2 CH 2 CH 2 C ⁇ C-).
  • Ammonia refers generally to a nitrogen radical which can be considered a derivative of ammonia, having the formula -N(X) 2 , where each "X” is independently H, 802.CIPF2 substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc.
  • the hybridization of the nitrogen is approximately sp .
  • Nonlimiting types of amino include -NH 2 , -N(alkyl) 2 , -NH(alkyl), -N(carbocyclyl)2, - NH(carbocyclyl), -N(heterocyclyl) 2 , -NH(heterocyclyl), -N(aryl) 2 , -NH(aryl), - N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), - N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc.
  • alkylamino refers to an amino group substituted with at least one alkyl group.
  • Nonlimiting examples of amino groups include -N3 ⁇ 4, -NH(CH 3 ), -N(CH 3 ) 2 , -NH(CH 2 CH 3 ), - N(CH 2 CH 3 ) 2 , - NH(phenyl), -N(phenyl) 2 , -NH(benzyl), -N(benzyl) 2 , etc.
  • Substituted alkylamino refers generally to alkylamino groups, as defined above, in which at least one substituted alkyl, as defined herein, is attached to the amino nitrogen atom.
  • Non-limiting examples of substituted alkylamino includes -NH(alkylene-C(0)-OH), -NH(alkylene-C(0)-0-alkyl), -N(alkylene-C(0)-OH) 2 , -N(alkylene-C(0)-0-alkyl) 2 , etc.
  • Aryl means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms.
  • Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.
  • Arylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl radical.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l -yl, naphthylmethyl, 2-naphthylethan-l -yl, naphthobenzyl,
  • the arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also an sp 2 carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the 802.CIPF2 alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein.
  • the arylalkenyl group can comprise 8 to 20 carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • Arylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with an aryl radical.
  • the aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein.
  • the arylalkynyl group can comprise 8 to 20 carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.
  • substituted in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc. , for example, "substituted alkyl"
  • substituted alkylene means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.
  • Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.
  • prodrug refers to any compound that when
  • a prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.
  • substituents and other moieties of the compounds of Formula I-III and Formula IV- VI should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition.
  • the definitions and substituents for various genus and subgenus of the present compounds are described and illustrated herein. It should be understood by one skilled in the art that any combination of the definitions and substituents described above should not result in an inoperable species or compound.
  • "Inoperable species or compounds” means compound structures that violates relevant scientific principles (such as, for example, a carbon atom connecting to more than four covalent bonds) or compounds too unstable to permit isolation and formulation into pharmaceutically acceptable dosage forms.
  • Heteroalkyl refers to an alkyl group where one or more carbon atoms have been replaced with a heteroatom, such as, O, N, or S.
  • a heteroatom e.g., O, N, or S
  • the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3 , etc.), an amine (e.g., -NHCH 3 , -N(CH 3 ) 2 , etc.), or a thioalkyl group (e.g., -SCH 3 ).
  • the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH 2 CH 2 -O-CH3, etc.), an alkyl amine (e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.), or a thioalkyl ether (e.g.,-CH 2 -S-CH 3 ).
  • an alkyl ether e.g., -CH 2 CH 2 -O-CH3, etc.
  • an alkyl amine e.g., -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , etc.
  • a thioalkyl ether e.g.,-CH 2 -S-CH 3
  • the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,
  • a heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.
  • -C 6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.
  • heterocycle includes a "carbocycle” as defined herein, wherein one or more (e.g. 1 , 2, 3, or 4) carbon atoms have been replaced with a heteroatom ⁇ e.g. O, N, or S).
  • heteroatom e.g. O, N, or S
  • heterocyclyl includes saturated rings, partially unsaturated rings, and aromatic rings ⁇ i.e., heteroaromatic rings).
  • Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups.
  • a non-limiting example of a carbonyl substituted heterocyclyl is:
  • heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,
  • tetrahydrothiophenyl sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzoiuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4- piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
  • octahydroisoquinolinyl azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-1,5,2- dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH- carbazolyl, carbazolyl, ⁇ -car
  • carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyn-ole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1 , 3, 4, 5, 6, 7, or 8 of an isoquinoline.
  • carbon bonded heterocycles include 2- pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5- pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6- pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4- thiazolyl, or 5-thiazolyl.
  • nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3- pyrroline, imidazole, imidazolidine, 2 -imidazoline, 3 -imidazoline, pyrazole, pyrazolone, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H- indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • nitrogen bonded heterocycles include 1 -aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1 -pyrazolyl, and 1 -piperidinyl.
  • Heterocyclylalkyl refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety).
  • Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH 2 -, 2- 802.CIPF2 (heterocyclyl)ethan-l-yl, and the like, wherein the "heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern Heterocyclic Chemistry.
  • heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylm ethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.
  • heterocycles such as thiazolylmethyl, 2-thiazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc.
  • 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl,
  • Heterocyclylalkenyl refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also a sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl- alkenylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • Heterocyclylalkynyl refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl - 802.CIPF2 alkynylene- moiety).
  • the heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modem Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein.
  • heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.
  • the heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.
  • Heteroaryl refers to an aromatic heterocyclyl having at least one heteroatom in the ring.
  • suitable heteroatoms which can be included in the aromatic ring include oxygen, sulfur, and nitrogen.
  • suitable heteroaryl rings include all of those aromatic rings listed in the definition of
  • heterocyclyl including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.
  • Carbocycle or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle.
  • Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms.
  • Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings.
  • Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l - enyl, 1 -cyclopent-2-enyl, l -cyclopent-3-enyl, cyclohexyl, 1 -cyclohex-l -enyl, 1 - cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl.
  • Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.
  • Carbocyclylalkyl refers to an acyclic alkyl radical in which one of the 802.CIPF2 hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein.
  • Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylm ethyl, cyclopentylmethyl and cyclohexylmethyl.
  • Arylheteroalkyl refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein.
  • the aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety.
  • an arylheteroalkyl group can have the general formulae -alkylene- O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc.
  • any of the alkylene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.
  • Heteroarylalkyl refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein.
  • Non- limiting examples of heteroaryl alkyl include -CH 2 -pyridinyl, -CH 2 -pyrrolyl,
  • optionally substituted in reference to a particular moiety of the compound of Formula I-III and Formula IV-VI (e.g., an optionally substituted aryl 802.CIPF2 group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of "substituted” or as otherwise indicated.
  • non-terminal carbon atom(s) in reference to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to the carbon atoms in the moiety that intervene between the first carbon atom of the moiety and the last carbon atom in the moiety. Therefore, by way of example and not limitation, in the alkyl moiety -CH 2 (C * )H 2 (C * )H 2 CH 3 or alkylene moiety -CH 2 (C * )FI 2 (C * )H 2 CH 2 - the C * atoms would be considered to be the non-terminal carbon atoms.
  • Certain Y and Y 1 alternatives are nitrogen oxides such as + N(0)(R) or + N(0)(OR). These nitrogen oxides, as shown here attached to a carbon atom, can also
  • Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms.
  • Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • sulfur-linked or "phosphorous-linked” mean that if a bond between two moieties can be formed by using more than one type of atom in a moiety, then the bond fonned between the moieties is through the atom specified.
  • a nitrogen-linked 802.CIPF2 amino acid would be bonded through a nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.
  • the carbon atoms of the compounds of Formula I- III and Formula IV- VI are intended to have a valence of four.
  • the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen.
  • Protecting group refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole.
  • the chemical substructure of a protecting group varies widely.
  • One function of a protecting group is to serve as an intermediate in the synthesis of the parental drug substance.
  • Chemical protecting groups and strategies for protection/deprotection are well known in the art. See: “Protective Groups in Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the effi ciency 802.CIPF2 of desired chemical reactions, e.g. making and breaking chemical bonds in an ordered and planned fashion.
  • Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools.
  • Chemically protected intermediates may themselves be biologically active or inactive.
  • Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs.
  • Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug.
  • Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.
  • Prodrug moiety means a labile functional group which separates from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, pp. 1 13- 191).
  • Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases.
  • Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.
  • a prodrug moiety may include an active metabolite or drug itself.
  • Exemplary prodrug moieties include the hydrolytically sensitive or labile
  • R 30 is Ci-C 6 alkyl, Ci-C 6 substituted alkyl, C 6 -C 20 aryl or C 6 -C 2 o substituted aryl.
  • the acyloxyalkyl ester was used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756.
  • a prodrug moiety is part of a phosphate group.
  • the acyloxyalkyl ester may be used to deliver phosphoric acids across cell membranes and to enhance oral bioavailability.
  • a close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention.
  • the phosphate group may be a phosphate prodrug moiety.
  • the prodrug moiety may be sensitive to hydrolysis, such as, but not limited to those comprising a pivaloyloxymethyl carbonate (POC) or POM group.
  • the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.
  • Aryl esters of phosphorus groups are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-41 1 5). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-ox para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phenol or an alkylated phenol may generate the phenolic compound through the action of enzymes, e.g.
  • a compound of Formula I-III and Formula IV- VI and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs.
  • crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism).
  • crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures.
  • the pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism).
  • the instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I-III and Formula IV- VI and their pharmaceutically acceptable salts.
  • 802.CIPF2 A compound of Formula I-III and Formula IV-VI and its pharmaceutically acceptable salts may also exist as an amorphous solid.
  • an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This definition applies as well when the crystal size is two nanometers or less.
  • Additives, including solvents may be used to create the amorphous forms of the instant invention.
  • the instant invention comprises all amorphous forms of the compounds of Formula I-III and Formula IV-VI and their pharmaceutically acceptable salts.
  • R comprises a R y substituent.
  • R y can be R.
  • R can be W 3 .
  • W 3 can be W 4 and W 4 can be R or comprise substituents comprising R y .
  • One of ordinary skill in the art of medicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.
  • W 3 and R y are recursive substituents in certain embodiments.
  • each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 1 1, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 , or 0, times in a given embodiment.
  • each recursive substituent can independently occur 12 or fewer times in a given embodiment.
  • each recursive substituent can independently occur 3 or fewer times in a given embodiment.
  • W 3 will occur 0 to 8 times
  • R y will occur 0 to 6 times in a given
  • W 3 will occur 0 to 6 times and R y will occur 0 to 4 times in a given embodiment. 802.CIPF2
  • Recursive substituents are an intended aspect of the invention.
  • One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents.
  • the compounds of the Formula I-III and Formula IV- VI may comprise a
  • each Y or Y 1 is, independently, O, S, NR, + N(0)(R), N(OR), + N(0)(OR), or N-NR 2 ;
  • W 1 and W 2 when taken together, are -Y 3 (C(R y ) 2 ) 3 Y 3 -; or one of W 1 or W 2 together with either R 3 or R 4 is -Y 3 - and the other of W 1 or W ⁇ is Formula la; or W 1 and W2 are each, independently, a group of Formula la:
  • each Y 2 is independently a bond, O, CR 2 , NR, + N(0)(R), N(OR), + N(0)(OR), N-NR 2 , S, S-S, S(O), or S(0) 2 ;
  • each Y is independently O, S, or NR;
  • M2 is 0, 1 or 2;
  • each R x is independently R y , a protecting group, or the formula:
  • Mia, Ml c, and Mid are independently 0 or 1 ;
  • M12c is 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 or 12;
  • each R is H, halogen, (Ci-Q) alkyl, (Cj-Cg) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, C 6 -C 2 o aryl, C 6 -C 2 o substituted aryl, C 2 -C 2 o heterocycle, C 2 -C 20 substituted heterocyclyl, aryl alkyl, substituted aryl alkyl or a protecting group;
  • W 3 is W 4 or W 5 ;
  • W 4 is R, -C(Y')R y , -C(Y')W 5 , -S0 2 R y , or -S0 2 W 5 ; and
  • W 5 is a carbocycle or a heterocycle wherein W 5 is independently substituted with 0 to 3 R y groups.
  • W 5 carbocycles and W 5 heterocycles may be independently substituted with 0 to 3 R y groups.
  • W 5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle.
  • W 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms.
  • the W 5 rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or di- unsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.
  • a W 5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, 802.C1PF2 P, and S).
  • W 5 heterocyclic monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S).
  • W 5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system.
  • the W 5 heterocycle may be bonded to Y 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.
  • W 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyiTolyl.
  • W 5 also includes, but is not limited to, examples such as:
  • W 5 carbocycles and heterocycles may be independently substituted with 0 to 3 R groups, as defined above.
  • substituted W 5 carbocycles include: 802.CIPF2
  • substituted phenyl carbocycles examples include: 802.CIPF2
  • a is the point of attachment to R ;
  • Ar is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1 -3 R 20 groups;
  • each R y is independently (Ci-C 8 ) alkyl or C 5 -C 6 carbocyclyl, wherein the
  • alkyl and carbocyclyl are optionally substituted with 1 -3 R groups;
  • each R is independently H, (C]-C 6 ) alkyl, or arylalkyl;
  • Embodiments of of Formula I-III and Formula IV-VI compounds include substructures such as: 802.CIPF2
  • each Y is, independently, O or N(R).
  • each Y 2b is O and each R x is independently:
  • Ml 2c is 1 , 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S.
  • one Y 2b -R x is NH(R) and the other Y 2b -R x is O R x wherein R x is:
  • each Y D is O and each R x is independentl :
  • each Y D is O and each R x is independently: 802.CIPF2
  • Ml 2c is 1 and Y is a bond, O, or CR 2 .
  • each Y is, independently, O or N(R).
  • each Y 3 is O.
  • the substracture is:
  • R y is W 5 as defined herein.
  • Another embodiment of of Formula I-III and Formula IV- VI includes the substractures: 802.CIPF2
  • each Y is, independently, O, N(R y ) or S.
  • R or R is -Y " - and the other of W or W is Formula la.
  • Such an embodiment is represented by a compound of Formula lb selected from:
  • each Y and Y 3 is O.
  • W 1 or W 2 is Y 2b -R x ; each Y, Y 3 and Y 2b is O and R x is:
  • Ml 2c is 1, 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S
  • W 1 or W 2 is Y 2b -R x ; each Y, Y 3 and Y 2b is O and R x is: 802.CIPF2
  • W 1 or W 2 is Y 2b -R x : each Y Y 3 and Y 2b is O and R x is:
  • Ml 2c is 1 and Y is a bond, O, or CR 2 .
  • Another embodiment of of Formula I-III and Formula IV- VI compounds includes a substructure
  • W is a carbocycle such as phenyl or substituted phenyl.
  • the substructure is: 802.CIPF2
  • R x is:
  • M12c is 1 , 2 or 3 and each Y 2 is independently a bond, O, CR 2 , or S
  • Another embodiment of of Formula I-III and Formula IV-VI includes substru
  • the chiral carbon of the amino acid and lactate moieties may be either the R or S configuration or the racemic mixture.
  • R y is (Ci-Cg) alkyl, (Cj-Cg) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl.
  • R y is (C]-C 8 ) alkyl, (C]-C 8 ) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl; and R is CH 3 .
  • R y is (Ci-Cg) alkyl, (Cj-Cg) substituted alkyl, (C 2 -C 8 ) alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl or (C 2 -C 8 ) substituted alkynyl; R is CH 3 ; and each Y 2 is -NH-.
  • R is CH 3 ; and each Y 2 is -NH-.
  • W 1 and ⁇ T are, independently, nitrogen-linked, naturally occurring amino acids or naturally occurring amino acid esters.
  • W' and W are, independently, naturally-occurring 2-hydroxy carboxylic acids or naturally- occurring 2 -hydroxy carboxylic acid esters wherein the acid or ester is linked to P through the 2-hydroxy group.
  • each R x is, independently, (Cj-C 8 ) alkyl. In another aspect of this embodiment, each R x is, independently, C 6 -C 20 aryl or C 6 -C 20 substituted aryl.
  • W 1 and W 2 are independently selected from one of the formulas in Tables 20.1 -20.37 and Table 30.1 below.
  • the variables used in Tables 20.1-20.37 e-g-, W 23 , R 21 , etc. pertain only to Tables 20.1-20.37, unless otherwise indicated.
  • each R 21 is independently H or (C 1 -C 8 )alkyl
  • each R is independently H, R , R or R wherein each R is independently substituted with 0 to 3 R 23 ;
  • each R 23 is independently R 23a , R 23b , R 23c or R 23d , provided that when R 23 is bound to a heteroatom, then R 23 is R 23c or R 23d ;
  • each R 23a is independently F, CI, Br, I, -CN, N 3 or -N0 2 ;
  • each R 23b is independently Y 21 ;
  • each R 2x is independently H, (C r C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, aryl, heteroaryl; or two R 2x taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S- or -NR -; and wherein 802.CIPF2 one or more of the non-terminal carbon atoms of each said (Ci-C 8 )alkyl may be optionally replaced with -0-, -S- or -NR 21 -;
  • each R 24 is independently (Ci-Cg)alkyl, (C 2 -C 8 )alkenyl, or (C2-C 8 )alkynyl;
  • each R is independently R wherein each R " is substituted with 0 to 3 R " groups;
  • each R 25a is independently (Ci-C 8 )alkylene, (C 2 -Q)alkenylene, or (C 2 -
  • C 8 )alkynylene is substituted with 0-3 R ⁇ "3 groups
  • each W 23 is independently W 24 or W 25 ;
  • each W" is independently carbocycle or heterocycle wherein is independently substituted with 0 to 3 R ⁇ groups;
  • each Y is independently O or S.
  • Embodiments of R include esters, carbamates, carbonates, thioesters, amides, thioamides and urea groups:
  • any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt thereof.
  • physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na + , Li + , K + > Ca + 2 and Mg + 2), ammonium and NiL ⁇ + (wherein R is defined herein).
  • Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid,
  • naphthalenedisulfonic acid polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromine, and iodine.
  • Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na + and NR 4 + .
  • salts of active ingredients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a 802.CIPF2 physiologically acceptable acid or base.
  • salts of acids or bases which are not physiologically acceptable may also find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.
  • compositions herein comprise compounds of the invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.
  • the compounds of the invention may have chiral centers, e.g. chiral carbon or phosphorus atoms.
  • the compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.
  • the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms.
  • the chiral centers apparent from the depictions are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized,
  • racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the separation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances.
  • optically active adjuncts e.g., acids or bases followed by conversion back to the optically active substances.
  • the desired optical isomer is synthesized by means of stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have 802.CIPF2 different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non- superimposable mirror images of one another.
  • racemic mixture A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized resonance structure may be depicted, all such 802.CIPF2 forms are contemplated within the scope of the invention.
  • ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible tautomeric forms are within the scope of the invention.
  • pyrrolo[l ,2-fJ[l ,2,4]triazine, imidazo[l ,5-fj[l ,2,4]triazine, imidazo[l,2-fJ[l,2,4]triazine, and [l ,2,4]triazolo[4,3- fj[l ,2,4]triazine nucleosides can exist in tautomeric fomis.
  • structures (a) and (b) can have equivalent tautomeric fomis as shown below:
  • Another aspect of the invention relates to methods of inhibiting the activity of HCV polymerase comprising the step of treating a sample suspected of containing 802.CIPF2 HCV with a composition of the invention.
  • compositions of the invention may act as inhibitors of HCV polymerase , as intermediates for such inhibitors or have other utilities as described below.
  • the inhibitors will bind to locations on the surface or in a cavity of HCV polymerase having a geometry unique to HCV polymerase .
  • Compositions binding HCV polymerase may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are ideal candidates for use in this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the detection of HCV polymerase .
  • the invention relates to methods of detecting HCV polymerase in a sample suspected of containing HCV polymerase comprising the steps of: treating a sample suspected of containing HCV polymerase with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the activity of the label.
  • Suitable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.
  • the compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.
  • samples suspected of containing HCV polymerase include natural or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like);
  • sample will be suspected of containing an organism which produces HCV polymerase , frequently a pathogenic organism such as HCV.
  • Samples can be contained in any medium including water and organic solvenfVwater mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.
  • the treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the 802.CIPF2 sample.
  • the addition step comprises any method of administration as described above.
  • the activity of HCV polymerase after application of the composition can be observed by any method including direct and indirect methods of detecting HCV polymerase activity. Quantitative, qualitative, and semiquantitative methods of determining HCV polymerase activity are all contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.
  • Organisms that contain HCV polymerase include the HCV virus.
  • the compounds of this invention are useful in the treatment or prophylaxis of HCV infections in animals or in man.
  • compositions of the invention are screened for inhibitory activity against HCV polymerase by any of the conventional techniques for evaluating enzyme activity.
  • typically compositions are first screened for inhibition of HCV polymerase in vitro and compositions showing inhibitory activity are then screened for activity in vivo.
  • the compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are 802.CIPF2 prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkylcellulose,
  • hydroxyalkylmethylcellulose hydroxyalkylmethylcellulose, stearic acid and the like.
  • the pH of the formulations ranges from about 3 to about 1 1, but is ordinarily about 7 to 10.
  • the formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefore and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.
  • the formulations include those suitable for the foregoing administration routes.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be administered as a bolus, electuary or paste.
  • a tablet is made by compression or molding, optionally with one or more 802.CIPF2 accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and optionally are fonnulated so as to provide slow or controlled release of the active ingredient therefrom.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1 % w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w.
  • the active ingredients may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.
  • the oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax
  • 802.CIPF2 the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties.
  • the cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.
  • compositions according to the present invention comprise a combination according to the invention together with one or more phannaceutically acceptable carriers or excipients and optionally other therapeutic agents.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic phannaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating 802.CIPF2 agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.
  • Tablets may be uncoated or may be coated by known techniques including
  • microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium phosphate or kaolin
  • an oil medium such as peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate,
  • polyvinylpyrrolidone gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a naturally-occurring phosphatide e.g., lecithin
  • a condensation product of an alkylene oxide with a fatty acid e.g., polyoxyethylene stearate
  • a condensation product of ethylene oxide with a long chain aliphatic alcohol e.g., hept
  • the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
  • Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium tartrate
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium bicarbonate, sodium bicarbonate, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these.
  • Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate.
  • the emulsion may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • sweetening agents such as glycerol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent.
  • compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1 ,3-butane-diol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may be employed.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightrweight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion may contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • a suitable carrier especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%,
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid earner.
  • Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1 , 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or 802.CIPF2 dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HCV infections as described below.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be
  • Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use.
  • sterile liquid carrier for example water for injection
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • the invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefore.
  • Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient.
  • compositions may be administered orally, parenterally or by any 802.CIPF2 other desired route.
  • controlled release formulations in which the release of the active ingredient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingredient.
  • Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used
  • prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day.
  • the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.
  • One or more compounds of the invention are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.
  • An advantage of the compounds of this invention is that they are orally bioavailable and can be dosed orally.
  • Combinations of the compounds of Formula I-III and Formula IV-VI are typically selected based on the condition to be treated, cross-reactivities of ingredients 802.CIPF2 and pharmaco-properties of the combination.
  • an infection e.g., HCV
  • the compositions of the invention are combined with other active therapeutic agents (such as those described herein).
  • compositions of the invention are also used in combination with one or more other active ingredients.
  • the other active therapeutic ingredients or agents are interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate
  • decarboxylase antagonists antagonists of the renin-angiotensin system, other anti- fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors,
  • pharmacokinetic enhancers or other drugs for treating HCV or mixtures thereof.
  • one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of
  • interferons e.g., pegylated rIFN-alpha 2b (PEG-lntron), pegylated rlFN- alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021 , glycosylated interferon alpha-2b (AVI-005), PEG-l
  • ribavirin and its analogs e.g., ribavirin (Rebetol, Copegus), and taribavirin (Viramidine),
  • HCV NS3 protease inhibitors e.g., boceprevir (SCH-503034 , SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-
  • alpha-glucosidase 1 inhibitors e.g., celgosivir (MX-3253), Miglitol, and
  • hepatoprotectants e.g., emericasan (IDN-6556), ME-3738, GS-9450 (LB- 84451), silibilin, and MitoQ,
  • nucleoside or nucleotide inhibitors of HCV NS5B polymerase e.g., R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851 , BCX-4678, valopicitabine (NM-283), and MK-0608,
  • non-nucleoside inhibitors of HCV NS5B polymerase e.g., filibuvir (PF- 868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281 , VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941 , XTL-2125, and GS-9190,
  • filibuvir PF- 868554
  • ABT-333 ABT-072
  • BI-207127 VCH-759, VCH-916, JTK-652, MK-3281 , VBY-708, VCH-222, A848837
  • ANA-598 GL60667, GL59728, A-63890
  • HCV NS5A inhibitors e.g., AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,
  • TLR-7 agonists e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,
  • cyclophillin inhibitors e.g., DEBIO-025, SCY-635, and NIM81 1,
  • HCV IRES inhibitors e.g., MCI-067,
  • pharmacokinetic enhancers e.g., B AS- 100, SPI-452, PF-4194477, TMC- 41629, GS-9350, GS-9585, and roxythromycin,
  • mevalonate decarboxylase antagonists e.g., statins, HMGCoA synthase inhibitors (e.g., hymeglusin), squalene synthesis inhibitors (e.g., zaragozic acid);
  • angiotensin II receptor antagonists e.g., losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan; 802.CIPF2 16) angiotensin-converting enzyme inhibitors, e.g., captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;
  • endothelin antagonists e.g. bosentan and ambrisentan.
  • compositions comprising a compound of the present invention, or a phamiaceutically acceptable salt, solvate, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient.
  • the therapeutic agent used in combination with the compound or composition of the present invention can be any agent having a therapeutic effect when used in combination with the compound of the present invention.
  • the therapeutic agent used in combination with the compound or composition of the present invention can be interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers or other drugs for treating HCV; or mixtures thereof.
  • compositions of one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of
  • interferons e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylated rlFN- alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021 , 802.CIPF2 glycosylated interferon alpha-2b (AVI-005)
  • ribavirin and its analogs e.g., ribavirin (Rebetol, Copegus), and taribavirin (Viramidine),
  • HCV NS3 protease inhibitors e.g., boceprevir (SCH-503034 , SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI-
  • alpha-glucosidase 1 inhibitors e.g., celgosivir (MX-3253), Miglitol, and UT-231B,
  • hepatoprotectants e.g., emericasan (1DN-6556), ME-3738, GS-9450 (LB- 84451 ), silibilin, and MitoQ,
  • nucleoside or nucleotide inhibitors of HCV NS5B polymerase e.g., R1626, R7128 (R4048), IDX184, IDX-102, PSI-7851 , BCX-4678, valopicitabine (NM-283), and MK-0608,
  • non-nucleoside inhibitors of HCV NS5B polymerase e.g., filibuvir (PF- 868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281 , VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,
  • filibuvir PF- 868554
  • ABT-333 ABT-072
  • BI-207127 VCH-759, VCH-916, JTK-652, MK-3281 , VBY-708, VCH-222, A848837
  • ANA-598 GL60667, GL59728, A-63890
  • HCV NS5A inhibitors e.g., AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,
  • TLR-7 agonists e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691 , and SM-360320,
  • cyclophillin inhibitors e.g., DEB1O-025, SCY-635, and NIM811,
  • HCV IRES inhibitors e.g., MCI-067,
  • pharmacokinetic enhancers e.g., B AS- 100, SPI-452, PF-4194477, TMC- 41629, GS-9350, GS-9585, and roxythromycin, 802.CIPF2 13
  • other drugs for treating HCV e.g., thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIV -401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), GS-9525, RN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-1 1 1, ITX2865, TT-033i, ANA 971 , NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituximab, MDX-1 106
  • mevalonate decarboxylase antagonists e.g., statins, HMGCoA synthase inhibitors (e.g., hymeglusin), squalene synthesis inhibitors (e.g., zaragozic acid);
  • angiotensin II receptor antagonists e.g., losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;
  • angiotensin-converting enzyme inhibitors e.g., captopril, zofenopril, enalapril, ramipril, quinapril, perindopril, lisiiiopril, benazepril, fosinopril;
  • endothelin antagonists e.g. bosentan and ambrisentan.
  • the present application provides a combination pharmaceutical agent comprising:
  • a) a first pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, solvate, or ester thereof; and b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibiting compounds, HI V non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, S3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors,
  • hepatoprotectants non-nucleoside inhibitors of HCV, and other drugs for treating HCV, and combinations thereof.
  • Combinations of the compounds of Formula I-III and Formula IV-VI and additional active therapeutic agents may be selected to treat patients infected with HCV and other conditions such as HIV infections.
  • the compounds of 802.CIPF2 Formula I-III and Formula IV-VI may be combined with one or more compounds useful in treating HIV, for example HIV protease inhibiting compounds, HIV non- nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, alpha- glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.
  • HIV protease inhibiting compounds
  • one or more compounds of the present invention may be combined with one or more compounds selected from the group consisting of 1) HIV protease inhibitors, e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-1 14, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and
  • HIV protease inhibitors e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir,
  • GW640385X DG17, PPL- 100, 2) a HIV non-nucleoside inhibitor of reverse transcriptase, e.g., capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+) calanolide A, etravirine, GW5634, DPC-083, DPC-961 , DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK- 453,061, RDEA806, 3) a HIV nucleoside inhibitor of reverse transcriptase, e.g., zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir ( ⁇
  • emtricitabine phosphazide, fozivudine tidoxil, fosalvudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine, 4) a HIV nucleotide inhibitor of reverse transcriptase, e.g., tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz, and adefovir, 5) a HIV integrase inhibitor, e.g., curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffe
  • combination may be administered in two or more administrations.
  • Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both present in the body of the patient.
  • Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents.
  • a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents.
  • a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes.
  • a unit dose of a compound of the invention may be desirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.
  • the combination therapy may provide "synergy” and "synergistic", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately.
  • a synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in 802.CIPF2 parallel as separate formulations; or (3) by some other regimen.
  • a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e. serially
  • effective dosages of two or more active ingredients are administered together.
  • a synergistic anti-viral effect denotes an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.
  • the present application provides for methods of inhibiting HCV polymerase in a cell, comprising: contacting a cell infected with
  • HCV with an effective amount of a compound of Formula I-III and Formula IV- VI, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, whereby HCV polymerase is inhibited.
  • the present application provides for methods of inhibiting HCV polymerase in a cell, comprising: contacting a cell infected with
  • HCV with an effective amount of a compound of Formula I-III and Fonnula IV- VI, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby HCV polymerase is inhibited.
  • the present application provides for methods of inhibiting HCV polymerase in a cell, comprising: contacting a cell infected with
  • HCV with an effective amount of a compound of Fonnula I-III and Formula IV- VI, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 802.CIPF2 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixture
  • the present application provides for methods of treating HCV in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-III and Formula IV- VI, or a
  • the present application provides for methods of treating HCV in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-III and Formula IV- VI, or a
  • the present application provides for methods of treating HCV in a patient, comprising: administering to the patient a therapeutically effective amount of a compound of Formula I-III and Formula IV- VI, or a
  • a pharmaceutically acceptable salt, solvate, and/or ester thereof and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.
  • additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analog
  • the present application provides for the use of a compound of the present invention, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, for the preparation of a medicament for treating an HCV infection in a patient.
  • the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.
  • Such products typically are identified by preparing a radiolabeled (e.g. or 3 ⁇ 4) compound of the invention, administering it parenterally in a detectable dose (e.g.
  • metabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art.
  • the conversion products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HCV polymerase inhibitory activity of their own.
  • compositions and methods for determining stability of compounds in surrogate gastrointestinal secretions are known.
  • Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo.
  • the prodrugs of the invention typically will be stable in the digestive system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.
  • Trimethyl phosphate (0.5-1.0 mL) is added. The solution is cooled with ice-water bath. POCl 3 (40-45 mg) is added and stirred at 0°C until the reaction is complete (1 to 4 h; the reaction progress is monitored by ion-exchange HPLC; analytical samples are prepared by taking ⁇ 3 iL of the reaction mixture and diluting it with 1.0 M
  • the crude reaction mixture is subjected to C-18 HPLC first and then ion exchange HPLC purification to afford the desired product as a triethylammonium salt.
  • Compound TP-2 was prepared by the general method using Compound 3 as starting material.
  • Non-limiting examples of mono-phosphoramidate prodrugs comprising the instant invention may be prepared according to general Scheme 1.
  • the general procedure comprises the reaction of an amino acid ester salt 19b, e.g., HCl salt, with an aryl dichlorophosphate 19a in the presence of about two to ten equivalents of a suitable base to give the phosphoramidate 19c.
  • suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DABCO, and substituted amidines such as DBN and DBU. Tertiary amines are particularly preferred.
  • the product of each step is used directly in the subsequent steps without recrystallization or chromatography.
  • a nucleoside base 19d reacts with the phosphoramidate 19c in the presence of a suitable base.
  • suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DABCO, and substituted amidines such as DBN and DBU.
  • the product B may be isolated by recrystallization and/or chromatography.
  • Phenyl ethoxyalaninyl phosphorochloridate (124 mg, 0.42 mmol; prepared according to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) was added to a mixture of Compound 3 (20 mg, 0.065 mmol) and N-methylimidazole (42 ⁇ , 0.52 mmol) in anhydrous trimethyl phosphate (0.8 mL). The reaction mixture is stirred for 3 h at room temperature, and then methanol was added to quench the reaction. The methanol solvent is removed under reduced pressure.
  • Compound C-2a was obtained in a procedure similar to that exemplified for Compound C-la but using the methionine ester.
  • Compound C-4 was obtained in a procedure similar to that exemplified for Compound C-1 using Compound 3 and C-4 a.
  • Compound C-6 was obtained in a procedure similar to that exemplified for Compound C-1 using Compound 3 and the sulphone analog of C-la.
  • Solvents Acetonitrile with 0.1% formic acid, Water with 0.1 % formic acid

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Abstract

L'invention concerne des nucléosides à imidazo[1,2-f][1,2,4]triazinyle choisis, des nucléoside-phosphates et des promédicaments de ceux-ci, la position 2' du sucre du nucléoside étant substituée par des substituants halogénés et carbonés. Les composés, les compositions et les procédés de l'invention sont utiles pour le traitement d'infections à virus de la famille de Flaviviridae, en particulier d'infections de type hépatite C provoquées par des souches aussi bien de type de sauvage que mutantes du VHC. Formula (I)
EP11715792.5A 2010-09-20 2011-03-22 Analogues carbanucléosidiques 2'-fluoro-substitués pour traitement antiviral Withdrawn EP2619206A1 (fr)

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US12/885,917 US7973013B2 (en) 2009-09-21 2010-09-20 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment
US13/050,820 US8455451B2 (en) 2009-09-21 2011-03-17 2'-fluoro substituted carba-nucleoside analogs for antiviral treatment
PCT/US2011/029441 WO2012039791A1 (fr) 2010-09-20 2011-03-22 Analogues carbanucléosidiques 2'-fluoro-substitués pour traitement antiviral

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CA2807496A1 (fr) 2012-03-29
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CO6680669A2 (es) 2013-05-31
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JP2016074732A (ja) 2016-05-12
BR112013008017A2 (pt) 2016-06-14
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NZ608070A (en) 2015-11-27
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MA34593B1 (fr) 2013-10-02

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