WO2006135383A2 - Indazoles - Google Patents

Indazoles Download PDF

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Publication number
WO2006135383A2
WO2006135383A2 PCT/US2005/027730 US2005027730W WO2006135383A2 WO 2006135383 A2 WO2006135383 A2 WO 2006135383A2 US 2005027730 W US2005027730 W US 2005027730W WO 2006135383 A2 WO2006135383 A2 WO 2006135383A2
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WIPO (PCT)
Prior art keywords
heteroaryl
heterocyclic
thiocarbamyl
carbamyl
amido
Prior art date
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PCT/US2005/027730
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English (en)
Inventor
Ashok Bajji
Scott Morham
Mark B. Anderson
Robert J. Mchugh
Richard Trovato
Warren S. Weiner
Se-Ho Kim
Original Assignee
Myriad Genetics, Inc.
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Publication of WO2006135383A2 publication Critical patent/WO2006135383A2/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates generally compounds and pharmaceutical compositions with therapeutic activity.
  • Viral infection of humans is a major health problem, and viral infection of domesticated animals is a major economic concern.
  • Combating viral infection has proven to be highly effective in some cases like smallpox where the disease was essentially eradicated with the advent of smallpox vaccination.
  • smallpox was essentially eradicated by about 1980, there is considerable justified fear of the emergence of a new epidemic of smallpox since there are existing stockpiles of the virus and bioterrorism has moved beyond the realm of possibility to reality.
  • Other viral infections have been much more difficult to fight.
  • Hepatitis B and C, human immunodeficiency virus (HIV), herpes simplex viruses and influenza are just a few prominent members of a list of viruses that pose significant health threats worldwide.
  • the present invention generally relates to novel compounds of Formula I and methods for treating viral infections with these compounds.
  • the present invention also relates to treating and/or delaying the onset of symptoms caused by viral infections with pharmaceutical compositions having a compound of Formula I.
  • the invention provides novel compounds and compositions useful for treating viral infection as well as a number of diseases including cancer.
  • the inventors have discovered novel compounds of Formula I, including Formulas I(a) through 1(1) below which have antiviral activity (see Detailed Description of the Invention for structures).
  • the invention provides compounds of Formula I (including Formulas I(a) through 1(1)) and pharmaceutical compositions having the compounds of Formula I (including Formulas I(a) through 1(1)) along with a pharmaceutically acceptable carrier.
  • a method for treating viral infection is provided by administering to a patient in need of such treatment a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of Formula I.
  • the method and composition are used to treat viral infection.
  • the method and composition are used to treat one or more symptoms of a viral infection.
  • methods for inhibiting viral egress are also provided by administering to a patient in need of such treatment a pharmaceutical composition or medicament having an amount of a compound of Formula I sufficient to inhibit the egress of a virus from human or animal cells.
  • the method of inhibiting viral egress involves treating humans or other animals infected with a virus.
  • the present invention relates to methods for inhibiting viral budding from host cells by administering to the cells a pharmaceutical composition or medicament having an amount of a compound of Formula I sufficient to inhibit the budding of a virus from the host cells.
  • the method of inhibiting viral budding involves treating humans or other animals infected with a virus.
  • methods for inhibiting viral entry are also provided by administering to a patient in need of such treatment a pharmaceutical composition or medicament having an amount of a compound of Formula I sufficient to inhibit the entry of a virus into human or animal cells.
  • the method of inhibiting viral entry involves treating humans or other animals infected with a virus.
  • the present invention relates to methods for treating viral infection, which comprise the steps of (1) identifying an individual diagnosed with a viral infection; and (2) administering to the individual a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of Formula I.
  • the method of treating viral infection involves treating humans or other animals infected with a virus.
  • the present invention further provides methods for delaying the onset of viral infection symptoms comprising administering a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I to an individual having a viral infection, or at risk of infection by a virus, or at risk of developing symptoms of viral infection.
  • the method of inhibiting or delaying the onset of viral infection symptoms involves treating humans or other animals infected with a virus.
  • a method for treating a person who is a carrier of any of the HIV family of retroviruses, i.e., infected with HIV, but has not developed AIDS (which is defined by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function).
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I.
  • the method can be used in treating acute primary HIV infection syndrome (which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache) or asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4 T-cells).
  • a method is provided for treating a person who is either actively infected with Hepatitis B virus (HBV), Hepatitis C virus (HCV), or who is a carrier of these viruses that has either not developed symptoms of the viral infection (which is defined by liver damage) or has experienced diminution of such symptoms, or who has recently been exposed to such viruses.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a therapeutically effective, or prophylactically effective, amount of a compound of Formula I.
  • a method for treating a person who is either actively infected with herpes simplex virus type-1, type-2, or type-4 (also known as Epstein-Barr virus), or who is a carrier of these viruses who has either not developed symptoms of the viral infection or has experienced diminution of such symptoms, or who has recently been exposed to such viruses.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a therapeutically effective, or prophylactically effective, amount of a compound of Formula I.
  • a method for treating an individual who is either actively infected with influenza virus type- A, type-B, or type-C, or who is a carrier of these viruses who has either not developed symptoms of the viral infection, or has experienced diminution of such symptoms, or who has recently been exposed to such viruses.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a therapeutically effective, or prophylactically effective, amount of a compound of Formula I.
  • a method for treating a person who is either actively infected with any of the poxvirus family of viruses, i.e., the smallpox virus, or who is a carrier of these viruses who has either not developed symptoms of the viral infection (which is defined by more serious smallpox-defining illnesses) or has experienced diminution of such symptoms, or who has recently been exposed to such viruses.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a therapeutically effective, or a prophylactically effective, amount of a compound of Formula I.
  • a method for treating a person who is either actively infected with any of the coronavirus family of viruses, i.e., infected with a SARS-associated coronavirus, or who is a carrier of such viruses who has either not developed symptoms of the viral infection (which is defined by more serious SARS- defining illnesses) or who has experienced diminution of such symptoms, or who has recently been exposed to such viruses.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I.
  • a method for treating a person or an animal that is either actively infected with West Nile virus, or is a carrier of the West Nile virus and has either not developed symptoms of the viral infection, or has experienced diminution of such symptoms, or has recently been exposed to West Nile virus.
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I.
  • a method for treating a person or an animal that has cancer, is suspected of having cancer, and/or desires prophylaxis against cancer (e.g., cancer was treated surgically and patient needs or desires treatement to prevent recurrence).
  • the method includes identifying such an individual in need of treatment and administering to the individual a pharmaceutical composition or medicament having a therapeutically and/or prophylactically effective amount of a compound of Formula I.
  • the compounds of the invention can be used to treat a variety of additional disease or conditions such as hypertension, cancer (including metastasis), immune system related diseases, autoimmune diseases, bacterial infections (e.g., those of the digestive track), retinopathies, neurological disorders, and any disease mediated by rho-kinase activity (I or II) or a rho-kinase mediated pathway.
  • additional disease or conditions such as hypertension, cancer (including metastasis), immune system related diseases, autoimmune diseases, bacterial infections (e.g., those of the digestive track), retinopathies, neurological disorders, and any disease mediated by rho-kinase activity (I or II) or a rho-kinase mediated pathway.
  • the compounds of Formula I for use in the instant invention can be provided as a pharmaceutical composition with one or more salts, carriers, or excipients. Some of the compounds for use in the invention have chiral centers, and the invention therefore includes the use of all stereoisomers, enantiomers, diastereomers, and mixtures thereof.
  • the present invention also provides pharmaceutical compositions or medicaments for the combination therapy of viral infections.
  • the compositions comprise a therapeutically effective amount of a first compound according to Formula I and a therapeutically effective amount of a second antiviral compound, which is different from the first compound.
  • antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, immunomodulators, and vaccines.
  • the present invention provides novel compounds of Formula I and pharmaceutical compositions for the treatment and prevention of certain diseases.
  • the pharmaceutical compositions are used for treating (or delaying the onset) of viral infection and particularly symptoms caused by the viral infection.
  • such compounds are inhibitors of host cell proteins required by viruses during their infective cycle.
  • the compounds of the invention include those of Formula I:
  • the invention provides compounds of Formula I where Ql and Q2 are both -N-, Q3 is -CH-, there is a double bond between Q2 and Q3, and a hydrogen atom is attached to the -N- of Ql .
  • the invention provides compounds of Formula I where Q2 and Q3 are both -N-, Ql is -CH-, there is a double bond between Ql and Q2, and a hydrogen atom is attached to the -N- of Q3.
  • Ql and Q3 can be -O- and Q2 is -CH 2 -.
  • Preferred compounds of Formula I according to the invention includes those of Formulas I(a)-I(l):
  • each of Z1-Z6, if present, is an atom independently chosen from -C-, -N-, -O-, or -S-, there may or may not be a double bond between any of Z1-Z6 (depending on the ring formed by Z1-Z6, the skilled artisan recognizes that the valences of certain Z atoms are completed through a covalent bond to a hydrogen atom); and pharmaceutically acceptable salts thereof.
  • the ring system containing Z can be saturated, partially saturated, or unsaturated.
  • Z2 is -N- and the Zl, Z3-Z6 are -C- if present.
  • Ri, R 3 -R 6 if present are all hydro so that together with Zi, Z 3 -Z 6 , they each represent -CH 2 - groups and R 2 is chosen from aryl, heteroaryl, and heterocyclic.
  • the aryl, heteroaryl, or heterocyclic group of R 2 is substituted with 1-5 substituents independently chosen from acyloxy, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heterocyclic, hydro, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, O-carbamyl, N-carbamyl, O-thiocarbamyl, N- thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thio
  • each of Ri, R3, and R 4 are hydro.
  • the 1-5 substituents on the phenyl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , R 4 , and R5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 3 , R 4 , and Rs are hydro.
  • the 1-5 substituents on the phenyl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R3, R 4 , R5, and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl
  • each of Ri, R 3 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the phenyl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thio
  • each of Ri, R3, and R 4 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R3, R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thio
  • each of Ri, R 3 , R 4 , and R 5 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , R 4 , R 5 , and Re are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thioc
  • each of Ri, R 3 , R 4 , Rs, and R 6 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thioc
  • each of Ri, R 3 , and R 4 are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-
  • compounds of Formula I having the following structure wherein each of R], R 3 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl
  • the heterocyclic group OfR 2 is chosen from tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl.
  • each of Ri, R3, R 4 , and R5 are hydro.
  • the 1-5 substituents on the heterocyclic group ofR 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • R] R 3 , R 4 , R 5 , and R ⁇ are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio
  • each of Ri, R 3 , R 4 , R 5 , and Re are hydro.
  • the 1-5 substituents on the heterocyclic group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarba
  • each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thioc
  • each of Ri, R 3 , and R 4 are hydro.
  • the 1-5 substituents on the phenyl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 3 , R 4 , and R 5 are hydro.
  • the 1-5 substituents on the phenyl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • R), R 3 , R 4 , R5, and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamate,
  • each of Ri, R 3 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the phenyl group ofR 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thioc
  • each of R 1 , R 3 , and R 4 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 3 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • the heteroaryl of R 2 is chosen from pyridyl (pyridinyl), 2-pyridyl, 3- pyridyl, 4-pyridyl, and pyrimidinyl.
  • each of Ri, R 3 , R 4 , and R5, are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R3, R 4 , R5, and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of R 1 , R3, R 4 , R5, and R 6 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalom ethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • the 1-5 substituents on the heteroaryl group of R 2 are independently chosen from fluoro, chloro, bromo, -NH 2 , -NO 2 , -CF3, cyano, - C(O)H, -COOH, -C(O)-O-CH 3 , -S-CH 3 , -CH 2 -OH, -CH 2 -CH 2 -OH, -O-CH3, - S(O) 2 -CH 3 , -S(O) 2 -NH 2 , -C(O)-CH 3 , -C(O)NH 2 , -S(0) 2 -NH-cyclopropyl, - S(O) 2 -piperazinyl-CH 3 , -C(O)-O-CH 2 -CH 3 , -
  • compounds of Formula I having the following structure: wherein each of Ri, R 3 , and R 4 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-
  • each of Ri, R 3 , and R 4 are hydro.
  • the 1-5 substituents on the heterocyclic group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thio
  • Ri, R 3 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulf ⁇ nyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarba
  • each of Ri, R3, R 4 , and R 5 are hydro.
  • the 1-5 substituents on the heterocyclic group of R 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulf ⁇ nyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N
  • each of Ri, R 3 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio,
  • each of Ri, R 3 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 2 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thioc
  • each of Ri, R 2 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 2 , R 4 , and Rs are hydro.
  • the 1-5 substituents on the phenyl group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , and R5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 2 , R 4 , and R 5 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalom ethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 2 , R 4 , and R 5 are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl,
  • each of Ri, R 2 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl,
  • each of Ri, R 2 , R 4 , and R5 are hydro.
  • the 1-5 substituents on the phenyl group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , and R5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulf ⁇ nyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carba
  • each of Ri, R 2 , R 4 , and R5, are hydro.
  • the 1-5 substituents on the heteroaryl group of R 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • R ]s R 2 , R 4 , and R 5 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarba
  • each of Ri, R 2 , R 4 , and R 5 are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl,
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarba
  • each of Ri, R 2 , R 4 , R5, and R 6 are hydro.
  • the 1-5 substituents on the phenyl group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Rj, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, .carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio
  • each of Ri, R 2 , R 4 , R 5 , and R ⁇ are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamide, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl, O-thiocarbamy
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio,
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the phenyl group ofR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocyanoto, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O- thio
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the heteroaryl group of R 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, and N-amido.
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N- carbamyl
  • each of Ri, R 2 , R 4 , R 5 , and R 6 are hydro.
  • the 1-5 substituents on the heterocyclic group OfR 3 are independently chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, cyano, cyanato, cycloalkyl, halo, haloalkyl, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanato, thiocarbonyl, trihalomethane, sulfonamide, O-carbamyl, N-carbamy
  • one of R 2 and R 3 is aryl and the other is hydro, where the aryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-c
  • one of R 2 and R 3 is phenyl and the other is hydro, where the aryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-
  • one of R 2 and R3 is heteroaryl and the other is hydro, where the heteroaryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-c
  • one of R 2 and R 3 is heterocyclic and the other is hydro, where the heterocyclic group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-c
  • one of R 2 and R 3 is aryl and the other is hydro, where the aryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-c
  • one OfR 2 and R 3 is phenyl and the other is hydro, where the aryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-
  • one of R 2 and R 3 is heteroaryl and the other is hydro, where the heteroaryl group is substituted with 1-5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-c
  • one of R 2 and R 3 is heterocyclic and the other is hydro, where the heterocyclic group is substituted with 1 -5 substituents chosen from acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, alkylthio, amino, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, aryloxy, arylthio, carbocyclic, cyano, cyanato, cycloalkyl, halo, haloalkyl, heteroaryl, heteroaryloxy, heteroarylalkoxy, heterocyclic, hydro, hydroxyl, isocyanato, isothiocyanato, nitro, sulfinyl, sulfonyl, sulfonamido, thiocarbonyl, thiocyanoto, trihalomethane, sulfonamide, O-
  • composition having one or more compounds of Formula I (including those of Formulas I(a)-I(l)) and a pharmaceutically acceptable carrier.
  • acylamino (or “acylamido”) groups are any Ci-6 acyl (alkanoyl) as defined herein, attached to an amino nitrogen, e.g., acetamido, chloroacetamido, propionamido, butanoylamido, pentanoylamido and hexanoylamido, as well as aryl-substituted Ci -6 acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido,
  • acyloxy groups are any Ci -6 acyl (alkanoyl) as definided herein, attached to an oxy (-O-) group, e.g., formyloxy, acetoxy, propionoyloxy, butanoyloxy, pentanoyloxy and hexanoyloxy.
  • alkenyl refers to, by itself or as part of another group, a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including at least one double bond between two of the carbon atoms in the chain.
  • alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl.
  • alkoxy refers to both an -O-alkyl and an -O- cycloalkyl group, as defined herein.
  • Lower alkoxy refers to -0-lower alkyl groups.
  • Non-limiting alkoxy groups include oxygen substituted by one of the CM O alkyl groups mentioned above, which may be optionally substituted.
  • Alkoxy substituents include, without limitation, halo, morpholino, amino including alkylamino and dialkylamino, and carboxy including esters thereof.
  • alkyl refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups.
  • the alkyl group has 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20" refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to and including 20 carbon atoms). More preferably, it is a medium size alkyl having 1 to 10 carbon atoms. Even more preferably, it is a lower alkyl having 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is preferably one or more individually selected from cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, C-carboxy, O-carboxy, cyanato, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, and amino.
  • CM O alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, /er/-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
  • alkylthio refers to both an S-alkyl and an -S- cycloalkyl group, as defined herein.
  • Non-limiting alkylthio groups include sulfur substituted by one of the CM O alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
  • alkynyl refers to a straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, wherein there is at least one triple bond between two of the carbon atoms in the chain.
  • Typical alkynyl groups include ethynyl, 1-propynyl, l-methyl-2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl.
  • amino refers to an -NRn Ri 8 group, with Rj 7 and Ri 8 being hydro to give an -NH 2 group.
  • Rn and Ri 8 may also be hydro, Ci-io alkyl or cycloalkyl groups, or R n and R [7 are combined with the N to form a ring structure, such as a piperidine, or R] 7 and Ri 8 are combined with the N to form a ring, such as a piperazine.
  • One of Rn and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • aryl refers to, by itself or as part, of another group a monocyclic, bicyclic or tricyclic aromatic groups containing from 6 to 14 carbons in the ring portion.
  • Non-limiting aryl groups include C 6-I4 aryl, preferably C 6 - I0 aryl.
  • Typical C 6-M aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • arylalkyl refers to any of the C MO alkyl groups substituted by any of the above-mentioned C 6-H aryl groups as defined herein.
  • the arylalkyl group is benzyl, phenethyl or naphthylmethyl.
  • arylalkenyl is used herein to mean any of the above-mentioned C 2-I0 alkenyl groups substituted by any of the above-mentioned C 6-I4 aryl groups.
  • arylalkynyl refers to any of C 2-I o alkynyl groups substituted by any of the above-mentioned C 6-M aryl groups as defined herein.
  • arylalkoxy refers to any of the CM O alkoxy groups substituted by any of the aryl groups as defined herein, which may be optionally substituted.
  • arylalkoxy groups include benzyloxy and phenethyloxy.
  • aryloxy refers to oxygen substituted by any of the C 6- I 4 aryl groups defined herein, which may be optionally substituted. Examples of aryloxy groups include phenoxy and 4-methylphenoxy.
  • arylthio refers to both an -S-aryl and an -S- heteroaryl group, as defined herein.
  • carbocycle or “carbocyclic” refers to cycloalkyl and partially saturated carbocyclic groups.
  • Non-limiting carbocyclic groups are C 3-8 cycloalkyl and cycloalkenyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl.
  • cyano refers to a -C ⁇ N group.
  • cyanato refers to a -CNO group.
  • halo or halogen group refers to a fluoro, chloro, bromo and iodo group.
  • haloalkyl refers to C 1-1O alkyl groups substituted by one or more fluoro, chloro, bromo or iodo groups, e.g., fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • the halo groups can be independently selected.
  • hydro refers to an -H group.
  • hydroxyl refers to an -OH group.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 ⁇ electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatoms.
  • Non-limiting heteroaryl groups include thienyl (thiophenyl), benzo[Z>]thienyl, naphtho[2,3-£]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, including without limitation 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), including without limitation 2-pyridyl, 3-pyridyl, and 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridiny
  • heteroaryl group contains a nitrogen atom in a ring
  • nitrogen atom may be in the form of an N- oxide, e.g., a pyridyl N-oxide, pyrazinyl N-oxide and pyrimidinyl N-oxide.
  • heteroaryloxy refers to oxygen substituted by a heteroaryl group as defined herein, which may be optionally substituted.
  • ⁇ on- limiting heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy, pyrazolyloxy, imidazolyloxy and thiophenyloxy.
  • heterocycle refers to a saturated or partially saturated 3-7 membered monocyclic, or 7-10 membered bicyclic ring system, which consists of carbon atoms and from one to four heteroatoms independently selected from the group consisting of O, N, and S, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized, the nitrogen can be optionally quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring, and wherein the heterocyclic ring can be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • Non-limiting saturated or partially saturated heterocyclic groups include tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl and tetramoyl groups.
  • heteroarylalkoxy refes to a C 1-10 alkoxy groups substituted by a heteroaryl group as defined herein, which may be optionally substituted.
  • isocyanato refers to a -NCO group.
  • isothiocyanato refers to a -NCS group.
  • nitro refers to a -NO 2 group.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • Rn and Ri 8 may be hydro, C MO alkyl or cycloalkyl groups, or R i7 and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or Rn and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • Rn and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • R can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
  • thiocyanato refers to a -CNS group.
  • R 17 and Ri 8 may be hydro, C MO alkyl or cycloalkyl groups, or R n and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or R ]7 and Rj 8 are combined with the N and to form a ring, such as a piperazine.
  • Rn and R] 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • RJ 8 may be hydro; Ri 7 and Ri 8 may be Ci -I0 alkyl or cycloalkyl groups, or Rn and Rj 8 are combined with the N to form a ring structure, such as a piperidine, or Rj 7 and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • One of Rj 7 and Rj 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ri 7 and Ri 8 may be hydro, CMO alkyl or cycloalkyl groups, or R] 7 and R ]8 are combined with the N to form a ring structure, such as a piperidine, or Rj 7 and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • R ]7 and R] 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ri 7 may be hydro;
  • R 17 and R ]8 may be Ci -I0 alkyl or cycloalkyl groups.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • R n and R 18 may be hydro, Ci -10 alkyl or cycloalkyl groups, or R n and Ri 8 are combined with the N to form a ring structure, such as a piperidine, or R 17 and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • One of R ]7 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Optional substituents on the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, carbocyclic and heterocyclic groups include one or more halo, hydroxy, carboxyl, amino, nitro, cyano, Ci-C 6 acylamino, C 1 -C 6 acyloxy, Ci-C 6 alkoxy, aryloxy, alkylthio, C 6 -Ci 0 aryl, C 4 -C 7 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Ci 0 aryl(C 2 -C 6 )alkenyl, C 6 -Ci 0 aryl(C 2 -C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl.
  • Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, Ci-C 6 haloalkyl, C 6 -C 10 aryl, C 4 -C 7 cycloalkyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C) 0 aryl(C,-C 6 )alkyl, C 6 -C 10 aryl(C 2 -C 6 )alkenyl, C 6 -Ci 0 aryl(C 2 -C 6 )alkynyl, C 1 -C 6 hydroxyalkyl, nitro, amino, ureido, cyano, Ci-C 6 acylamino, hydroxy, thiol, CpC 6 acyloxy, azido, Ci-C 6 al
  • a pharmaceutically acceptable salt of the compound of the present invention is exemplified by a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, and a salt with an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid and the like.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like
  • an organic acid such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, benzoic acid, citric acid, malic acid, methanesulfonic acid, benzenesulfonic acid and the like.
  • pharmaceutically acceptable salts include acid salt of inorganic bases, such as salts containing alkaline cations (e.g., Li + , Na + or K + ), alkaline earth cations (e.g., Mg "1"1" , Ca +4 ⁇ or Ba + *), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations, such as those arising from protonation of peralkylation of thriethyl amine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N,N- dimethylaminopyridine (DMAP), l,4-diazabiclo[2.2.2]octane (DABCO), 1,5- diazavicyclo[4.3.0]non-5-ene (DBN) and l,8-diazabicyclo[5.4.0]undec-7-en
  • the compounds of Formula I can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms.
  • optical isomers or enantiomers, racemates, and diastereomers are also encompassed in the compounds of Formula I.
  • the methods of present invention include the use of all such isomers and mixtures thereof. Methods of separation of enantiomeric and diastereomeric mixtures are well known to one skilled in the art.
  • the present invention encompasses any isolated racemic or optically active form of compounds described in Formula I, or any mixture thereof, which possesses anti-viral activity.
  • the compounds of Formula I are particularly effective in inhibiting viral infection and/or viral entry into, or viral egress from host cells. While not wishing to be bound by any theory or hypothesis, it is believed that the compounds specifically target and inhibit certain host cell proteins that are utilized by viruses to carry out specific tasks during the viruses' life cycle. Inhibition of these host cell proteins results in either the inhibition of the entry, the inhibition of egress (i.e., release of viruses from host cells), or the inhibition of budding (i.e., viral particles pinching off host cell intracellular or plasma membranes) of viruses into and out of host cells, or some combination thereof. Since the compounds target host cell proteins, rather than viral proteins, the compounds are believed to be significantly less susceptible to the loss of efficacy caused by the development of viral resistance, which typically develops after an extended period of treatment with traditional antiviral drugs that specifically target viral proteins.
  • the present invention provides methods for treating viral infection by administering to a patient (either a human or other animal) that is a carrier of a virus a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of Formula I.
  • a carrier of a virus can be identified by conventional diagnostic techniques known in the art, as described above.
  • the identified carrier can be administered with a compound of Formula I, preferably in a pharmaceutical composition having a pharmaceutically acceptable carrier.
  • the present invention provides methods for treating an active viral infection by administering to a patient (either a human or other animal) that exhibits characteristic symptoms of a viral infection a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of Formula I.
  • a patient either a human or other animal
  • the presence of viral infection may be detected or determined directly by any appropriate method in the art.
  • the infected individual so identified can be administered with a compound of Formula I, preferably in a pharmaceutical composition having a pharmaceutically acceptable carrier.
  • the methods of the present invention may be generally useful in treating or preventing diseases or disorders associated with viral infection in animals, particularly humans.
  • viral infection can be caused by viruses including, but not limited to, lentiviruses such as human immunodeficiency virus types 1 and 2 (HIV), human T-cell lymphotropic virus type 1 and 2 (HTLV-I and HTLV-II), SIV, EIAV (equine infectious anemia virus), BIV, FIV, CAEV, VMV, and MMLV (Moloney murine leukemia virus).
  • viruses including, but not limited to, lentiviruses such as human immunodeficiency virus types 1 and 2 (HIV), human T-cell lymphotropic virus type 1 and 2 (HTLV-I and HTLV-II), SIV, EIAV (equine infectious anemia virus), BIV, FIV, CAEV, VMV, and MMLV (Moloney murine leukemia virus).
  • Such viral infections can also be caused by hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, hepatitis E virus, hepatitis G virus, human foamy virus, or by human herpes viruses (e.g., herpes simplex virus type-1, herpes simplex virus type-2, herpes simplex virus type-3 (also known as Varicella-zoster virus), herpes simplex virus type-4 (also known as Epstein Barr virus or EBV), herpes simplex virus type-5, herpes simplex virus type-7).
  • herpes simplex virus type-1 herpes simplex virus type-2, herpes simplex virus type-3 (also known as Varicella-zoster virus), herpes simplex virus type-4 (also known as Epstein Barr virus or EBV), herpes simplex virus type-5, herpes simplex virus type-7).
  • herpes simplex virus type-1 e.g., herpes simplex virus type-1,
  • Such viral infections can also be caused by influenza viruses (types A, B or C), human parainfluenza viruses, respiratory syncytial virus, smallpox virus (variola virus), monkeypox virus, vaccinia virus, human papilloma virus, human parechovirus 2, mumps virus, Measles virus, Rubella virus, Semliki Forest virus, West Nile virus, Colorado tick fever virus, foot-and-mouth disease virus, Ebola virus, Marburg virus, polyomavirus, TT virus, Lassa virus, lymphocytic choriomeningitis virus, vesicular stomatitis virus, rotavirus, varicella virus, parvovirus, cytomegalovirus, encephalitis viruses, adenovirus, echovirus, rhinoviruses, filoviruses, coxachievirus, coronavirus (such as SARS-associated coronavirus), Dengue viruses, yellow fever virus, hantaviruses, regional hemorrhagi
  • the methods can be used in treating or preventing infection by viruses that utilize cellular machineries of membrane/vescicle trafficking or cellular multivesicular body (MVB) sorting pathway.
  • the methods are used in treating or preventing infections by enveloped viruses.
  • particular viruses known to infect humans and cause disease are treated by the methods of the present invention.
  • HIV infection generally encompasses infection of a host animal, particularly a human host, by the human immunodeficiency virus (HIV) family of retroviruses including, but not limited to, HIV I (also known as HTLV-III), HIV II (also known as LAV-I), HIV IH (also known as LAV-2), and the like.
  • HIV can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV family.
  • treating HIV infection will encompass the treatment of a person who is a carrier of any of the HIV family of retroviruses or a person who is diagnosed of active AIDS, as well as the treatment or prophylaxis of the AIDS-related conditions in such persons.
  • a carrier of HIV may be identified by any methods known in the art.
  • a person can be identified as HIV carrier on the basis that the person is anti-HIV antibody positive, or is HIV-positive, or has symptoms of AIDS. That is, "treating HIV infection” should be understood as treating a patient who is at any one of the several stages of HIV infection progression, which, for example, include acute primary infection syndrome (which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache), asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4 T-cells), and AIDS (which is defined by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 T-cell count to below a level that is compatible with effective immune function).
  • acute primary infection syndrome which can be asymptomatic or associated with an influenza-like illness with fevers, malaise, diarrhea and neurologic symptoms such as headache
  • asymptomatic infection which is the long latent period with a
  • the term "delaying the onset of HIV infection” means treating an individual who (1) is at risk of infection by HIV, or (2) is suspected of infection by HIV or of exposure to HIV, or (3) has suspected past exposure to HIV, to delay the onset of acute primary infection syndrome by at least three months.
  • clinical findings typically associated with acute primary infection syndrome may include an influenza-like illness with fevers, malaise, nausea/vomiting/diarrhea, pharyngitis, lymphadenopathy, myalgias, and neurologic symptoms such as headache, encephalitis, etc.
  • the individuals at risk may be people who perform any of following acts: contact with HIV-contaminated blood, blood transfusion, exchange of body fluids, "unsafe" sex with an infected person, accidental needle stick, injection of drug with contaminated needles or syringes, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
  • the term "delaying the onset of HIV infection” may also encompass treating a person who has not been diagnosed as having HIV infection but is believed to be at risk of infection by HIV, or has been exposed to HIV through contaminated blood, etc.
  • the term "delay the onset of AIDS” means delaying the onset of AIDS (which is characterized by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function, i.e. below about 200/ ⁇ l) and/or AIDS-related conditions, by treating an individual (1) at risk of infection by HIV, or suspected of being infected with HIV, or (2) having HIV infection but not AIDS, to delay the onset of AIDS by at least six months.
  • Individuals at risk of HIV infection may be those who are suspected of past exposure, or considered to be at risk of present or future exposure, to HIV by, e.g., contact with HIV-contaminated blood, blood transfusion, transplantation, exchange of body fluids, "unsafe" sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
  • treating AIDS means treating a patient who exhibits more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function (typically below about 200/ ⁇ l).
  • the term “treating AIDS” also encompasses treating AIDS-related conditions, which means disorders and diseases incidental to or associated with AIDS or HIV infection such as AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), anti-HIV antibody positive conditions, and HIV-positive conditions, AIDS-related neurological conditions (such as dementia or tropical paraparesis), Kaposi's sarcoma, thrombocytopenia purpurea and associated opportunistic infections such as Pneumocystis carinii pneumonia, Mycobacterial tuberculosis, esophageal candidiasis, toxoplasmosis of the brain, CMV retinitis, HIV- related encephalopathy, HIV-related wasting syndrome, etc.
  • AIDS-related conditions
  • HBV infection generally encompasses infection of a human by any strain or serotype of hepatitis B virus, including acute hepatitis B infection and chronic hepatitis B infection.
  • treating HBV infection means the treatment of a person who is a carrier of any strain or serotype of hepatitis B virus, or a person who is diagnosed with active hepatitis B, to reduce the HBV viral load in that person or to alleviate one or more symptoms associated with HBV infection and/or hepatitis B, including, e.g., nausea and vomiting, loss of appetite, fatigue, muscle and joint aches, elevated transaminase blood levels, increased prothrombin time, jaundice (yellow discoloration of the eyes and body) and dark urine.
  • a carrier of HBV may be identified by any method known in the art.
  • a person can be identified as HBV carrier on the basis that the person is anti-HBV antibody positive ⁇ e.g., based on hepatitis B core antibody or hepatitis B surface antibody), or is HBV-positive (e.g., based on hepatitis B surface antigens (HBeAg or HbsAg) or HBV RNA or DNA) or has symptoms of hepatitis B infection or hepatitis B.
  • anti-HBV antibody positive e.g., based on hepatitis B core antibody or hepatitis B surface antibody
  • HBV-positive e.g., based on hepatitis B surface antigens (HBeAg or HbsAg) or HBV RNA or DNA
  • HBV-positive e.g., based on hepatitis B surface antigens (HBeAg or HbsAg) or HBV RNA or
  • treating HBV infection will also encompass treating individuals with a suspected HBV infection after suspected exposure to HBV by, e.g., contact with HBV-contaminated blood, blood transfusion, exchange of body fluids, "unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
  • treating HBV infection will also encompass treating a person who is free of HBV infection but is believed to be at risk of infection by HBV.
  • a method of treating HBV infection in a patient co- infected with HBV and HIV is provided by administering a therapeutically effective amount of a compound according to Formula I to such a patient.
  • HIV infection is associated with an approximate threefold increase in the development of persistent hepatitis B.
  • the compounds according to Formula I are particularly suitable for patients co-infected with HIV and HBV.
  • the compounds are especially effective in inhibiting HBV infection and/or egress.
  • the compounds are also effective in inhibiting HIV entry into and/or egress (particularly budding) from host cells.
  • the presently marketed drug interferon alpha is not effective in treating HBV and HIV co-infection.
  • Lamivudine and some other reverse transcriptase inhibitors are useful in treating such co-infections, but Lamivudine is particularly toxic and can cause hepatic injury which worsens hepatitis B. In addition, such reverse transcriptase inhibitors often must be used in cocktails. In contrast, the compounds according to the present invention are significantly less toxic, and are less likely to result in evolved viral resistance.
  • a compound according to Formula I is administered alone, or in combination with another anti-HIV or anti-HBV drug, in a therapeutically effective amount to a mammal, particularly a human co-infected with both HBV and HIV.
  • the method may include a step of identifying a patient co-infected with HBV and HIV by techniques commonly known in the art. For example, PCR tests can be used to detect HBV DNA or RNA and HIV RNA in blood samples obtained from a test subject. Alternatively, virus-specific antibodies or antigens may be also employed for the detection of HBV and HIV infection.
  • preventing hepatitis B as used herein means preventing in a patient who has an HBV infection, is suspected to have an HBV infection, or is at risk of contracting an HBV infection, from developing hepatitis B (which are characterized by more serious hepatitis-defining symptoms), cirrhosis, or hepatocellular carcinoma.
  • HCV infection generally encompasses infection of a human by any types or subtypes of hepatitis C virus, including acute hepatitis C infection and chronic hepatitis C infection.
  • treating HCV infection means the treatment of a person who is a carrier of any types or subtypes of hepatitis C virus, or a person who is diagnosed with active hepatitis C, to reduce the HCV viral load in that person or to alleviate one or more symptoms associated with HCV infection and/or hepatitis C.
  • a carrier of HCV may be identified by any methods known in the art.
  • a person can be identified as HCV carrier on the basis that the person is anti-HCV antibody positive, or is HCV-positive (e.g., based on HCV RNA or DNA) or has symptoms of hepatitis C infection or hepatitis C (e.g., elevated serum transaminases).
  • HCV infection should be understood as treating a patient who is at any one of the several stages of HCV infection progression.
  • treating HCV infection will also encompass treating individuals with a suspected HCV infection after suspected past exposure to HCV by, e.g., contact with HCV-contaminated blood, blood transfusion, exchange of body fluids, "unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
  • treating HCV infection will also encompass treating a person who is free of HCV infection but is believed to be at risk of infection by HCV.
  • preventing HCV means preventing in a patient who has HCV infection or is suspected to have HCV infection or is at risk of HCV infection from developing hepatitis C (which is characterized by more serious hepatitis-defining symptoms), cirrhosis, or hepatocellular carcinoma.
  • HIV infection is associated with a significant increase in the development of persistent hepatitis C, with higher titers of HCV, more rapid progression to HCV- related liver disease, and an increased risk for HCV-related cirrhosis (scarring) of the liver.
  • HCV may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiretroviral medications (Thomas, D.L. Hepatology 36:S201-S209, (2002) and National Center for HIV, STD and TB Prevention report at http://www.cdc.gov/hiv/pubs/facts/HIV-HCV Coinfection.htm).
  • a method of treating HCV infection in a patient co-infected with HCV and HIV is provided by administering a therapeutically effective amount of a compound according to Formula I to such a patient.
  • the compounds according to Formula I are particularly suitable for patients co-infected with HIV and HCV.
  • the compounds are especially effective in inhibiting HCV infection and/or egress from host cells.
  • the compounds are also effective in inhibiting HIV entry into and/or egress (particularly budding) from host cells.
  • the compounds according to the present invention are significantly less toxic, and are less like to result in evolved viral resistance.
  • a compound according to Formula I is administered alone, or in combination with another anti-HIV or anti-HCV drug, in a therapeutically effective amount to a mammal, particularly a human co-infected with both HCV and HIV.
  • the method may include a step of identifying a patient co-infected with HCV and HIV by techniques commonly known in the art. For example, PCR tests can be used to detect HCV DNA or RNA and HIV RNA in blood samples obtained from a test subject. Alternatively, virus-specific antibodies or antigens may be also employed for the detection of HCV and HIV infection.
  • Herpesviruses are one of the most common human pathogens. Members of the herpesvirus family include herpes simplex virus type-1 (HSV-I), herpes simplex virus type-2 (HS V-2), Varicella-zoster virus (herpes simplex virus type-3 or HSV-3; also known as chicken pox), and Epstein-Barr virus (herpes simplex virus type-4 or HSV-4).
  • HSV-I commonly causes herpes labialis (also called oral herpes, cold sores, fever blisters), which are highly infectious open sores that crust over before healing. HSV-I can also cause eye and brain infection.
  • HS V-2 commonly causes genital herpes.
  • HSV-I can also cause genital herpes, though far less frequently than HS V-2.
  • HSV-I and HS V-2 After an initial infectious cycle, HSV-I and HS V-2 generally establish life-long latent infections in sensory neurons near the site of infection. These latent infections exist without showing any signs or symptoms of infection or disease, until some event reactivates the virus. Reactivation generally causes recurrent lesions close to, or in the same location as, the site of initial infection. Reactivation seems to occur during periods of emotional stress, or periods of reduced immune system function.
  • HSV-I and HS V-2 can cause other diseases.
  • diseases include herpes simplex encephalitis - a rare but potentially fatal herpetic infection of the brain; neonatal herpes, - a rare but potentially severe HSV infection in newborns (resulting from transmission of the virus from the mother to the baby during delivery); herpetic whitlow- an HSV infection of the finger (acquired either from transfer of the infection from another part of the body or from direct contact with another party having an HSV infection); and herpes keratitis - an HSV infection of the eye (one of the most common causes of blindness).
  • herpes simplex virus infection of humans is a significant health problem.
  • Genital herpes is primarily treated with suppressive and episodic therapies.
  • Suppressive therapy is used to treat outbreaks before they occur, while episodic therapy treats outbreaks when they occur.
  • Treatment with valacyclovir HCl, acyclovir, and famciclovir, can be used in both suppressive and episodic therapies.
  • Epstein-Barr virus (herpes simplex virus-4), hereafter referred to as "EBV", occurs worldwide. In fact, most people become infected with EBV during their lives. A large percentage of adults in the United States have been infected. Infants are susceptible to EBV as soon as maternal antibody protection present at birth disappears. Many children become infected with EBV, and these infections usually cause no symptoms. The symptoms of EBV infection in children can be indistinguishable from the symptoms of other typical childhood illnesses. Individuals not infected as a child have a risk of being infected during adolescence or young adulthood, which often causes infectious mononucleosis (mono).
  • infectious mononucleosis Symptoms of infectious mononucleosis include fever, sore throat, and swollen lymph glands, less often a swollen spleen or liver involvement may develop. Rarely, heart problems or involvement of the central nervous system occur. Infectious mononucleosis is almost never fatal. The symptoms of infectious mononucleosis usually resolve in 1 or 2 months, but EBV remains dormant or latent in a few cells in the throat and blood for the rest of the infected person's life. Periodically, the virus can reactivate and is commonly found in the saliva of infected persons. Reactivation usually occurs without symptoms of illness.
  • EBV is thought to be associated with a number of other diseases including Burkitt's lymphoma, nasopharyngeal carcinoma, and Hodgkin's disease. Diseases caused by EBV are particularly common among people with reduced immunity. EBV is associated with a tumor often found in organ transplant patients that is referred to as post-transplant lymphoproliferative disease. The immune systems of such patients are usually artificially suppressed by drug therapy to help prevent the body from rejecting the new organ. Individuals infected with HIV, and have AIDS, also have reduced immunity and commonly suffer from oral hairy leukoplakia, a condition involving considerable replication of EBV in cells along the edge of the tongue. It has also been suggested that the high incidence of malaria in countries where Burkitt's lymphoma is prevalent may also play a role in the disease by suppressing the body's immune system.
  • herpes simplex virus or HSV refers to any strain of herpes simplex virus, including, but not limited to HSV-I, HSV-2, HSV-3 (Varcella-zoster virus or chicken pox), and HSV-4 (or EBV).
  • HSV-I herpes simplex virus
  • HSV-2 HSV-2
  • HSV-3 Varcella-zoster virus or chicken pox
  • HSV-4 or EBV.
  • "treating HSV infections” will encompass the treatment of a person who is actively infected with, or carrier of a latent infection of, any of the HSV family of herpes viruses.
  • HSV infection generally encompasses infection of a human by any strain of herpes simplex virus, and includes both active and latent infections.
  • treating HSV infection means the treatment of a person who is a carrier of any strain of HSV.
  • a person can be identified as an HSV carrier on the basis that the person is anti-HSV antibody positive or has symptoms of an HSV infection.
  • treating HSV infection should be understood as treating a patient who is at any one of the several stages of HSV infection progression.
  • treating HSV infection will also encompass treating individuals with a suspected HSV infection after suspected exposure to HSV by, e.g., contact with HSV-contaminated blood, blood transfusion, exchange of body fluids, "unsafe” sex with an infected person, accidental needle stick, receiving a tattoo or acupuncture with contaminated instruments, or transmission of the virus from a mother to a baby during pregnancy, delivery or shortly thereafter.
  • treating HSV infection will also encompass treating a person who is free of HSV infection but is believed to be at risk of infection by HSV.
  • a method of treating HSV infection in a patient co- infected with HSV and HIV is provided by administering a therapeutically effective amount of a compound according to Formula I to such a patient.
  • HIV infection is associated with an increase in active HSV infections, presumably due to the immunocompromised state created by the HIV infection.
  • the compounds according to Formula I are particularly suitable for patients co-infected with HIV and HSV.
  • the compounds are especially effective in inhibiting HSV infection and/or egress.
  • the compounds are also effective in inhibiting HIV entry into and/or egress (particularly budding) from host cells.
  • the presently marketed drug interferon alpha is not effective in treating HBV and HIV co-infection.
  • Lamivudine and some other reverse transcriptase inhibitors are useful in treating such co-infections, but Lamivudine is particularly toxic and can cause hepatic injury which worsens hepatitis B. In addition, such reverse transcriptase inhibitors often must be used in cocktails. In contrast, the compounds " according to the present invention are significantly less toxic, and are less likely to result in evolved viral resistance.
  • a compound according to Formula I is administered alone, or in combination with another anti-HIV or anti- HSV drug, in a therapeutically effective amount to a mammal, particularly a human co-infected with both HSV and HIV.
  • the method may include a step of identifying a patient co- infected with HSV and HIV by techniques commonly known in the art. For example, PCR tests can be used to detect HSV DNA or RNA and HIV RNA in blood samples obtained from a test subject. Alternatively, virus-specific antibodies or antigens may be also employed for the detection of HSV and HIV infection.
  • delaying the onset of HSV-associated symptoms means preventing in a patient who has an HSV infection, is suspected to have an HSV infection, or is at risk of contracting an HSV infection, from developing oral herpes, genital herpes, chickenpox or shingles, or a chronic EBV infection.
  • Influenza infection is associated with an average of 36,000 deaths and 114,000 hospitalizations per year in the United States alone. Although there are three recognized types of influenza viruses, influenza A, B, and C, types A and B are responsible for annual winter flu epidemics. Influenza A infects many different animal species besides humans, including ducks, chickens, pigs, whales, horses, and seals. Influenza B viruses generally only infect humans.
  • influenza virus has genomes composed of eight different RNA helices, which encodes a single gene and are bound by a nucleoprotein that determines the viral type: A, B, or C.
  • the influenza genome is made up of eight separate pieces of nucleic acid that can come together to form viruses with new combinations of viral genes when cells become co-infected by more than one viral type.
  • Two of these RNA helices encode the important viral surface proteins hemagglutinin and neuramidase, which are embedded in the lipid bilayer of a mature virus particle. Variations in the viral hemagglutinin and neuramidase determine the viral subtype.
  • Hemagglutinin is responsible for entry of the virus into the host cell, while neuramidase is important in the release of newly formed viruses from the infected cells.
  • Antibodies to hemagglutinin can neutralize the virus and are the major determinant for immunity.
  • Antibodies to neuramidase do not neutralize the virus but may limit viral replication and the course of infection.
  • Host antibodies to specific types of hemagglutinin and neuramidase prevent and generally ameliorate future infection by the same viral strain.
  • immunity gained through successful resistance to one strain gained during an infection one year may be useless in combating a new, recombined, variant strain the next year.
  • Antigenic drift results in small changes in surface antigens, and occurs essentially continuously over time. When these changes occur in the right places in the genes, they render the new antigens unrecognizable by the antibodies raised against other influenza virus strains during previous infections.
  • Antigenic shift is an abrupt, major change in an influenza A virus that results from a new hemagglutinin and/or new hemagglutinin and neuraminidase protein appearing in an influenza A strain. Such shifts are generally thought to occur when a new combination of viral genomic RNAs is created, possibly in a non-human species, and that new combination is passed to humans. When such an antigenic shift occurs, most humans have little or no protection against the virus, and an infection can prove lethal.
  • Influenza pandemics have resulted in massive loss of life during the history of man.
  • the influenza pandemic of 1918-1919 resulted in the deaths of about 20-40 million people.
  • molecular analyses recently demonstrated that the influenza virus responsible for the 1918-19 pandemic is related to a swine influenza virus that belongs to the same family of influenza virus that still causes the flu in humans today.
  • the flu shot involves vaccination with killed or inactivated influenza viruses.
  • the antiviral drugs available for treating influenza infection including amantadine, rimantadine, zanamivir, and osteltamivir. Amantadine and rimantadine are used for treating and preventing influenza A infection, zanamivir is used for treating influenza A and B infection, and osteltamivir is used for treating and preventing influenza A and B infection.
  • influenza and “influenza virus” refer to any type or subtype of influenza, including types A, B and C, and all subtypes thereof. Consequently, the term “influenza infection” encompasses infection by any strain of influenza, and the term “treating influenza infection” is understood to mean the treatment of an animal, particularly a human, infected by any strain of influenza. In addition, the term “treating influenza infection” will also encompass treating individuals with a suspected influenza infection after suspected exposure to influenza. The term “treating influenza infection” will also encompass treating a person who is apparently free of an influenza infection but is believed to be at risk of infection by influenza.
  • smallpox virus or "variola virus” refers to any strain of smallpox virus including variola major and variola minor (also referred to as alastrim). Examples of such human variola virus isolates are well known and the complete genomic nucleotide sequence one strain has been determined (See, e.g., Harrison's 15 th Edition Principles of Internal Medicine, Braunwald et al. EDS. McGraw-Hill, United States, and Genbank accession no. NCJ)0161 1). Skilled artisans are capable of diagnosing individuals infected or suspected of being infected with smallpox.
  • treating smallpox or “treating variola virus” refers to both treating the symptoms of the disease as well as reducing the viral load, infectivity and/or replication of the virus.
  • delaying the onset of symptoms associated with smallpox infection means treating a patient who is free of smallpox infection, or is believed to be at risk of infection by smallpox, or is infected with smallpox to delay the onset of one or more symptoms associated with smallpox infection by at least 3 months.
  • treating smallpox also encompasses treating a person who either has smallpox infection, is suspected to have smallpox infection, or is at risk of developing smallpox from a smallpox virus infection (which is characterized by more serious smallpox-defining symptoms like macular rash, fever, vesicular lesions and pustular lesions).
  • monkeypox virus belongs to the group of viruses that includes the smallpox virus (variola), the virus used in the smallpox vaccine (vaccinia), and the cowpox virus.
  • smallpox virus variola
  • vaccinia the virus used in the smallpox vaccine
  • cowpox virus the cowpox virus.
  • the signs and symptoms of monkeypox are like those of smallpox, but usually much milder, although monkeypox, unlike smallpox causes the lymph nodes to swell.
  • Africa where most cases of monkeypox are known to occur, infections result in deaths of between 1% and 10% of infected individuals.
  • the term “treating monkeypox” or “treating monkeypox virus” refers to both treating the symptoms of the disease as well as reducing the viral load, infectivity and/or replication of the virus.
  • the term of "preventing monkeypox infection” as used herein means preventing infection in a patient who is free of monkeypox infection but is believed to be at risk of infection by monkeypox.
  • the term of "delaying the onset of symptoms associated with monkeypox infection” as used herein means treating a patient who is free of monkeypox infection, or is believed to be at risk of infection by monkeypox, or is infected with monkeypox to delay the onset of one or more symptoms associated with monkeypox infection by at least 3 months.
  • SARS-CoV SARS-associated Coronavirus
  • SARS-CoV any strain of coronavirus associated with severe acute respiratory syndrome.
  • human coronavirus isolates are known as HCoV-OC43 and HCoV-229E ⁇ See, e.g., Marra et al. Science 300:1399 (2003) and Rota et al. Science 300:1394 (2003)(Genbank accession no. AY278741).
  • Skilled artisans are capable of diagnosing individuals infected or suspected of being infected with a SARS associated Coronavirus.
  • treating SARS or “treating SARS associated Cornoavirus” refers to both treating the symptoms of the disease, as well as reducing the infectivity and/or replication of the SARS-associated Coronavirus.
  • the term “treating SARS” also encompasses treating a person who is free of SARS-CoV infection but is believed to be at risk of infection by SARS-CoV.
  • preventing SARS as used herein means preventing in a patient who has SARS-CoV infection or is suspected to have SARS-CoV infection or is at risk of SARS-CoV infection from developing SARS (which is characterized by more serious SARS- CoV-defining symptoms like severe repiratory illness, fever, dry nonproductive cough, shortness of breath, and atypical pneumonia).
  • WN virus West Nile (WN) virus has emerged in recent years in temperate regions of Europe and North America, presenting a threat to public, equine, and animal health. The most serious manifestation of WN virus infection is fatal encephalitis (inflammation of the brain) in humans and horses, as well as mortality in certain domestic and wild birds. WN virus infection is a growing problem in North America. During 2002 in the United States alone, there were 4, 156 documented cases of WN virus infections of humans and 284 deaths. As used herein, the terms "treating West Nile virus,” “treating West Nile disease” refer to treating the symptoms of the disease in both known and suspected cases of WN virus infection.
  • the methods of treatment are generally used to treat an individual experiencing an active viral infection, whether acute or chronic, by any of the aforementioned viruses. • In another embodiment, the methods are generally used for treating a carrier of any of the aforementioned viruses who is not experiencing an active viral outbreak. In yet another embodiment, the methods are generally used to treat an individual who is known or suspected to have been exposed to any of the aforementioned viruses. In still another embodiment, the methods are generally used to prophylactically treat an individual who is likely to be exposed to, or is at risk of being exposed to, any of the aforementioned viruses, and thereby prevent infection or lessen its symptoms.
  • the methods are used for treating an HIV carrier who is not diagnosed as having developed AIDS (which is characterized by more serious AIDS-defining illnesses and/or a decline in the circulating CD4 cell count to below a level that is compatible with effective immune function, i.e., below about 200/ ⁇ l).
  • the methods can be used in treating a patient at any stages the HIV infection prior to diagnosis of AIDS, including acute HIV syndrome (or acute primary HIV infection syndrome) and asymptomatic infection (which is the long latent period with a gradual decline in the number of circulating CD4 T cells).
  • the present invention provides methods for treating viral infection - at any stage, and caused by any of the aforementioned viruses, and particularly HIV - in patients who have been, or are being, treated with one or more established antiviral drugs.
  • antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and combinations thereof.
  • the compounds of Formula I can be administered to patients who do not respond well to other antiviral drugs (e.g., non-responding, or developing viral resistance) or who experience relapses after treatment with one or more other antiviral drugs or regimens.
  • non-responding patient or patient “who does not respond well to other antiviral drugs” connote professional observations or judgment by a physician under relevant medical standard or customary practice in the field of antiviral infection therapy.
  • a patient may be characterized as non-responding or not responding well if his or her plasma HIV RNA level (or equivalent thereof) does not substantially decrease after treatment with one or more other anti-HIV drugs for a sufficient period of time, or if the reduction of plasma HIV RNA level (or equivalent thereof) is less than a tenfold drop by 4 weeks following the initiation of therapy.
  • the method of the present invention includes a step of identifying such a patient and subsequently administering to the patient a pharmaceutical composition or medicament having a therapeutically effective amount of a compound of Formula I.
  • a compound of Formula I is administered to a patient who has undergone a treatment with one or more drugs that target a viral protein such as viral protease, reverse transcriptase, integrase, envelope protein (e.g., gpl20 and gp41 for anti-fusion or homolog thereof), and has not responded well to the treatment.
  • the compounds of the present invention belong to a novel class of antiviral drug that is believed to target certain host cell protein(s). Their mode of action is distinct from other antiviral drugs. Thus, they can be especially effective in treating virus-infected patients who do not respond to one or more other antiviral drugs of a different class or who experience relapse after treatment with one or more antiviral drugs of a different class.
  • the present invention further provides methods for delaying the onset of acute infection comprising administering a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I to an individual having an acute viral infection or at risk of viral infection or at risk of developing symptomatic infection.
  • a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I to an individual having an acute viral infection or at risk of viral infection or at risk of developing symptomatic infection.
  • an individual infected with a virus or at risk of viral infection can be identified, and administered with a prophylactically effective amount of a compound according to Formula I, that is, an amount sufficient to delay the onset of acute viral infection by at least six months.
  • an amount is used sufficient to delay the onset of acute viral infection by at least 12 months, 18 months or 24 months.
  • the present invention also provides methods for delaying the onset of a symptomatic viral infection comprising identifying an individual who (1) is at risk of infection by a virus, or (2) is suspected of infection by a virus or of exposure to a virus, or (3) has a suspected past exposure to a virus, and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I.
  • a compound of the present invention may be used in combination with one or more other antiviral compounds, preferably other antiviral compounds that act through different mechanisms of action.
  • antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and a combination thereof.
  • Co-administration or coadministering means that the active pharmaceutical agents are administered together as a part of the same therapeutic or treatment regime.
  • the active pharmaceutical agents can be administered separately at different times of the day or at the same time.
  • the present invention also provides a pharmaceutical composition having a compound according to Formula I and a compound selected from protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, immunomodulators, vaccines, and combinations thereof.
  • a pharmaceutical composition having a compound according to Formula I and a compound selected from protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, immunomodulators, vaccines, and combinations thereof.
  • such other antiviral compounds should not interfere with, or adversely affect, the intended effects of the active compounds of this invention.
  • Co-administering to an individual in need of treatment a therapeutically effective amount of a compound of Formula I and a therapeutically effective amount of one or more other antiviral compounds
  • the present invention also provides pharmaceutical compositions or medicaments useful for the above treatment and prevention purposes and having a therapeutically effective amount of a compound according to Formula I and a therapeutically effective amount of one or more other antiviral compounds.
  • such other antiviral compounds have a different mode of action than that of the compounds according to Formula I.
  • such other antiviral compounds target a viral protein.
  • examples of such compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, integrase inhibitors, fusion inhibitors, and combinations thereof.
  • the present invention further provides an article of manufacture comprising a pharmaceutical composition or medicament having a therapeutically or prophylactically effective amount of a compound according to Formula I.
  • the pharmaceutical composition or medicament can be in a container such as bottle, gel capsule, vial or syringe.
  • the article of manufacture may also include instructions for the use of the pharmaceutical composition or medicament in the various antiviral applications provided above.
  • the instructions can be printed on paper, or in the form of a pamphlet or book.
  • the article of manufacture according to the present invention further comprises a therapeutically or prophylactically effective amount of one or more other antiviral compounds as described above.
  • the compounds of the invention can be used to treat a variety of additional disease or conditions such as hypertension, cancer (including metastasis), immune system related diseases, autoimmune diseases, bacterial infections (e.g., those of the digestive track), retinopathies, neurological disorders, and any disease mediated by rho-kinase activity (I or II) or a rho-kinase mediated pathway.
  • additional disease or conditions such as hypertension, cancer (including metastasis), immune system related diseases, autoimmune diseases, bacterial infections (e.g., those of the digestive track), retinopathies, neurological disorders, and any disease mediated by rho-kinase activity (I or II) or a rho-kinase mediated pathway.
  • Cancer includes, but is not limited to, bone marrow leukemia, lymphocytic leukemia, gastric cancer, colon cancer, lung cancer, pancreatic cancer, liver cancer, cancer of esophangus, ovarian cancer, breast cancer, skin cancer, cervical cancer, orchioncus, neuroblastoma, urinary epithelial cancer, multiple myeloma, uterine cancer, melanoma, cerebral tumor and the like, and anti-cancer means inhibition of formation, infiltration, metastasis, growth and the like of these tumors.
  • the immune diseases include, but are not limited to, allergic diseases, rejection in organ transplantation and the like.
  • the autoimmune disease include, but are not limited to, articular rheumatism, systemic lupus erythematodes, Sjogren's disease, multiple sclerosis, myasthenia gravis, type I diabetes, endocrine ophthalmopathy, primary biliary cirrhosis, Crohn's disease, glomerulonephritis, sarcoidosis, psoriasis, pemphigus, hyoplastic anemia, essential thrombocytopenic purpura and the like.
  • Bacterial infection of digestive tract means various diseases caused by the invasion of Salmonella, dysentery bacillus, intestinal pathogenic Escherichia coli and the like into intestinal mucosa epithelial cells.
  • Retinopathy includes, but is not limited to, angiopathic retinopathy, arteriosclerosis retinopathy, central angiospastic retinopathy, central serous retinopathy, circinate retinopathy, diabetic retinopathy, dysproteinemic retinopathy, hypertensive retinopathy, leukemic retinopathy, lipemic retinopathy, proliferative retinopathy, renal retinopathy, sickle retinopathy, toxemic retinopathy of pregnancy and the like.
  • Neurological disorders include, but are not limited to, Alzheimer's disease, Parkinson's disease, psychotic condition due to cerebral hemorrhage, cerebral thrombus, cerebral embolus, subarachnoid hemorrhage, transient cerebral ischemic stroke, hypertensive encephalopathy, cerebral arteriosclerosis, subdural hematoma, extradural hematoma, cerebral hypoxia, cerebral edema, cerebritis, cerebral tumor, external injury in head, mental disease, metabolite poisoning, drug poisoning, temporal respiratory arrest, deep anesthesia during operation, physical disorder and the like, and sequelae, decreased attention, hyperactivity, logopathy, delayed mental development, lethe, dementia (inclusive of wandering, nocturnal delirium, aggressive behavior and the like associated with dementia) caused by the above-mentioned diseases.
  • the toxicity profile and therapeutic efficacy of the therapeutic agents can be determined by standard pharmaceutical procedures in suitable cell models or animal models.
  • the LD 50 represents the dose lethal to about 50% of a tested population.
  • the ED50 is a parameter indicating the dose therapeutically effective in about 50% of a tested population.
  • Both LD 50 and ED 50 can be determined in cell models and animal models.
  • the IC 50 which stands for the circulating plasma concentration that is effective in achieving about 50% of the maximal inhibition of the symptoms of a disease or disorder, may also be obtained in cell models and animal models.
  • Such data may be used in designing a dosage range for clinical trials in humans.
  • the dosage range for human use should be designed such that the range centers around the ED50 and/or ICs 0 , but significantly below the LD50 obtained from cell or animal models.
  • compounds according to Formula I can be effective at an amount of from about 0.01 ⁇ g/kg to about 100 mg/kg per day based on total body weight.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at predetermined intervals of time.
  • the suitable dosage unit for each administration can be, e.g., from about 1 ⁇ g to about 2000 mg, preferably from about 5 ⁇ g to about 1000 mg.
  • a therapeutically effective amount of one or more other antiviral compounds can be administered in a separate pharmaceutical composition, or alternatively included in the pharmaceutical composition according to the present invention which contains a compound according to Formula I.
  • the pharmacology and toxicology of many of such other antiviral compounds are known in the art. See e.g., Physicians Desk Reference, Medical Economics, Montvale, NJ; and The Merck Index, Merck & Co., Rahway, NJ.
  • the therapeutically effective amounts and suitable unit dosage ranges of such compounds used in art can be equally applicable in the present invention.
  • the therapeutically effective amount for each active compound can vary with factors including but not limited to the activity of the compound used, stability of the active compound in the patient's body, the severity of the conditions to be alleviated, the total weight of the patient treated, the route of administration, the ease of absorption, distribution, and excretion of the active compound by the body, the age and sensitivity of the patient to be treated, and the like, as will be apparent to a skilled artisan.
  • the amount of administration can be adjusted as the various factors change over time.
  • the active agents can be in any pharmaceutically acceptable salt form.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, organic or inorganic salts of the active compounds, including inorganic or organic acid addition salts of the compound.
  • salts of basic active ingredient compounds include, but are not limited to, hydrochloride salts, hydrobromide salts, sulfate salts, bisulfate salts, nitrate salts, acetate salts, phosphate salts, nitrate salts, oxalate salts, valerate salts, oleate salts, borate salts, benzoate salts, laurate salts, stearate salts, palmitate salts, lactate salts, tosylate salts, citrate salts, maleate, salts, succinate salts, tartrate salts, napththylate salts, fumarate salts, mesylate salts, laurylsuphonate salts, glucoheptonate salts, and the like.
  • salts of acidic active ingredient compounds include, e.g., alkali metal salts, alkaline earth salts, and ammonium salts.
  • suitable salts may be salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.
  • organic salts may also be used including, e.g., salts of lysine, N 9 N 1 - dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and tris.
  • the active compounds can be incorporated into a formulation that includes pharmaceutically acceptable carriers such as binders (e.g., gelatin, cellulose, gum tragacanth), excipients (e.g., starch, lactose), lubricants (e.g., magnesium stearate, silicon dioxide), disintegrating agents (e.g., alginate, Primogel, and corn starch), and sweetening or flavoring agents (e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint).
  • binders e.g., gelatin, cellulose, gum tragacanth
  • excipients e.g., starch, lactose
  • lubricants e.g., magnesium stearate, silicon dioxide
  • disintegrating agents e.g., alginate, Primogel, and corn starch
  • sweetening or flavoring agents e.g., glucose, sucrose, saccharin, methyl salicylate, and peppermint
  • Suitable oral formulations can also be in the form of suspension, syrup, chewing gum, wafer, elixir, and the like. If desired, conventional agents for modifying flavors, tastes, colors, and shapes of the special forms can also be included.
  • the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and safflower oil.
  • the active compounds can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • Topical administration examples include nasal, bucal, mucosal, rectal, or vaginal applications.
  • the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols.
  • one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.
  • a special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al, Annual Review of Medicine, 39:221-229 (1988), which is incorporated herein by reference.
  • Subcutaneous implantation for sustained release of the active compounds may also be a suitable route of administration. This entails surgical procedures for implanting an active compound in any suitable formulation into a subcutaneous space, e.g., beneath the anterior abdominal wall. See, e.g., Wilson et al, J. Clin. Psych. 45:242-247 (1984).
  • Hydrogels can be used as a carrier for the sustained release of the active compounds. Hydrogels are generally known in the art. They are typically made by crosslinking high molecular weight biocompatible polymers into a network, which swells in water to form a gel like material. Preferably, hydrogels are biodegradable or biosorbable.
  • hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al, J. Pharmaceut. Sci., 73:1718-1720 (1984).
  • the active compounds can also be conjugated, to a water soluble non- immunogenic non-peptidic high molecular weight polymer to form a polymer conjugate.
  • an active compound is covalently linked to polyethylene glycol to form a conjugate.
  • such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity.
  • the active compound in the conjugate when administered to a patient, can have a longer half-life in the body, and exhibit better efficacy. See generally, Burnham, Am. J. Hosp. Pharm., 15:210- 218 (1994).
  • PEGylated proteins are currently being used in protein replacement therapies and for other therapeutic uses.
  • PEGylated interferon PEG- INTRON A ®
  • PEGylated adenosine deaminase ADAGEN ®
  • SCIDS severe combined immunodeficiency disease
  • PEGylated L-asparaginase (ONCAPSPAR ® ) is being used to treat acute lymphoblastic leukemia (ALL). It is preferred that the covalent linkage between the polymer and the active compound and/or the polymer itself is hydrolytically degradable under physiological conditions. Such conjugates known as "prodrugs" can readily release the active compound inside the body. Controlled release of an active compound can also be achieved by incorporating the active ingredient into microcapsules, nanocapsules, or hydrogels generally known in the art.
  • Liposomes can also be used as carriers for the active compounds of the present invention.
  • Liposomes are micelles made of various lipids such as cholesterol, phospholipids, fatty acids, and derivatives thereof. Various modified lipids can also be used. Liposomes can reduce the toxicity of the active compounds, and increase their stability. Methods for preparing liposomal suspensions containing active ingredients therein are generally known in the art. See, e.g., U.S. Patent No. 4,522,811; Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. Y. (1976).
  • the active compounds can also be administered in combination with another active agent that synergistically treats or prevents the same symptoms or is effective for another disease or symptom in the patient treated so long as the other active agent does not interfere with or adversely affect the effects of the active compounds of this invention.
  • additional active agents include but are not limited to anti-inflammation agents, antiviral agents, antibiotics, antifungal agents, antithrombotic agents, cardiovascular drugs, cholesterol lowering agents, anti-cancer drugs, hypertension drugs, and the like.
  • Mass spectra were obtained on a Thermo Finnigan LCQ-Deca (injection volume 5 uL, XTerra MS-Ci 8 3.5 ⁇ m 2.1 x 50mm column, XTerra MS-Cj 8 5 ⁇ m 2.1 x 20mm guard column), ESI source, analytical HPLC was performed on an HP1050 (injection volume 5 ⁇ l, XTerra RP-Ci 8 5 ⁇ m 4.6 x 250 mm column, with an XTerra MS-C] 8 5 ⁇ m 2.1 x 20mm guard column), and preparative HPLC was performed on an Agilent 1100 Prep-LC with various columns and conditions depending on the compound.
  • the compound of formula 3 (Ref: Org.Lett, 2002, Vol. 4, No. 21, 3703-3706) can be prepared either by heating a mixture of compound 1 and substituted aryl halide 2, CuI, and sodium hydroxide in 2-propanol at 50 -90 0 C for 1 -24 h or reacting formula 1 and aryl halide in DMF using base such as K 2 CO 3 , Et 3 N, DIEA or NaOH at 25- 150 0 C.
  • the compound of formula 3 was treated with oxidizing agent such as sulfur trioxide-trimethyl amine complex, triethyl amine in DMSO to give compound 4.
  • the compound of formula 4 is dissolved a suitable solvent (tetrahydrofuran, methanol, ethanol or an optionally mixed solvent thereof etc), and catalytic quantity of acid, a reducing agent (Na(OAc) 3 BH, sodium borohydride, sodium cyanoborohydride) generally used is added and the mixture is reacted at 0-60 0 C for 1- 24 h or it can heated in microwave reactor at 130 0 C for 5- 10 min to give compound of formula 5.
  • a suitable solvent tetrahydrofuran, methanol, ethanol or an optionally mixed solvent thereof etc
  • a reducing agent Na(OAc) 3 BH, sodium borohydride, sodium cyanoborohydride
  • the compound of the formula 5 can be prepared alternatively as described in general synthetic scheme 2 by reacting 1 and 2 in a suitable solvent ( tetrahydrofuran, methanol, ethanol or an optionally mixed solvent thereof etc), and catalytic quantity of acid, a reducing agent (Na(OAc) 3 BH, sodium borohydride, sodium cyanoborohydride) generally used is added and the mixture is reacted at 0-60 0 C for 1- 24 h or it can heated in microwave reactor at 130 0 C for 5- 10 min to give compound of formula 3.
  • a suitable solvent tetrahydrofuran, methanol, ethanol or an optionally mixed solvent thereof etc
  • a reducing agent Na(OAc) 3 BH, sodium borohydride, sodium cyanoborohydride
  • Example 8A and Example 8B were synthesized from the corresponding BOC protected intermediates by a similar procedure described for Example 8.
  • the title product (0.08 g, 14%) was prepared by the analogous procedure to that described in Example 5 using the Example 3 (0.387 g, 1.624 mmol) , 5- aminoindazole (0.216 g, 1.624 mmol) and BH3-Pyridine complex (1.4 mL, 2.11 mmol).
  • Example 11 The title product (0.042 g, 28%) was prepared according to the procedure described in Example 11 (Method B) using the compound of Example 8 (0.200 g, 0.451 1 mmol), 4-fluoronitrobenzene (0.064 g, 48 ⁇ L) and K 2 CO 3 (0.081 g, 0.586 mmol).
  • Example 25-52 listed in the following Table 2 were prepared in a manner analogous to the procedure described for Example 24.
  • Examples 54-73 were prepared in an analogous manner to that described for Example 53 using appropriate aryl halides and aminopiperidine or aminopyrrolidine intermediate starting material, and are summarized in Table 3.
  • Examples 75-103 were prepared and are summarized in Table 4. Table 4
  • reaction was filtered through silica and washed with EtOAc, then purified by MPLC (SiO 2 / 0 - 100% EtOAc in hexanes) yielding title compound as a brown foam (0.107 g, 69%).
  • Example 109 Title compound was prepared (0.090 g, 52%) in a similar manner to Example 109 using Example 108 (0.141 g, 0.346 mmol), DIPEA (0.14 mL, 0.80 mmol) and TFAA (58 ⁇ L, 0.42 mmol).
  • Example 108 The title compound was prepared in a similar manner to Example 109, using Example 108 (0.144 g, 0.353 mmol), DIPEA (0.14 mL, 0.80 mmol) and Tf 2 O (70 ⁇ L, 0.43 mmol).
  • Example 109 The title compound was prepared (0.101 g, 60%) in a similar manner to Example 109 using Example 108 (0.141 g, 0.346 mmol), DIPEA (0.14 mL, 0.80 mmol) and MsCl (33 ⁇ L, 0.43 mmol).
  • Example 106 The title compound was prepared (1.078 g, 54%) in a similar manner to Example 107, using Example 106 (1.429 g, 4.52 mmol), K 2 CO 3 (0.943 g, 6.82 mmol) and 1-fluoro- 2-nitro-benzene (0.62 mL, 5.9 mmol) in acetone (45 mL).
  • the crude material was purified by MPLC (SiO 2 / 0 - 15% /-PrOH in CHCl 3 ).
  • Example 113 10% Pd-C (27 mg) was added to a solution of Example 113 (0.903 g, 2.06 mmol) in 95% EtOH (15 mL). This was degassed then reacted under 50 psi of hydrogen for 7 h then 30 psi of hydrogen for 3 days. EtOAc (20 mL) was added and the solution was filtered through silica and washed with EtOAc. The solvent was evaporated and residue was purified by MPLC (SiO 2 / 0 - 30% acetone in hexanes) to give title compound.
  • Example 109 Title compound was prepared (0.068 g, 51%) in a similar manner to Example 109 using Example 114 (0.108 g, 0.265 mmol), DIPEA (100 ⁇ L, 0.574 mmol) and TFAA (56 ⁇ L, 0.40 mmol).
  • Example 109 The title compound (0.08 g, 49%) was prepared in a similar manner to Example 109 using Example 114 (0.123 g, 0.302 mmol), DIPEA (100 ⁇ L, 0.574 mmol) and Tf 2 O (74 ⁇ L, 0.45 mmol).
  • Example 109 The title compound (0.034 g 19%). was prepared in a similar manner to Example 109, using Example 114 (crude)( ca. 0.40 mmol), pyridine (50 ⁇ L, 0.62 mmol) and AcCl (34 ⁇ L, 0.48 mmol).
  • Example 114 The title compound (0.065 g, 22%) was prepared in a similar manner to Example 109, using Example 114 (0.250 g, 0.613 mmol), DIPEA (0.14 mL, 0.80 mmol) and MsCl (52 ⁇ L, 0.67 mmol) yielding a yellow oil after MPLC (acetone in hexanes gradient).
  • 1 H NMR (CDCl 3 ) ⁇ 1.73 - 1.65 (m, 10H), 1.84 (m, IH), 1.97 (m, IH), 2.10 (m, IH), 2.57 (m, IH), 2.78 (m, IH), 2.90-3.00 (m, 4H), 3.24 (m, IH), 3.72 (m, IH), 3.88 (bs, IH),
  • Example 117 A solution of Example 117 (0.034 mg, 0.076 mmol) in TFA (2 mL) was stirred for 30 min, then concentrated on a rotary evaporator. Saturated NaHCO 3 (2 mL) was added and extracted with EtOAc (3 x 3 mL). The combined organic portions were washed with saturated NaHCO 3 (1 x 2 mL) and saturated NaCl (1 x 3 mL), then dried (MgSO 4 ) and filtered through silica with an EtOAc wash.
  • Example 118 (0.065 g, '0.13 mmol) in 2:1 DCM:TFA (v/v; 3 mL) was stirred for 4 h, then concentrated. The residue was purified by MPLC (SiO 2 / 0 - 100% EtOAc in hexanes).
  • Examples 122-149 were prepared analogously to the procedure described for Example 121 using appropriate starting materials and are listed in Table 5. Table 5
  • a heterocyclic amine of Formula 1 can be reacted with ketone of Formula 2 in suitable solvent (methanol, tetrahydrofuran, or an optionally mixed solvent) using catalytic quantity of acetic acid, a reducing agent (BH 3 -Pyridine complex, sodium cyano borohydride or sodium triacetoxy borohydride) generally used is added and the mixture is stirred under cooling to the ambient temperature 1 to 24 h to give a compound of formula 3.
  • suitable solvent methanol, tetrahydrofuran, or an optionally mixed solvent
  • a reducing agent BH 3 -Pyridine complex, sodium cyano borohydride or sodium triacetoxy borohydride
  • Examples 154 - 193 listed in the following table were prepared analogously to the procedure described for Example 152 or Example 153 using appropriate starting materials and are listed in Table 6.
  • Example 182 A mixture of Example 182 (0.031 g, 0.94 mmol) and large excess of pyrrolidine (1 mL) was heated to 80 -100 0 C for 3 to 8 h. At the end of this period the reaction mixture was concentrated. The crude product was purified by preparative TLC using mixture of 10% methanol in dichloromethane to give title compound (0.030 g, 88%).
  • Examples 195-212 listed in the following table were prepared analogously to the procedure described for Example 194 using substituted [l-(2-chloropyrimidin-4- yl)piperidin-3-yl]-lH-indazol-5-yl)amine or substituted [l-(4-chloropyrimidin-2- yl)piperidin-3-yl]-(lH-indazol-5-yl)amine and appropriate amines or NaOMe with or without solvents. Some of the reactions were extracted with ethyl acetate and washed with water. Ethyl acetate layer was dried (Na 2 SO 4 ), filtered and solvent was evaporated to dryness. The products were purified by preparative HPLC or preparative TLC and listed in Table 7.
  • Spodoptera frugiperda ovary (Sf9) cells are infected with baculovirus carrying GST-ROCK II, and cultured to provide a sufficient number of cells expressing GST- ROCK II.
  • the cells are lysed with a lysis buffer (e.g., 50 mM Tris-HCl, pH 7.5, 2 raM EGTA, 1 mM DTT, 10 ⁇ M (p-amidinophenyl)methanesulfonyl fluoride, 1 g/ml leupeptin, and 10% sucrose by sonication and are centrifuged.
  • the supernatant is applied to a glutathione-Sepharose column to obtain substantially purified GST- ROCK II.
  • ROCK II can be expressed and purified in yeast cells.
  • the kinase buffer contains 50 mM Hepes (pH7.5), 10 mM MgCi 2 , 1 mg/ml bovine serum albumin (BSA), 1 mM dithiothreitol (DTT), 5 uM PKI- S21 substrate peptide (GRTGRRNSI-NH 2 ), and one of four fixed [ ⁇ - 32 P]ATP concentrations (10, 30, 60, 100 uM) (-250 cpm/pmol), a particular concentration of one or more test compounds. About 10 nM kinase (ROCK-I or ROCK-II (for ROCK- II, amino acid residues 1 1-552) is included in the reaction buffer.
  • ROCK-I or ROCK-II for ROCK- II, amino acid residues 1 1-552
  • Reaction is initiated by addition of [ ⁇ - 32 P]ATP and incubated at 24°C for 20 min, and then terminated by adding 3% phosphoric acid.
  • the reaction mixture is transferred to 96-well P81 phosphocellulose filter plate.
  • the plate is washed 6 times by 1% phosphoric acid with vacuum.
  • the filters in the plate are dried with vacuum and 100 ul of scintillation fluid MicroSint-20 is added into the wells.
  • the plate is counted in Topcount for radioactivity.
  • the results from such assays are given in the following table.
  • 5 x 10 4 293T cells are seeded into a well of 24-well plate with 0.6 ml of fresh DMEM supplemented with 10% FBS and 1 x NEAA without antibiotics.
  • 0.6 ⁇ g of pEGFP-Gag(HIV-l) plasmid DNA is diluted with 50 ⁇ l of Opti-MIM I medium.
  • the same amount of a plasmid with HIV GAG mutated at the p6 late domain motif [pEGFP-Gag(HIV-l /LIRL)] is diluted in the same manner.
  • Each of the diluted plasmid DNA is combined with 2 ⁇ l ofLipofectAmine 2000 reagent (Invitrogen) in 50 ⁇ l of Opti-MEM I medium and used subsequently in transfecting the plated 293T cells according standard protocols provided by manufacturer.
  • Different concentrations of a compounds of Formula I e.g., [l-(2- Fluoro-4-nitro-phenyl)-piperidin-3-yl]-(lH-indazol-5-yl)-amine
  • a compounds of Formula I e.g., [l-(2- Fluoro-4-nitro-phenyl)-piperidin-3-yl]-(lH-indazol-5-yl)-amine
  • the remaining culture media in the cell culture plate is removed and the cells are lysed with cell lysis buffer and processed for protein expression assays.
  • kit from PerkinElmer Life Sciences, Inc. are used according standard protocols provided by the manufacturer. Briefly, the above- described processed sample is mixed with buffer and incubated in the wells of anti- p24 antibody-coated Microplate to allow antibody-antigen binding. The plate is then washed with diluted wash buffer. Detector Antibody is then added to the wells, and incubated at 37 0 C for 1 hour. The plate is then washed again with diluted wash buffer. Diluted Streptavidin-HRP is added to all wells, and incubated at room temperature for 30 minutes.
  • the plate is washed again with diluted wash buffer. OPD substrate solution is added to all wells, and incubated at room temperature for 30 minutes. The reaction is stopped by adding 100 ⁇ l of Stop Solution to all wells. The plate is read at 490 nm within 15 minutes after stop.
  • PBMCs peripheral blood mononuclear cells
  • RT reverse transcriptase
  • TTP Tritiated thymidine triphosphate
  • Poly rA and oligo dT are prepared as a stock solution, which is kept at - 20 0 C.
  • the RT reaction buffer is prepared fresh on a daily basis and consists of 125 ⁇ l IM EGTA, 125 ⁇ l dH2O, 1 10 ⁇ l 10% SDS, 50 ⁇ l IM Tris (pH 7.4), 50 ⁇ l IM DTT, and 40 ⁇ l IM MgCL2. These three solutions are mixed together in a ratio of 2 parts TTP, 1 part poly rA:oligo dT, and 1 part reaction buffer. Ten microliters of this reactions mixture is placed at a round bottom microtiter plate and 15 ⁇ l of virus containing supernatant is added and mixed. The plate is incubated at 37°C in a water bath with a solid support to prevent submersion of the plate and incubated for 60 min.
  • the assay plates are stained with the soluble tetrazolium- based dye MTS (CellTiter Reagent, Promega) to determine cell viability and quantify compound toxicity.
  • MTS is metabolized by the mitochondrial enzymes of metabolically active cells to yield a soluble formazan product, allowing the rapid quantitative analysis cell viability and compound cytotoxicity.
  • the MTS is a stable solution that does not require preparation before use.
  • 20 microliters of MTS reagent is added per well. The wells are incubated overnight for the HIV cytoprotection assay at 37°C. The incubation intervals are chosen based on empirically determined times for optimal dye reduction in each cell type.
  • Adhesive plate sealers are used in place of the lids, the sealed plate is inverted several times to mix the soluble formazan product and the plate is read spectrophotometrically at 490 nm with a Molecular Devices Vmax plate reader.
  • HIV-infected cells treated with the compounds are also studied under an electronic microscope or similar devices to examine if the viruses are defective in viral budding from the cells.
  • the EIAV construct used for these experiments is pEV53.
  • the plasmid contains an EIAV proviral sequence with a partial deletion of the Env gene cloned into the pcDNA3.1 mammalian expression vector (Invitrogen; Carlsbad, CA). Transfection of cultured cells is done with EIAV Provirus plasmid and cells are treated with individual compounds according to Formula I.
  • 1 x 10 5 293T cells/well are seeded into a 12-well plate with 1 ml of fresh DMEM (10% FBS, Ix NEAA without antibiotics) and allowed to adhere for 24 h. Transfection is carried out according to manufacturer's recommendations. Briefly, 1 ⁇ g of pEV53 plasmid DNA is combined with 100 ⁇ l of Opti-MIM I medium. 3 ⁇ l of LipofectAmine 2000 reagent (Invitrogen) is then added to 100 ⁇ l of Opti-MEM I medium & incubated at RT for 5 min. The DNA/Opti-MIM I & Lipofectamine 2000/Opti-MEM I solutions are then combined and mixed gently followed by incubation at room temperature for 20 min.
  • DNA/Lipofectamine 2000 solution 200 ⁇ l of DNA/Lipofectamine 2000 solution is then added to the 293T cells in each well of the plate and mixed gently by rocking. The plate is then placed at 37 0 C, 5% CO 2 in a humidified incubator for 2 h. Various concentrations of individual compounds according to Formula I (dissolved in water or another suitable solvent) are added to each well of the plate and incubated for 48 h post-transfection.
  • 1.0 ml of post-transfection cell culture medium is collected, passed through a 0.45 ⁇ m syringe filter and layered on top of 200 ⁇ l of 20% sucrose. This discontinuous gradient is then centrifiiged at 14,000 rpm (4 0 C) for 90 minutes. The supernatant is carefully removed leaving ⁇ 20 ⁇ l in the tube. The pellet contained in the remaining ⁇ 20 ⁇ l is resuspended in 150 ⁇ l of HBSS (Hank's Balanced Salt Solution, Invitrogen) and used for the Reverse Transcriptase Assay.
  • HBSS Hors Balanced Salt Solution, Invitrogen
  • This assay is used to quantitate the reverse transcriptase activity present in retroviral virions.
  • the level of reverse transcriptase activity is used as surrogate measurement for viral particle output from cells transfected with EIAV (Equine infectious anemia virus) proviral DNA. A reduction in the level of reverse transcriptase activity indicates inhibition of viral replication.
  • the reverse transcription assay is carried out according to manufacturer's recommendations.
  • Example 219 Inhibition of MMLV infectivity with compounds of Formula I
  • MMLV infectivity is assessed using the procedure of Telesnitsky A., et al. Assays for retroviral reverse transcriptase. Methods Enzymol. 262:347-362 (1995). The results of this assay demonstrate whether or not the compounds of Formula I reduce or inhibit the infectivity of the virus MMLV.
  • Compounds of the Formula I are tested in an MT-4 cell survival assay to determine if they have ant-HIV activity. Compounds of Formula I were shown to have anti-HIV activity in this assay.
  • the HTLV-I transformed T cell line, MT-4 is highly susceptible to and permissive for HIV-I infection.
  • Potential anti-HIV- 1 agents can be evaluated in this target cell line by protection from the HIV-induced cytopathic effect.
  • viability of both HIV-I and mock-infected cells are assessed in a colorimetric assay that monitors the ability of metabolically-active cells to reduce the tetrazolium salt WST-I. Cytoprotection by antiviral compounds is indicated by the positive readout of increased WST-I cleavage.
  • MT-4 cells are mock-infected or batch-infected with the HIV-I laboratory strain, NL4-3, at a low (generally 0.0005) multiplicity of infection (M.O.I.) for 2 hours. Cells are then washed to remove unbound virus and plated in the presence of increasing concentrations of the indicated compound. Following four days incubation (optimized to allow a spreading infection resulting in cell death), cell viability is analyzed using the WST-I assay. Data is then normalized to the mock-infected solvent control sample, and compound activity is scored based on cytoprotection. For a more detailed description of this assay, see Pauwels, R. et al. J. Vir. Methods 16: 171-185 (1987) and Pauwels, R. et al. J. Vir. Methods 20:309-321 (1988).

Abstract

L'invention concerne des procédés et compositions pharmaceutiques permettant de traiter et/ou retarder le début d'une infection virale. Ces compositions pharmaceutiques comprennent des composés possédant un noyau d'indazole. En outre, ces compositions peuvent être utilisées pour traiter des troubles cardio-vasculaires et le cancer.
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US10329282B2 (en) 2017-06-30 2019-06-25 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
CN110582489A (zh) * 2017-06-30 2019-12-17 北京泰德制药股份有限公司 Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途
US10323023B2 (en) 2017-06-30 2019-06-18 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising the same, as well as preparation method and use thereof
JP2020525522A (ja) * 2017-06-30 2020-08-27 ベイジン タイド ファーマシューティカル カンパニー リミテッドＢｅｉｊｉｎｇ Ｔｉｄｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌ Ｃｏ．， Ｌｔｄ． Ｒｈｏ−関連プロテインキナーゼ阻害剤、それを含む医薬組成物並びにその調製方法及び使用
CN110582489B (zh) * 2017-06-30 2023-10-27 北京泰德制药股份有限公司 Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途
WO2019001572A1 (fr) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Inhibiteur de protéine kinase associée à rho, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
CN110573501B (zh) * 2017-06-30 2023-09-29 北京泰德制药股份有限公司 Rho相关蛋白激酶抑制剂、包含其的药物组合物及其制备方法和用途
AU2018294054B2 (en) * 2017-06-30 2022-05-26 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
JP7311228B2 (ja) 2017-06-30 2023-07-19 ベイジン タイド ファーマシューティカル カンパニー リミテッド Ｒｈｏ－関連プロテインキナーゼ阻害剤、それを含む医薬組成物並びにその調製方法及び使用
US11390609B2 (en) 2017-06-30 2022-07-19 Beijing Tide Pharmaceutical Co., Ltd. Rho-associated protein kinase inhibitor, pharmaceutical composition comprising same, and preparation method and use thereof
WO2019145729A1 (fr) * 2018-01-25 2019-08-01 Redx Pharma Plc Triazoles substitués par hétérocyclylamino utilisés en tant que modulateurs de la protéine kinase associée à rho
US11497751B2 (en) 2018-01-25 2022-11-15 Redx Pharma Plc Modulators of Rho-associated protein kinase
EP4026834A1 (fr) * 2018-01-25 2022-07-13 Redx Pharma Plc Triazoles substitués par hétérocyclylamino utilisés en tant que modulateurs de la protéine kinase associée à rho
JP2021512158A (ja) * 2018-01-25 2021-05-13 レデックス・ファーマ・パブリック・リミテッド・カンパニーＲｅｄｘ Ｐｈａｒｍａ ＰＬＣ Ｒｈｏ関連プロテインキナーゼのモジュレーター
CN111655681A (zh) * 2018-01-25 2020-09-11 莱德克斯制药公共有限公司 杂环基氨基取代的三唑类化合物作为Rho相关蛋白激酶的调节剂
CN111655681B (zh) * 2018-01-25 2024-01-05 莱德克斯制药公共有限公司 杂环基氨基取代的三唑类化合物作为Rho相关蛋白激酶的调节剂
US11878020B2 (en) 2018-01-25 2024-01-23 Redx Pharma Plc Modulators of Rho-associated protein kinase

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