WO2007076161A2 - Compounds with therapeutic activity - Google Patents

Compounds with therapeutic activity Download PDF

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Publication number
WO2007076161A2
WO2007076161A2 PCT/US2006/049558 US2006049558W WO2007076161A2 WO 2007076161 A2 WO2007076161 A2 WO 2007076161A2 US 2006049558 W US2006049558 W US 2006049558W WO 2007076161 A2 WO2007076161 A2 WO 2007076161A2
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WIPO (PCT)
Prior art keywords
oxazol
phenyl
amine
indazol
ylamino
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PCT/US2006/049558
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French (fr)
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WO2007076161A3 (en
Inventor
Ashok C. Bajji
Se-Ho Kim
Richard Trovato
Robert J. Mchugh
Benjamin Markovitz
Mark B. Anderson
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Myriad Genetics, Inc
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Publication of WO2007076161A2 publication Critical patent/WO2007076161A2/en
Publication of WO2007076161A3 publication Critical patent/WO2007076161A3/en

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    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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 anew 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 diseases (e.g, viral infections or cancer) with these compounds.
  • the present invention also relates to treating and/or delaying the onset of symptoms caused by a disease (e.g., viral infections) with a pharmaceutical composition having a compound of Formula I.
  • a disease e.g., viral infections
  • novel compounds of Formula I which have antiviral activity and activity in other disease models such as cancer (see Detailed Description of the Invention for structures).
  • the invention provides compounds of Formula I and pharmaceutical compositions having the compounds of Formula I along with a pharmaceutically acceptable carrier.
  • the invention provides a method for treating viral infection 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 (e.g., mammals) infected with a virus.
  • the present invention relates to a method for inhibiting viral budding from a host cell by administering to the cell 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 cell.
  • the method of inhibiting viral budding involves treating humans or other animals infected with a virus.
  • methods for inhibiting viral entry are 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 comprising (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 provides methods for delaying the onset of one or more 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-def ⁇ ning 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 an individual in need of such 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).
  • 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
  • asymptomatic infection which is the long latent period with a gradual decline in the number of circulating CD4 T-cells.
  • a method 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 an individual in need of such 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- defming 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 is provided 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 an individual in need of such 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.
  • 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.
  • 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 compounds of the invention can also exist as tautomers, and the invention includes all tatutomeric forms of these compounds.
  • the present invention also provides pharmaceutical compositions or medicaments for the combination treatment 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.
  • compositions having a compound of Formula I are useful for the treatment and prevention of certain diseases, like viral diseases.
  • the compounds of the invention also have activity in several disease models including cancer.
  • 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 invention relates to compounds of Formula I,
  • Rl and R2 are independently chosen from hydro, or an optionally substituted - L-aryl, -L-heteroaryl, -L-heterocyclic, or -L-cycloalkyl group;
  • R3 is an optionally substituted -L-heterocyclic or -L-heteroaryl group; and pharmaceutically acceptable salts thereof.
  • each n is independently chosen from 0, 1 , 2, 3, 4, 5, 6, 7, and 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C1-3 alkyl, and C 3 . 6 cycloalkyl groups.
  • L is a covalent bond.
  • R3 is optionally substituted with one or more optional substituents and is a heterocyclic group chosen indazolyl, IH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H- benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, lH-quinaxolin-2-one, 4H- benzo[l,4]oxazin-3-one, iso
  • R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, 1 H-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2- one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro- indol-2-one, and 2,3-dihydro ⁇ benzo[l,4]dioxrne.
  • the compounds of the invention include those of Formula
  • Rl is hydro;
  • pyridyl (pyridinyl), 2-pyridyl, 3 -pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, ⁇ -carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4- dihydroquinoxaline
  • R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H- benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro- indol-2-o ⁇ e, 2,3-dihydro-benzo[l,4]dioxine.
  • the compounds of the invention include those of Formula I, wherein Rl is hydro; R2 is optionally substituted with one or more optional substituents and is chosen from pyridinyl, indolyl, benzofuranyl, benzothiophene, 2,3 dihydrobenzofuran.
  • R3 is optionally substituted with one or more optional substituents and is a heterocyclic group chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H-benzo[l,4]oxazin-3- one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4- bjpyridine, lH-quinaxolin-2
  • R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H- benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxoIin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1 ,3 dihydro- indol-2-one, and 2,3-dihydro-benzo[l,4]dioxine.
  • the R2 group attached to the oxazole group of the compounds of the invention is chosen from Pyrimidine, Chloro-benzene, 1,2- Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene, Diethyl-phenyl-amine, Benzoic acid methyl ester, Methanesulfonyl-benzene, Nitro-benzene, Phenyl-methanol, (4-Methyl-piperazin-l- yl)-phenyl-methanone, MorphoIi ⁇ -4-yl-phenyl-methanone, Phenyl-pyrrolidin- 1 -yl- methanone, N,N-Diethyl-benzamide, Vinyl-benzene, (E)-3-Phenyl-acrylic acid methyl ester, (Z)-3-Phenyl-acrylic acid methyl ester,
  • the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000.
  • the compounds of the invention include those of Formula I wherein Rl is hydro; R2 is optionally substituted with one or more optional substituents and is chosen from -L-aryl, -L-heteroaryl, -L- heterocyclic, and -L-cycloalkyl, provided R2 is not phenol (ortho), 2-aminophenyl, or 2-nitrophenyl.
  • the compounds of the invention include those of Formula I wherein Rl is chosen from an optionally substituted heteroaryl, heterocyclic, aryl, and cycloalkyl group, provided Rl is not phenyl, 4-(diethylamino)phenyl, or 4-methoxyphenyl; R2 is a hydro; and R3 is a heterocyclic group.
  • R3 is an optionally substituted indazole group; and pharmaceutically acceptable salts thereof.
  • L is saturated, partially saturated, or unsaturated, and is chosen from -(CH 2 ) n CC— O)N(CH 2 ) n -, -
  • the phenyl group of R2 has one or more substituents chosen from halo, alkoxy, methoxy, chloro, fluoro, iodo, and bromo.
  • R2 has one or more substituents chosen from chloro and methoxy.
  • the pyrazolyl group of R2 is substituted with a cyano group.
  • the compounds of the invention include those of
  • Rl is hydro; R2 is an optionally substituted phenyl group; and R3 is a pyridinyl or pyrazolyl group; and pharmaceutically acceptable salts thereof.
  • the phenyl group of R2 has one or more substituents chosen from halo, alkoxy, methoxy, chloro, fluoro, iodo, and bromo.
  • R2 has one or more substituents chosen from chloro and methoxy.
  • the pyrazolyl group of R2 is substituted with a cyano group.
  • the R3 group in compounds of the invention is chosen from Indazole, Indazole- 1-carboxylic acid tert-butyl ester, 3-Phenyl-lH- indazole, 3-Bromo-lH-indazole, lH-Indazol-3-ylamine, 3-((E)-Styryl)-lH-indazole, lH-Indole, Benzothiazole, lH-Benzotriazole, Benzooxazole, Benzoimidazole-1- carboxylic acid tert-butyl ester, Benzoimidazole, Benzothiazole-2-thiol, 2- Methylsulfanyl-ben ⁇ othiazole,N-(2-Methoxy-phenyl)-acetamide, 3H-Benzooxazol-2- one, 4H-Benzo[l,4]oxazin-3-one, l,3-
  • Formula I) have an (lH-Indazol-6-yl)-oxazol-2-yl-amine core.
  • the substituents on this core can be chosen as in any of the other embodiements and aspects of the invention.
  • the R2 group attached to the oxazole group is chosen from Pyrimidine, Chloro-benzene, 1 ,2-Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene,
  • R-groups names are for the "free" R-group as named by Autonom 2000 with Isis chemical drawing software package (Elsevier MDL, San Ramon, CA). If the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000.
  • the compounds of the invention i.e., those of Formula I
  • the substituents on this core can be chosen as in any of the other embodiements and aspects of the invention.
  • the R2 group attached to the oxazole group is chosen from Pyrimidine, Chloro-benzene, 1 ,2-Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene, Diethyl-phenyl-amine, Benzoic acid methyl ester, Methanesulfonyl-benzene, Nitrobenzene, Phenyl-methanol, (4-Methyl-piperazin-l-yl)-phenyl-methanone, Morpholin- 4-yl-phenyl-methanone, Phenyl-pyrrolidin-1 -yl-methanone, N,N-Diethyl-benzamide, Vinyl-benzene, (E)-3-Phenyl-acrylic acid methyl ester, (Z)-3-Phenyl-acrylic acid methyl ester, napthyl,
  • the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000.
  • the other variables in the compounds of Formula I can be chosen as in any of the other aspects and embodiments of the invention.
  • Rl is an alkyl group. In some aspects of the invention Rl is a methyl group.
  • the other variables can be chosen as in any of the other aspects and embodiments of the invention.
  • the compound of Formula I is chosen from (lH-Indazol-5-yl)-(5-pyridin-2-yl-oxazol-2-yl)-amine, (lH-Indazol-5-yl)-(5-pyridin- 3-yl-oxazol-2-yl)-amme, [5-(2-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(4-Chloro-phenyl)- oxazol-2-yl]-(l H-indazol-5-yl)-amine, [5-(3,4-Dichloro-phenyl)-oxazol-2-yl]-(l H- indazol-5-yl)-amine
  • substituents may be attached to the remainder of the molecule via a number of positions and the preferred positions are as illustrated in the Examples.
  • 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- ⁇ 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, buta ⁇ oyloxy, penta ⁇ oyloxy 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.
  • Typical non-limiting examples of 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 Ci-io 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). In another aspect, it is a medium size alkyl having 1 to 10 carbon atoms. In yet another aspect, 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) can be one or more independently chosen 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.
  • Ci-io alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/-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 Ci -1O 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, 1 -methyl -2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl.
  • amino refers to an -NRi 7 Rig group, with Rn and Ri S being hydro to give an -NH 2 group.
  • Rn and Ri 8 may also be hydro, Ci-io alkyl or cycloalkyl groups, or R 17 and Rn are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and R ⁇ s are combined with the N to form a ring, such as a piperazine.
  • Rn and Ris 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 Cg -I4 aryl, preferably C O-1O aryl.
  • Typical C ⁇ -14 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
  • arylalkyl refers to any of the CL IO alkyl groups substituted by any of the above-mentioned C 6-I4 aryl groups as defined herein.
  • Non- limiting examples of arylalkyl group include benzyl, phenethyl, and naphthylmethyl.
  • arylalkenyl is used herein to mean any of the above-mentioned C2-10 alkenyl groups substituted by any of the above-mentioned C ⁇ -14 aryl groups.
  • arylalkynyl refers to any of C 2- io alkynyl groups substituted by any of the above-mentioned C6- 14 aryl groups as defined herein.
  • arylalkoxy refers to any of the Ci.1 0 alkoxy groups substituted by any of the aryl groups as defined herein, which may be optionally substituted.
  • arylalkoxy groups include benzyl oxy and phenethyloxy.
  • aryloxy refers to oxygen substituted by any of the C ⁇ -i4 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 C3-8 cycloalkyl and cycloalkenyl.
  • Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy], cyclohexenyl, and cycloheptyl.
  • cyanato refers to a -CNO group.
  • halo or halogen group refers to a fluoro, chloro, bromo and iodo group.
  • haloalkyl refers to Ci.10 alkyl groups substituted by one or more fluoro, chloro, bromo or iodo groups, e.g., fluoromethyl, difluoromethyl, trifiuoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups.
  • the halo groups can be independently chosen.
  • halophenyl refers to a phenyl group substituted with one or more fluoro, chloro, bromo or iodo groups.
  • the halo groups can be independently chosen, e.g., a di halo substituted phenyl can have a fluoro and a chloro substituent.
  • 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 heteroatorns.
  • Non-limiting heteroaryl groups include thienyl (thiophenyl), benzo[&]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, isoindolyU 3//-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl
  • heteroaryl group contains a nitrogen atom in a ring
  • such nitrogen atom may be in the form of an N- oxide, e.g., a pyridyl ⁇ T-oxide, pyrazinyl iV-oxide and pyrimidinyl N-oxide.
  • Heteroaryl groups can be monocyclic, bicyclic, tricyclic, and/or polycyclic.
  • 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, 7-10 membered bicyclic ring system, or 7-14 membered polycyclic ring system, which carbon atoms and from one to five heteroatoms independently selected from the group consisting of O, ⁇ , 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 (as is readily recognized by the skilled artisan).
  • ⁇ on-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 refers to a C MO alkoxy groups substituted by a heteroaryl group as. defined herein, which may be optionally substituted.
  • isocyanato refers to a - ⁇ CO group.
  • the term “isothiocyanato” refers to a - ⁇ CS group.
  • the term “nitro” refers to a - ⁇ O2 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.
  • Rj 7 and Ri 8 may be hydro, Ci-io alkyl or cycloalkyl groups, or Ri 7 and Ris are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and Rig are combined with the N and to form a ring, such as a piperazine.
  • One OfRi 7 and Ri 8 can be hydro and the other alkyl o ⁇ 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.
  • Ri 7 and R 18 may be hydro, C MO alkyl or cycloalkyl groups, or Ri 7 and Ri 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 OfRi 7 and Ri 8 can be hydro and the other alkyl or cycloalkyl.
  • the alkyl or cycloalkyl group may be optionally substituted.
  • Ris may be hydro;
  • Ri 7 and R] 8 may be C MO alkyl or cycloalkyl groups, or R ]7 and Rjg are combined with the N to form a ring structure, such as a piperidine, or Rn and R ⁇ are combined with the N and to form a ring, such as a piperazine.
  • One of Ri 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 R t8 may be hydro, C MO alkyl or cycloalkyl groups, or Rj 7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri 7 and Ri 8 are combined with the N and to form a ring, such as a piperazine.
  • One of Ri 7 and Rj 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 18 may ⁇ >e Cn 0 alkyl or cycloalkyl groups. The alkyl or cycloalkyl group may be optionally substituted.
  • C-amido refeis to a group.
  • Rj 7 and Ri 8 may be hydro, Ci-io alkyl or cycloalkyl groups, or Rn and R 18 are combined with the N to form a ring structure, such as a piperidine, or Rn and Rig are combined with the N and to form a ring, such as a piperazine.
  • One of Rn and R] 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-Ce acylamino, Ci-C 6 acyloxy, Ci-C 6 alkoxy, aryloxy, alkylthio, C 6 -CiO aryl, C 4 -C 7 cycloalkyl, d-C ⁇ alkenyl, C 2 -C 6 alkynyl, C6-C10 aryl(C2-C 6 )alkenyl, C 6 -Ci O aryI(C 2 -C 6 )alkynyl, saturated and unsaturated heterocyclic or heteroaryl unless otherwise specified.
  • Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, Ci-Ce haloalkyl, C 6 -Ci 0 aryl, C 4 -C 7 cycloalkyl, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -Ci 0 aryl(C ⁇ -C 6 )alkyl, C 6 -Ci 0 aryl(C 2 -C 6 )alkenyl, C 6 -C] 0 aryl(C 2 -C 6 )alkynyl, Ci-C 6 hydroxya ⁇ kyl, nitro, amino, ureido, cyano, Ci-C 6 acylamino, hydroxy, thiol, Ci-C 6 acyloxy, azido, Ci-
  • the invention also provides pharmaceutically accceaptable salts of the compounds of Formula I.
  • 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" , Ca +"1" or Ba +4 ), 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 thriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N 5 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. The inventors have discovered that the compounds of Formula I are effective in inhibiting viral infection and/or viral entry into, or viral egress from host cells.
  • 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 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. Consequently, 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.
  • Such 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 5 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 5 EIAV (equine infectious anemia virus), BIV, FIV, CAEV, VMV, and MMLV (Moloney murine leukemia virus).
  • HIV human immunodeficiency virus types 1 and 2
  • HTLV-I and HTLV-II human T-cell lymphotropic virus type 1 and 2
  • 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 ty ⁇ e-7).
  • 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 ty ⁇ e-7).
  • 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, f ⁇ loviruses, coxachievirus, coronavirus (such as SARS-associated coronavirus), Dengue viruses, yellow fever virus, hantaviruses, regional hemor
  • 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 III (also known as LAV-2), and the like.
  • HIV also known as HTLV-III
  • HIV II also known as LAV-I
  • HIV III also known as LAV-2
  • HTV 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 5 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-HTV 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-defming 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
  • 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 HP/ 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.
  • ARC AIDS-related complex
  • PDL progressive generalized lymphadenopathy
  • 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 DNA
  • 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 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 appears to adversely affect all stages of HCV infection. Particularly, HIV infection is associated with a significant increase in the development of persistent hepatitis C, with higher titers of HCV 3 more rapid progression to HCV- related liver disease, and an increased risk for HCV-related cirrhosis (scarring) of the liver. In turn, 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.htn ⁇ ).
  • 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 rype-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 HSV-2.
  • HSV-I and HSV-2 After an initial infectious cycle, HSV-I and HSV-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 HSV-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.
  • 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 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.
  • 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 nucleoprotem 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 KNA 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 vi ⁇ al 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. However, since the genetic makeup of viral strains is dynamic and ever-changing, 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.
  • Influenza pandemics or worldwide epidemics occur as a result of "antigenic shift.” 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.
  • Two categories of treatment/preventative strategies are available for influenza infection: vaccination with "the flu shot” and administration of antiviral drugs.
  • the flu shot involves vaccination with killed or inactivated influenza viruses.
  • the antiviral drugs available for treating influenza infection include 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. NC_001611). 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 Comoavirus” refers to both treating the symptoms of the disease, as well as reducing the infectivity and/or replication of the SARS-associated Coronavirus.
  • 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.
  • the methods are generally used for treating a carrier of any of the aforementioned viruses who is not experiencing an active viral outbreak.
  • the methods are generally used to treat an individual who is known or suspected to have been exposed to any of the aforementioned viruses.
  • 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, i ⁇ tegrase 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 examples 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.
  • a therapeutically effective amount of a compound of Formula I and a therapeutically effective amount of one or more other antiviral compounds provide a method according to this aspect of the invention.
  • the present invention also provides pharmaceutical compositions or medicaments useful for the above treatment and prevention purposes and having (1) a therapeutically effective amount of a compound according to Formula I and (2) 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. More preferably, 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 other diseases where the compounds show activity.
  • 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 other diseases where the compounds show activity.
  • Cancer includes, but is not limited to, bone marrow leukemia, lymphocytic leukemia, gastric cancer, breast cancer, prostate cancer, brain cancer, colon cancer, lung cancer, pancreatic cancer, liver cancer, cancer of esophangus, ovarian cancer, skin cancer, cervical cancer, orchioncus, neuroblastoma, urinary epithelial cancer, multiple myeloma, uterine cancer, melanoma, cerebral tumors 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, Pa ⁇ kinson'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 ED 50 is a parameter indicating the dose therapeutically effective in about 50% of a tested population.
  • Both LD 5 0 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 ED 50 and/or IC 50 , but significantly below the LD 50 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.
  • 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, hydrobrorhide 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,N'- 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 saff ⁇ ower 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.
  • 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. Routes of topical administration 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. ScL, 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.
  • a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity.
  • the active compound in the conjugate 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 ®
  • ALL acute lymphoblastic leukemia
  • 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.
  • Step 3 iV-(5-phenyloxazol-2-yl)-lH-indazo-5-amine
  • Examples 2 - 225 listed in the Table 1 were prepared analogously to the procedure described for Example 1 using appropriate starting materials. It is noted that some of the compounds in Table 1 are depicted as the TFA (trifiuoroacetic acid) salts. The skilled artisan readily recogonizes that these TFA salts can be converted to the free bases or other salt forms using standard organic chemistry techniques. The compounds in Table 1 that are listed as TFA salts are also meant to indicate the free base.
  • TFA trifiuoroacetic acid
  • Results from the MT-4 cytoprotection assay described in Example 236 are listed in table 3 below. These reulsts indicate that the compounds of Formula I have antiviral activity.
  • Example 232 VLP Assay 5 x 10 4 293T cells are seeded into a well of 24-well plate with 0.6 ml of fresh
  • DMEM fetal calf serum
  • Opti-MIM I medium 50 ⁇ l of Opti-MIM I medium.
  • a plasmid with HIV GAG mutated at the p6 late domain motif [pEGFP-Gag(Hl V-I /LIRL)] is diluted in the same manner.
  • Each of the diluted plasmid DNA is combined with 2 ⁇ l of LipofectAmine 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.
  • a compounds of Formula I e.g., [l-(2- Fluoro-4-nitro-phenyl)-piperidin-3-yl]-(lH-indazol-5-yl)-ami ⁇ e
  • concentrations of a compounds of Formula I are added to the transfec ted cells.
  • 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.
  • cell lysates as described above are subjected to electrophoresis in 4-12% NuPAGE Bis-Tris acrylamide gel.
  • the proteins are then transferred from the gel to a nitrocellulose membrane.
  • the blot is blocked with 5% milk in 1 X TBST for 60 min at room temperature, and then incubated in primary antibody diluted in 1 x TBST for 1 hour at room temperature.
  • the membrane is then washed and incubated for 30 min at room temperature with horseradish peroxidase (HRP) conjugated secondary antibody.
  • HRP horseradish peroxidase
  • the membrane is washed again and incubated in ECL reagent for 1 minute at room temperature.
  • the signal is detected by exposing the membrane to a film or by BioChemi system of '
  • UVP Biolmaging Systems Rabbit anti-GFP from Invitrogen is used as primary antibody.
  • 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 ju.1 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 s 293 T 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 293 T cells in each well of the plate and mixed gently by rocking. The plate is then placed at 37°C, 5% CO2 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 centrifuged at 14,000 rpm (4°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
  • Reverse Transcriptase Assay (Ouan-T-RT assay from Amersham Biosciences. Piscataway. ND 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 235 Inhibition of MMLV infectivity with compounds of Formula I
  • MMLV infectivity is assessed using the procedure of Telesnitsky A., et al.
  • results of this assay demonstrate whether or not the compounds of Formula I reduce or inhibit the infectivity of the virus MMLV.
  • 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 HTV-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.
  • M.O.I. multiplicity of infection

Abstract

Methods and pharmaceutical compositions for treating and/or delaying the onset of viral infection are provided. The pharmaceutical compositions include compounds having an oxazole core. Additionally, the compositions can be used to treat cardiovascular disorders and cancer.

Description

COMPOUNDS WITH THERAPEUTIC ACTIVITY
CROSS REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to United States provisional application number 60/754,559, filed December 27, 2005, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally compounds and pharmaceutical compositions with therapeutic activity.
BACKGROUND OF THE INVENTION
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. Although smallpox was essentially eradicated by about 1980, there is considerable justified fear of the emergence of anew 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. Additionally, emerging viral infections continue to threaten the world with human epidemics, as is illustrated by the recent outbreak of severe acute respiratory syndrome (SARS) which has now been associated with coronavirus infection. Treatments currently available for many viral infections are often associated with adverse side effects. In addition, antiviral therapeutics directed towards specific viral gene products frequently have the effect of driving the selection of viruses resistant to such therapeutics, and viral strains resistant to current methods of treatment are an increasing problem. Accordingly, there is a clear and ever-present need for new antiviral treatments. SUMMARY OF THE INVENTION
The present invention generally relates to novel compounds of Formula I and methods for treating diseases (e.g, viral infections or cancer) with these compounds. The present invention also relates to treating and/or delaying the onset of symptoms caused by a disease (e.g., viral infections) with a pharmaceutical composition having a compound of Formula I. Specifically, the inventors have discovered novel compounds of Formula I, which have antiviral activity and activity in other disease models such as cancer (see Detailed Description of the Invention for structures). Thus, the invention provides compounds of Formula I and pharmaceutical compositions having the compounds of Formula I along with a pharmaceutically acceptable carrier.
In one aspect, the invention provides a method for treating viral infection 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. In one particular embodiment of the invention, the method and composition are used to treat viral infection. In another embodiment, the method and composition are used to treat one or more symptoms of a viral infection.
In another aspect, 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. In one particular aspect of this embodiment of the invention, the method of inhibiting viral egress involves treating humans or other animals (e.g., mammals) infected with a virus.
In another aspect, the present invention relates to a method for inhibiting viral budding from a host cell by administering to the cell 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 cell. In one particular aspect of this embodiment of the invention, the method of inhibiting viral budding involves treating humans or other animals infected with a virus. In yet another aspect, methods for inhibiting viral entry are 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. In one particular aspect of this embodiment of the invention, the method of inhibiting viral entry involves treating humans or other animals infected with a virus.
In still another aspect, the present invention relates to methods for treating viral infection comprising (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. In one particular aspect of this embodiment of the invention, the method of treating viral infection involves treating humans or other animals infected with a virus.
In addition, the present invention provides methods for delaying the onset of one or more 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. In one particular aspect of this embodiment of the invention, the method of inhibiting or delaying the onset of viral infection symptoms involves treating humans or other animals infected with a virus.
In one aspect, a method is provided 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-defϊning 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 an individual in need of such treatment and administering to the individual a pharmaceutical composition or medicament having a prophylactically effective amount of a compound of Formula I. Thus, 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).
In another aspect, 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.
In another aspect, a method is provided 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.
In another aspect, a method is provided 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 an individual in need of such 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.
In yet another aspect, a method is provided 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.
In another aspect, a method is provided 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- defming 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.
In yet another aspect, a method is provided 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. In another aspect of the invention, a method is provided 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 an individual in need of such 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.
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 compounds of the invention can also exist as tautomers, and the invention includes all tatutomeric forms of these compounds.
The present invention also provides pharmaceutical compositions or medicaments for the combination treatment 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. Examples of 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 foregoing and other advantages and features of the invention, and the manner in which they are accomplished, will become more readily apparent upon consideration of the following detailed description of the invention taken in conjunction with the accompanying examples, which illustrate preferred and exemplary embodiments.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds of Formula I.
Pharmaceutical compositions having a compound of Formula I are useful for the treatment and prevention of certain diseases, like viral diseases. The compounds of the invention also have activity in several disease models including cancer. In a specific aspect of the invention, the pharmaceutical compositions are used for treating (or delaying the onset) of viral infection and particularly symptoms caused by the viral infection. Importantly, such compounds are inhibitors of host cell proteins required by viruses during their infective cycle.
In general, the invention relates to compounds of Formula I,
Figure imgf000007_0001
FORMULA I wherein:
Rl and R2 are independently chosen from hydro, or an optionally substituted - L-aryl, -L-heteroaryl, -L-heterocyclic, or -L-cycloalkyl group;
R3 is an optionally substituted -L-heterocyclic or -L-heteroaryl group; and pharmaceutically acceptable salts thereof.
L can be saturated, partially saturated, or unsaturated, and is chosen from - (CH2)n-(CH2)n-, -(CH2)nC(=O)(CH2)n-, -(CH2)nC(=O)N(CH2)n-, - (CH2)nNC(=O)O(CH2)n-, -(CH2)nNC(=O)N(CH2)n-, -(CH2)nNC(=S)S(CH2)n-, -
(CH2)nOC(=O)S(CH2)n-, -(CH2)nNH(CH2)n-, -(CH2)nO(CH2)n-, -(CH2)nS(CH2)n-, and -(CH2)nNC(=S)N(CH2)n~, where each n is independently chosen from 0, 1 , 2, 3, 4, 5, 6, 7, and 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C1-3 alkyl, and C3.6 cycloalkyl groups. In some embodiments and aspects of the invention, L is a covalent bond.
In one embodiment, the compounds of the invention, include those of Formula I wherein Rl is hydro; R2 is an aryl group chosen from phenyl, naphthyl, 1,1,4,4- tetramethyl-1 ,2,3,4-tetrahydronaphthalenyl, and phenyl substituted with one or more substituents chosen from alkyl, alkenyl, cyano, halo, alkoxy, haloalkoxy, haloalkyl, hydroxyl, diethyl amino, -CO2CH3, -SO2CH3, -NO2, -CH2OH, -C(=O)heterocyclic, - C(=O)N(CH2CH3)2, -CH=CHCO2CH3, -OC(K))CH3, methylenedioxy, ethylenedioxy, -OCHF2, -OCH2-phenyl, -OCH2CH2CH2CO2CH3, - OCH2CH2CH2CO2, -OCH2-halophenyl, -NC(=0)CH3, -SCH3, -OCH2CH2-phenyl, -O- CH2CH2-halophenyl, -C(CH3)NC(=O)CH3, -OCH2CH2OCH3, - OCH2CH2OCH2CH2OCH3, -
CH2CH2CH2C(=O)NC(CH2CH(CH3)2)(C(=O)OC(CH3)3), and - OCH2CC=O)OCH2CHa; R3 is optionally substituted with one or more optional substituents and is a heterocyclic group chosen indazolyl, IH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H- benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, lH-quinaxolin-2-one, 4H- benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro-indol-2-one, 2,3-dihydro- benzo[l,4]dioxine, thienyl (thiophenyl), benzo[έ]thienyl, naphtho[2,3-6]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, purinyl, 4/f-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1 ,4-dihydroquinoxaline-2,3-dione, 7-amino- isocoumarin, pyrido[l,2-α]pyrimidin-4-one, pyrazolo[l,5-α]pyrimidinyl, pyrazolo[l,5-α]pyrimidin-3-yl, 1 ,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, 2-oxobenzimidazolyl, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl, and tetramoyl.
In one aspect of the compounds of Formula I, R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, 1 H-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2- one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro- indol-2-one, and 2,3-dihydro~benzo[l,4]dioxrne. In one embodiment, the compounds of the invention include those of Formula
I wherein Rl is hydro; R2 is an aryl group chosen from phenyl, naphthyl, 1,1,4,4- tetramethyl-l,2,3,4-tetrahydronaphthalenyl, and phenyl substituted with one or more substituents chosen from -L-C(=O)OH, -L-CH=CHC(=O)OH, -L-C(=O)NH2, -L- C(=O)NH(C,-3 alkyl), -L-C(O)N(CL3 alkyl)2, -L-S(=O)2(C,.3alkyl), -L-SC=O)2NH2, -L-S(=O)2N(Ci.3 alkyl)2, -L-S(=O)2NH(Ci-3 alkyl), -L-C(=O)NHOH, -L- CC=O)CH2NH2, -L-C(=O)CH2OH, -L-C(=O)CH2SH, -L-CC=O)NHCN, -L- NHC(=O)ORo5 -L-C(=O)NHRo, -L-NH(C=O)NHR0, -L-C(=O)N(Ro)2, -L- NH(C=O)N(Ro)2, -L-sulfo, -L-(2,6 difluorophenol), -L-phosphono, and -L-tetrazolyl; R0 is chosen from alkyl and haloalkyl; R3 is optionally substituted with one or more optional substituents and is a heterocyclic group chosen from indazolyl, lH-indolyl, benzothiazolyl, 1 H-benzotriazolyl, benzooxazolyl, 1 H-benzoimidazolyl, 3H- benzooxazol-2-one, 4H-benzo[l ,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-όne, isoquinoline, indoline, 1,3 dihydro- indol-2-one, 2,3-dihydro-benzo[l,4]dioxine, thienyl (thiophenyl), benzo[Z>]thienyl, naphtho[2,3-ό]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H-pyrrolyl, imidazolyl, pyrazolyl. pyridyl (pyridinyl), 2-pyridyl, 3 -pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, 1,4- dihydroquinoxaline-2,3-dione, 7-aminoisocoumarin, pyrido[l,2-α]pyrimidin-4-one, pyrazolo[l,5-α]pyrimidinyl, pyrazolo[l,5-α]pyrimidin-3-yl, l,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, 2-oxobenzimidazolyl, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, moφholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl, and tetramoyl.
In one aspect of this embodiment, R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H- benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxolin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro- indol-2-oήe, 2,3-dihydro-benzo[l,4]dioxine.
In one embodiment, the compounds of the invention include those of Formula I, wherein Rl is hydro; R2 is optionally substituted with one or more optional substituents and is chosen from pyridinyl, indolyl, benzofuranyl, benzothiophene, 2,3 dihydrobenzofuran. όJ^aO.^.B.lS.lδ.lδαg-decahydro-S.S.ll.M.π^O- hexaoxacyclo-octadecene, 3,4-dihydro-2H-benzo[b][l,4]dioxepine, and indane; R3 is optionally substituted with one or more optional substituents and is a heterocyclic group chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H-benzooxazol-2-one, 4H-benzo[l,4]oxazin-3- one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4- bjpyridine, lH-quinaxolin-2-one, lH-quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1,3 dihydro-indol-2-one, 2,3-dihydro-benzo[l,4]dioxine, thienyl (thiophenyl), benzo[&]thienyl, naphtho[2,3-6]thienyl, thianthrenyl, furyl (furanyl), isobenzofuranyl, chromenyl, xanthenyl, phenoxanthiinyl, pyrrolyl, 2H- pyrrolyl, imidazolyl, pyrazolyl, pyridyl (pyridinyl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-cafbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, l,4-dihydroquinoxaline-2,3-dione, 7-amino- isocoumarin, pyrido[l,2-α]pyrimidin-4-one, pyrazolo[l,5-α]pyrimidinyl, pyrazolo[l,5-α]pyrimidin-3-yl, l,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl, 2-oxobenzimidazolyl, tetrahydrofuranyl, pyranyl, piperidinyl, piperazinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, isochromanyl, chromanyl, pyrazolidinyl, pyrazolinyl, tetronoyl, and tetramoyl.
In one aspect of this embodiment, R3 is chosen from indazolyl, lH-indolyl, benzothiazolyl, lH-benzotriazolyl, benzooxazolyl, lH-benzoimidazolyl, 3H- benzooxazol-2-one, 4H-benzo[l,4]oxazin-3-one, 1,3 dihydro-benzoimidazol-2-one, 3H-benzothialo-2-one, lH-pyrazolo[3,4-b]pyridine, lH-quinaxoIin-2-one, IH- quinaxolin-2-one, 4H-benzo[l,4]oxazin-3-one, isoquinoline, indoline, 1 ,3 dihydro- indol-2-one, and 2,3-dihydro-benzo[l,4]dioxine. In some aspects of the invention, the R2 group attached to the oxazole group of the compounds of the invention is chosen from Pyrimidine, Chloro-benzene, 1,2- Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene, Diethyl-phenyl-amine, Benzoic acid methyl ester, Methanesulfonyl-benzene, Nitro-benzene, Phenyl-methanol, (4-Methyl-piperazin-l- yl)-phenyl-methanone, MorphoIiπ-4-yl-phenyl-methanone, Phenyl-pyrrolidin- 1 -yl- methanone, N,N-Diethyl-benzamide, Vinyl-benzene, (E)-3-Phenyl-acrylic acid methyl ester, (Z)-3-Phenyl-acrylic acid methyl ester, napthyl, 1,1,4,4-tetramethyl- 1,2,3,4-tetrahydronaphthalene, phenol, 1,2-Dimethoxy-benzene, 1 ,2,3-Trimethoxy- benzene, Acetic acid 2-methoxy-phenyl ester, Benzonitrile, Benzene- 1,2-diol, 2- Methoxy-phenol, Difluoromethoxy-benzene, 6,7,9,10,12,13,15,16,18,19-Decahydro- 5,8, 11 ,14, 17,20-hexaoxa-benzocyclooctadecene, 2,3-Dihydro-benzofuran, Benzyloxy-phenyl, 1,2-Diethoxy-benzene, 4-(2-methoxy-phenoxy)-butyric acid, 4- Chloro-benzyloxy)-3-methoxy-phenyl, 3-Chloro-benzyloxy)-3-methoxy-phenyl, Benzyloxy-3-methoxy-phenyl, 4-(2-Methoxy-phenoxy)-buryric acid methyl ester, Trifluoromethoxy-benzene, 1 ,4-Dimethoxy-benzene, 1 -Bromo-4-methoxy-benzene, N-Phenyl-acetamide, 2-Methoxy-benzene-l,3-diol, Methylsulfanyl-benzene, 3- methoxy-4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl, 2-(4-Fluoro-phenyl)-ethoxy]-3- methoxy-phenyl, 1 -Iodo-2-methoxy-benzene, N-(2-Methoxy-phenyl)-acetamide, 2- Hydroxy-benzoic acid methyl ester, Benzoic acid, N-(l-Phenyl-ethyl)-acetamide, 4- Benzyloxy-3-methoxy-phenyl, 4-Chloro-benzyloxy)-4-rnethoxy-phenyl, 1-Methoxy- 2-propoxy-benzene, 1 -Methoxy-2-(2-methoxy-ethoxy)-benzene, 1 -Methoxy-2-[2-(2- methoxy-ethoxy)-ethoxy]-benzene.2-[4-(2-Methoxy-phenoxy)-butyrylamino]-4- methyl-pentanoic acid tert-butyl ester, (2-Methoxy-phenoxy)-acetic acid ethyl ester, l-Ethoxy-2 -methoxy-benzene, 1 -Isobutoxy-2-methoxy-benzene, l-Butoxy-2- methoxy-benzene, 1 -Methoxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-benzeπe, Ethyl- benzene, indan, 1,2,3,4-Tetrahydro-naphthalene, Biphenylyl, Phenylamine, 1,2- Diethyl-benzene, (2-Chloro-ethyl)-benzene, Thiophene, 2-methoxy-phenoxymethyl}- benzoic acid, 2-methoxy-phenoxymethyI} -benzoic acid methyl ester, 2-methoxy- phenoxymethyl} -benzoic acid, 2-methoxy-phenoxymethyl} -benzoic acid, l,2-Bis-[2- (2-methoxy-ethoxy)-ethoxy]-benzene, 1 ,2-Bis-(2~methoxy-ethoxy)-benzene, 4-[2-(2- Methoxy-phenoxy)-ethyl]-rnorpholine, and 3,4-Dihydro-2H-benzo[b][l ,4]dioxepine. If the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000.
In some aspects of the embodiments of the invention, the compounds of the invention include those of Formula I wherein Rl is hydro; R2 is optionally substituted with one or more optional substituents and is chosen from -L-aryl, -L-heteroaryl, -L- heterocyclic, and -L-cycloalkyl, provided R2 is not phenol (ortho), 2-aminophenyl, or 2-nitrophenyl.
In some aspects of the embodiments of the invention, the compounds of the invention include those of Formula I wherein Rl is chosen from an optionally substituted heteroaryl, heterocyclic, aryl, and cycloalkyl group, provided Rl is not phenyl, 4-(diethylamino)phenyl, or 4-methoxyphenyl; R2 is a hydro; and R3 is a heterocyclic group.
In another embodiment, the compounds of the invention include those of Formula I wherein Rl is hydro; R2 is an aryl group chosen from phenyl, naphthyl, l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene, and phenyl substituted with one or more substituents chosen from alkyl, alkenyl, cyano, halo, alkoxy, haloalkoxy, haloalkyl, hydroxyl, diethyl amino, -CO2CH3, -SO2CH3, -TSfO2, -CH2OH, - C(=O)heterocyclic, -C(O)N(CH2CH3)2, -CH=CH-CO2CH3, -O-C(=O) CH3, methylenedioxy, ethylenedioxy, -OCHF2, -O-CH2-ρhenyl, -0-CH2CH2CH2CO2CH3, - 0-CH2CH2CH2CO2, -O-CH2-halophenyl, -N-C(=O)CH3, -SCH3, -OCH2CH2-phenyl, - O-CH2CH2-haIophenyU -C(CH3)NC(=O)CH3, -OCH2CH2OCH3, - OCH2CH2OCH2CH2OCH3, -
OCH2CH2CH2C(=O)NC(CH2CH(CH3)2)(C(=O)OC(CH3)3), -OCH2C(=O)OCH2CH3, R3 is an optionally substituted indazole group; and pharmaceutically acceptable salts thereof. In another embodiment, the compounds of the invention include those of Formula I wherein Rl is hydro; R2 is an aryl group chosen from phenyl, naphthyl, l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene, and phenyl substituted with one ore more substituents chosen from alkyl, alkenyl, cyano, halo, alkoxy, haloalkoxy, haloalkyl, hydroxyl, diethyl amino, -L-C(=O)OH, -L-CH=CHCC=O)OH, -L-
CC=O)NH2, -L-CC=O)NH(C1-3 alkyl), -L-C(=O)N(CI-3 alkyl)* -L-S(=O)2(Ci-3alkyl)5 -L-SC=O)2NH2, -L-SC=O)2N(Ci-3 alkyl)2, -L-S(=O)2NH(Ci-3 alkyl), -L-C(=O)NHOH, -L-C(=O)CH2NH2, -L-C(=O)CH2OH, -L-C(=O)CH2SH, -L-CC=O)NHCN, -L- NHCC=O)OR0, -L-CC=O)NHRo, -L-NH(C=O)NHR0, -L-C(=O)NCRo)2, -L- NHCC=O)NCRO)2, -L-sulfo, -L-(2,6 difluorophenol), -L-phosphono, and -L-tetrazolyl; R3 is an optionally substituted indazole group; R0 is chosen from alkyl and haloalkyl; and pharmaceutically acceptable salts thereof.
In some aspects of the embodiments of the invention, L is saturated, and is chosen from -(CH2)n-(CH2)n-, -CCH2)nCC=O)CCH2)n-, -CCH2)nNHCCH2)n-, - CCH2)nO(CH2)n-, -CCH2)nSCCH2)n-, where each n is independently chosen from 0, 1, 2, and 3 and wherein each carbon can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C 1-3 alkyl, and C3-G cycloalkyl groups.
In some aspects of the embodiments of the invention, L is saturated, partially saturated, or unsaturated, and is chosen from -(CH2)nCC— O)N(CH2)n-, -
(CH2)nNC(=O)OCCH2)n-, -CCH2)nNCC=O)NCCH2)n-, -CCH2)nNCC=S)S(CH2)n-, - CCH2)nOCC=O)SCCH2)n-, and -CCH2)nNC(=S)NCCH2)n-, where each n is independently chosen from 0, 1, 2, and 3, and wherein each carbon can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, C]-3 alkyl, and C3-6 cycloalkyl groups.
In some aspects of the embodiments of the invention, L is saturated, and is chosen from -CCH2)n-CCH2)n-, -(CH2)nCC=O)CCH2)n-, -CCH2)nNH(CH2)n-, - (CH2)nOCCH2)n-, -CCH2)nSCCH2)n-, where each n is independently chosen from 0, 1, 2, and 3. In some aspects of the embodiments of the invention, L is saturated, partially saturated, or unsaturated, and is chosen from -CCH2)nCC=O)NCCH2)n-, - CCH2)nNCC=O)OCCH2)π-, -(CH2)nNCC=O)N(CH2)n-, -(CH2)nNCC=S)SCCH2)n-, - CCH2)nOCC=O)SCCH2)n-, and -CCH2)πNCC=S)NCCH2)n-, where each n is independently chosen from O, 1, 2, and 3. ; In another embodiment, the compounds of the invention include those of Formula I wherein Rl is hydro; R2 is an optionally substituted phenyl group; and R3 is a phenyl group with one or more substituents independently chosen from methoxy, cyano, -NC(=O)CH3, -NCC=O)OR0, -NC(=S)CH3, -NH2, -NC(=O)-L-heterocyclic; and pharmaceutically acceptable salts thereof. In one aspect of this embodiment, the phenyl group of R2 has one or more substituents chosen from halo, alkoxy, methoxy, chloro, fluoro, iodo, and bromo. In yet another aspect of this embodiment, R2 has one or more substituents chosen from chloro and methoxy. In one aspect of this embodiment, the pyrazolyl group of R2 is substituted with a cyano group. In another embodiment, the compounds of the invention include those of
Formula I wherein Rl is hydro; R2 is an optionally substituted phenyl group; and R3 is a pyridinyl or pyrazolyl group; and pharmaceutically acceptable salts thereof. In one aspect of this embodiment, the heterocyclic group of — NC(=O)-L-heterocyclic is chosen from an optional substituted piperazinyl, morpholino, piperidinyl, or pyrrolidinyl group. In another aspect of this embodiment, the phenyl group of R2 has one or more substituents chosen from halo, alkoxy, methoxy, chloro, fluoro, iodo, and bromo. In yet another aspect of this embodiment, R2 has one or more substituents chosen from chloro and methoxy. In one aspect of this embodiment, the pyrazolyl group of R2 is substituted with a cyano group. In some aspects of the invention, R3 is an indazole group with one or more substituents chosen from -C(=O)OC(CH3)3, phenyl, halo, -NH2, and -CH=CH- phenyl.
In some aspects of the invention, the R3 group in compounds of the invention is chosen from Indazole, Indazole- 1-carboxylic acid tert-butyl ester, 3-Phenyl-lH- indazole, 3-Bromo-lH-indazole, lH-Indazol-3-ylamine, 3-((E)-Styryl)-lH-indazole, lH-Indole, Benzothiazole, lH-Benzotriazole, Benzooxazole, Benzoimidazole-1- carboxylic acid tert-butyl ester, Benzoimidazole, Benzothiazole-2-thiol, 2- Methylsulfanyl-benκothiazole,N-(2-Methoxy-phenyl)-acetamide, 3H-Benzooxazol-2- one, 4H-Benzo[l,4]oxazin-3-one, l,3-Dihydro-benzoimidazol-2-one, Phenyl- carbamic acid methyl ester, 3H-Benzothiazol-2-one, N-Benzothiazol-2-yl-acetamide, lH-Quinoxalin-2-one, 3-Oxo-3,4-dihydro-quinoxaline-2-carboxylic acid methyl ester, 4H-Benzo[l,4]oxazin-3-one, Isoquinoline, pyrimidine, 1 ,2-Dimethoxy-benzene, Methoxy-benzene, lH-Pyrazole-4-carbonitrile, 4-Ethyl-pyridine, indan, 2,3-Dihydro- lH-indole, 3-[l-Pyridin-4-yl-meth-(Z)-ylidene]-l,3-dihydro-indol-2-one, 1,3- Dihydro-indol-2-one, 3H-Benzooxazol-2-one, 1 -Phenyl- lH-imidazole, 2-Methyl-3H- quinazolin-4-one, 2-(2-Oxo-benzooxazol-3-yl)-acetamide, phenol, 2-Amino-phenol, 2-Oxo-2,3-dihydro-21ambda*6*-benzo[l,2,3]oxathiazol-2-ol, Benzo[l,3]dioxole, 1- (2,3-Dihydro-indol-l-yI)-ethanone, 1 -Methyl- lH-indazoIe, 2-MethyI-3aH-indazole, 3 -Methyl- lH-indazole, l,3-Dihydro-indol-2-one, 2-Amino-quinazolin-4-ol,
Quinoline, 2-Methyl-3H-quinazolin-4-one, 2-Mθφholin-4-yl-N-phenyl-acetamide, N- Phenyl-2-piperidin-l -yl-acetamide, and 2-(3-Hydroxy-pyrrolidin-l -yI)-N-phenyl- acetamide. These R-groups names are for the "free" R-group as named by Autonom 2000 with Isis chemical drawing software package (Elsevier MDL, San Ramon, CA). In some aspects of the invention, the compounds of the invention (i.e., those of
Formula I) have an (lH-Indazol-6-yl)-oxazol-2-yl-amine core. The substituents on this core can be chosen as in any of the other embodiements and aspects of the invention. In a specific aspect of this embodiment, the R2 group attached to the oxazole group is chosen from Pyrimidine, Chloro-benzene, 1 ,2-Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene,
Diethyl-phenyl-amine, Benzoic acid methyl ester, Methanesulfonyl-benzene, Nitrobenzene, Phenyl-methanol, (4-Methyl-piperazin-l-yl)-phenyl-methanone, Morpholin- 4-yl-phenyl-methanone, Phenyl-pyrrolidin- 1 -yl-methanone, N,N-Diethyl-benzamide, Vinyl-benzene, (E)-3-Phenyl-acrylic acid methyl ester, (Z)-3-Phenyl-acrylic acid methyl ester, napthyl, l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene, phenol, 1,2- Dimethσxy-benzene, 1,2,3-Trimethoxy-benzene, Acetic acid 2-methoxy-phenyl ester, Benzonitrile, Benzene-l,2-diol, 2-Methoxy-phenol, Difluoromethoxy-benzene, 6,7,9,10,12,13,15,16,18,19-Decahydro-5,8,ll,14,17,20-hexaoχa- benzocyclooctadecene, 2,3-Dihydro-benzofuran, Benzyloxy-phenyl, 1 ,2-Diethoxy- benzene, 4-(2-methoxy-phenoxy)-butyric acid, 4-Chloro-benzyloxy)-3-methoxy- phenyl, 3-Chloro-benzyloxy)-3-rnethoxy-phenyl, Benzyl oxy-3-methoxy-phenyl, 4-(2- Methoxy-ρhenoxy)-butyric acid methyl ester, TrifJuoromethoxy-benzene, 1 ,4- Dimethoxy-benzene, l-Bromo-4-methoxy-benzene, N-Phenyl-acetamide, 2-Methoxy- benzene- 1 ,3-diol, Methylsulfanyl-benzene, 3-methoxy-4-[2-(4-methoxy-phenyl)- ethoxy]-phenyl, 2-(4-Fluoro-phenyl)-ethoxy]-3-methoxy-phenyl, 1 -Iodo-2-methoxy- benzene, N-(2-Methoxy-phenyl)-acetamide, 2-Hydroxy-benzoic acid methyl ester, Benzoic acid, N-(l-Phenyl-ethyl)-acetamide, 4-Benzyloxy-3-methoxy-phenyl, A- Chloro-benzyloxy)-4-methoxy-phenyl, 1 -Methoxy-2-propoxy-benzeπe, l-Methoxy-2- (2-methoxy-ethoxy)-benzene, l-Methoxy-2-[2-(2-methoxy-ethoxy)-ethoxy]-benzene, 2-[4-(2-Methoxy-phenoxy)-butyrylamino]-4-methyl-pentanoic acid tert-butyl ester, (2-Methoxy-phenoxy)-acetic acid ethyl ester, 1 -Ethoxy-2-methoxy-benzene, 1- Isobutoxy-2-methoxy-benzene, 1 -Butoxy-2-methoxy-benzene, 1 -Methoxy-2-[2-(2- methoxy-ethoxy)-ethoxy] -benzene, Ethyl-benzene, indan, 1, 2,3,4 -Tetrahydro- naphthalene, Biphenylyl, Phenylamine, 1 ,2-Diethyl-benzene, (2-Chloro-ethyl)- benzene, Thiophene, 2-methoxy-phenoxymethyl} -benzoic acid* 2-methoxy- phenoxymethyl} -benzoic acid methyl ester, 2-methoxy-phenoxymethyl} -benzoic acid, 2-methoxy-phenoxymethyl} -benzoic acid, l,2-Bis-[2-(2-methoxy-ethoxy)- ethoxy]-benzene, 1 ,2-Bis-(2-methoxy-ethoxy)-benzene, 4-[2-(2-Methoxy-phenoxy)- ethyl]-morpholine, and 3,4-Dihydro-2H-benzo[b][l,4]dioxepine. These R-groups names are for the "free" R-group as named by Autonom 2000 with Isis chemical drawing software package (Elsevier MDL, San Ramon, CA). If the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000.
In some aspects of the invention, the compounds of the invention (i.e., those of Formula I) have an (lH-Indazol-5-yl)-oxazol-2-yl-amihe core. The substituents on this core can be chosen as in any of the other embodiements and aspects of the invention. In a specific aspect of this embodiment, the R2 group attached to the oxazole group is chosen from Pyrimidine, Chloro-benzene, 1 ,2-Dichloro-benzene, fluoro-benzene, toluene, Methoxy-benzene, phenyl, Trifluoromethyl-benzene, Diethyl-phenyl-amine, Benzoic acid methyl ester, Methanesulfonyl-benzene, Nitrobenzene, Phenyl-methanol, (4-Methyl-piperazin-l-yl)-phenyl-methanone, Morpholin- 4-yl-phenyl-methanone, Phenyl-pyrrolidin-1 -yl-methanone, N,N-Diethyl-benzamide, Vinyl-benzene, (E)-3-Phenyl-acrylic acid methyl ester, (Z)-3-Phenyl-acrylic acid methyl ester, napthyl, l,l,4,4-tetramethyl-l,2,3,4-tetrahydronaphthalene, phenol, 1,2- Dimethoxy-benzene, 1,2,3-Trimethoxy-benzene, Acetic acid 2-methoxy-phenyl ester, Benzonitrile, Benzene-l,2-diol, 2-Methoxy-phenol, Difluoromethoxy-benzene, 6,7,9,10,12,13,15,16,18,19-Decahydro-5,8,11,14,17,20-hexaoxa- benzocyclooctadecene, 2,3-Dihydro-benzofuran, Benzyloxy-phenyl, 1,2-Diethoxy- benzene, 4-(2-methoxy-phenoxy)-butyric acid, 4-Chloro-benzyloxy)-3-methoxy- phenyl, 3-Chloro-benzyloxy)-3-methoxy-phenyl, Benzyloxy-3-methoxy-phenyl, 4-(2- Methoxy-phenoxy)-butyric acid methyl ester, Trifluoromethoxy-benzene, 1 ,4- Dimethoxy-benzene, l-Bromo-4-methoxy-benzene, N-Phenyl-acetamide, 2-Methoxy- benzene-1 ,3-diol, Methylsulfanyl-benzene, 3-methoxy-4-[2-(4-methoxy-phenyl)- ethoxy] -phenyl, 2-(4-Fluoro-phenyl)-ethoxy]-3-methoxy-phenyl, 1 -Iodo-2-methoxy- benzene, N-(2-Methoxy-phenyl)-acetamide, 2-Hydroxy-benzoic acid methyl ester, Benzoic acid, N-(l-Phenyl-ethyl)-acetamide, 4-Benzyloxy-3-methoxy-phenyl, 4- Chloro-benzyloxy)-4-methoxy-phenyl, l-Methoxy-2-propoxy-benzene, l-Methoxy-2- (2-methoxy-ethoxy)-benzene, 1 -Methoxy-2-[2-(2-methoxy-ethoxy)-ethoxy] -benzene, 2-[4-(2-Methoxy-phenoxy)-butyrylamino]-4-methyl-pentanoic acid tert-butyl ester, (2-Methoxy-phenoxy)-acetic acid ethyl ester, l-Ethoxy-2-methoxy-benzene, 1- Isobutoxy-2-methoxy-benzene, 1 -Butoxy-2-methoxy-benzene, 1 -Methoxy-2-[2-(2- methoxy-ethoxy)-ethoxy]-benzene, Ethyl -benzene, indan, 1 ,2,3,4-Tetrahydro- naphthalene, Biphenylyl, Phenylamine, 1 ,2-Diethyl-benzene, (2-Chloro-ethyl)- benzene, Thiophene, 2-methoxy-phenoxymethyl} -benzoic acid, 2-methoxy- phenoxymethyl} -benzoic acid methyl ester, 2-methoxy-phenoxymethyl} -benzoic acid, 2-methoxy-phenoxymethyl} -benzoic acid, 1 ,2-Bis-[2-(2-methoxy-ethoxy)- ethoxy]-benzene, l,2-Bis-(2-methoxy-ethoxy)-benzene, 4-[2-(2-Methoxy-phenoxy)- ethyl]-morpholine, and 3,4-Dihydro-2H-benzo[b][l,4]dioxepine. If the software was not able to identify the group (e.g., it cannot select priority for naming convention for the free form of the R-group in compounds like Example number 171), the R-groups were derived from the full-name of the compound as named by Autonom 2000. In some aspects of the invention, the nitrogen atom linking R3 to the oxazole ring is replaced with an — NC(=S)N- group. The other variables in the compounds of Formula I can be chosen as in any of the other aspects and embodiments of the invention.
In some aspects of the invention, Rl is an alkyl group. In some aspects of the invention Rl is a methyl group. The other variables can be chosen as in any of the other aspects and embodiments of the invention.
In one aspect of the invention, the compound of Formula I is chosen from (lH-Indazol-5-yl)-(5-pyridin-2-yl-oxazol-2-yl)-amine, (lH-Indazol-5-yl)-(5-pyridin- 3-yl-oxazol-2-yl)-amme, [5-(2-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(4-Chloro-phenyl)- oxazol-2-yl]-(l H-indazol-5-yl)-amine, [5-(3,4-Dichloro-phenyl)-oxazol-2-yl]-(l H- indazol-5-yl)-amine, [5-(3-Fluoro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-(5-p-tolyl-oxazol-2-yl)-amine, (lH-Indazol-5-yl)-[5-(4-methoxy- phenyl)-oxazol-2-yl]-amine, [5-(4-Bromo-phenyl)-4-methyl-oxazol-2-yl]-( 1 H- indazol-5-yl)-amine, (4,5-Diphenyl-oxazol-2-yl)-(lH-indazol-5-yl)-amine, [5-(4- Bromo-phenyl)-oxazol-2-yl]-( 1 H-indazol-5-yl)-amine, [5-(4-Fluorophenyl)-oxazol-2- yl]-(lH-indazol-5-yl)-amine, [5-(4-Fluoro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)- amine, [5-(4-Bromo-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, 4-[2-(1H-
Indazol-5-ylamino)-oxazol-5-yl]-benzoic acid methyl ester, (lH-Indazol-5-yl)-[5-(4- methanesulfonyl-phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5-yl)-[5-(3-nitro-phenyl)- oxazol-2-yl]-amine, (lH-Indazol-5-yl)-[5-(2-methoxy-phenyl)oxazol-2-yl]-amine, (lH-Indazol-5-yl)-(4-methyl-5-phenyl-oxazol-2-yl)-amine, 5-[5-(3-Nitro-phenyl)- oxazol-2-ylamino]-indazole-l-carboxylic acid tert-butyl ester, 5-[5-(4-
Methanesulfonyl-phenyl)-oxazol-2-ylamino]-indazole-l -carboxylic acid tert-butyl ester, 5-[5-(4-Bromo-phenyl)-oxazol-2-ylamino]-indazole-l -carboxylic acid tert-butyl ester, {4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-phenyl}-methanoI, {4-[2-(lH- Indazol-5-ylamino)-oxazol-5-yl]-phenyl}-(4-methyl-piperazin-l-yl)-methanone, {4- [2-(1H Indazol-5-ylamino)-oxazol-5-yl]-phenyl}-morpholin-4-yl-methanone, {4-[2- (1 H-Indazol-5-ylamino)-oxazol-5-yl]-phenyl} -pyrrolidin-1 -yl-methanoτie, N,N- Diethyl-4-[2-(lH-indazol-5-ylamino)-oxazol-5-yl]-benzamide, 5-[5-(4-Vinyl-phenyl)- oxazoI-2-yIamino]-indazole-l -carboxylic acid tert-butyl ester, 5-[5-(4-Vinyl-phenyl)- oxazol-2-ylamino]-indazole-l-caτboxylic acid tert-butyl ester, 5-{5-[4-((E)-2- Methoxycarbonyl-viny])-phenyl]-oxazol-2-ylamino}-indazole-l -carboxylic acid tert- butyl ester, 5-[5-(4-Methoxycarbonyl-phenyl)-oxazol-2-ylaminoj-indazole-l - carboxylic acid tert-butyl ester, (lH-Indazol-5-yl)-(5-naphthalen-2-yl-oxazol-2-yl)- amine, (lH-Indazol-5-yl)-[5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)- oxazol-2-yI]-arnine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(3-phenyl-lH-indazoI-5-yl)- amine, 4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-phenol, (3-Bromo-lH-indazol-5- yl)-[5-(4-chloro-phenyl)-oxazol-2-yl]-amine, N*5*-[5-(4-Chloro-phenyl)-oxazol-2- yI]-lH-indazole-3,5-diamine, (lH-Indazol-5-yl)-[5-(2,3,4-trimethoxy-phenyl)-oxazol- 2-yl]-amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(4- Chloro-phenyl)-oxazol-2-yl]-[3-((E)-styryl)-lH-indazol-5-yl]-amine, (5- Benzo[l ,3]dioxol-5-yl-oxazol-2-yl)-(lH-indazol-5-yl)-amine, Acetic acid 4-[2-(l H- indazol-5-ylamino)-oxazol-5-yl]-2-rnethoxy-phenyl ester, 3-[2-(lH-IndazoI-5- ylamino)-oxazol-5-yl]-benzonitrile, 4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]- benzonitrile, (5-Benzofuran-2-yl-oxazol-2-yl)-(l H-indazol-5-yl)-amine, (1H-Indazol- 5-yl)-[5-(lH-indol-2-yl)-oxazol-2-yl]-amine, (5-Benzo[b]thiophen-2-yl-oxazol-2-yl)- (lH-indazol-5-yl)-amine, 4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-benzene-l,2- diol, (1 H-Indazol-5-yl)-[5-(3,4,5-trimethoxy-phenyl)-oxazol-2-yl]-amine, [5-(2,3- Dihydro-benzofuran-5-yl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, 4-[2-(lH-IndazoI-5- ylamino)-oxazol-5-yl]-2-methoxy-phenol, [5-(4-Benzyloxy-phenyl)-oxazol-2-yl]- (lH-indazol-5-yl)-amine, [5-(4-Difluoromethoxy-phenyl)-oxazol-2-yl]-(lH-indazol- 5-yl)-amine, [5-(6,7,9,10,12,13,15,16,18,19-Decahydro-5,8,ll,14,17,20-hexaoxa- benzocyclooctadecen-2-yl)-oxazol-2-yl] -(I H-indazol-5-yl)-amine, [5 -(3 ,4-Diethoxy- phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, 4-{4-[2-(lH-Indazol-5-ylamino)- oxazol-5-yl]-2-methoxy-phenoxy}-butyric acid methyl ester, 4-{4-[2-(lH-Indazol-5- ylamino)-oxazol-5-yl]-2-methoxy-phenoxy}-butyric acid, {5-[4-(4-Chloro- benzyloxy)-3-methoxy-phenyl]-oxazol-2-yl}-(lH-indazol-5-yl)-amin.e, {5-[4-(3- Chloro-benzyloxy)-3-methoxy-phenyl]-oxazol-2-yl} -(I H-indazol-5-yl)-amine, [5-(4- Benzyloxy-3-methoxyphenyl)-oxazol-2-yl]-(l H-indazol-5-yl)-amine, ( 1 H-Indazol-6- yl)-(5-phenyl-oxazol-2-yl)-amine, ( 1 H-Indazol-6-yl)-(5-pyridin-2-yl-oxazol-2-yl)- amine, (lH-Indazol-6-yl)-(5-pyridin-3-yl-oxazol-2-yl)-amine, [5-(3-Chloro-ρhenyl)- oxazol-2-yl]-( 1 H-indazol-6-yl)-amine, ( 1 H-Indazol-6-yl)-(5-p-tolyl-oxazol-2-yl)- amine, [5-(2-Chloro-phenyl)-oxazol-2-yl]-(l H-indazol-6-yl)-amine, (1 H-Indazol-6- yl)-[5-(4-methoxy-phenyl)-oxazol-2-yl]-amiτie, ( 1 H-Indazol-6-yl)-(5-p-tolyl-oxazol- 2-yl)-amine, (lH-Indazol-6-yl)-[5-(4-trifluoromethyl-phenyl)-oxazol-2-yl]-amine, [5- (4-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-6-yl)-amine, [5-(4-Diethylamino- phenyI)-oxazol-2-ylj-(lH-indazol-6-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]- ( 1 H-indazol-7-yl)-amine, 1 -( 1 H-Indazol-5-yl)-3-(5-phenyl-oxazol-2-yl)-thiourea, 1 - (lH-Indazol-6-yl)-3-(5-phenyl-oxazol-2-yl)-thiourea, (lH-Indol-4-yl)-(5-phenyl- oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indol-4-yl)-amine, Benzothiazol-5-yl-(5-phenyl-oxazol-2-yl)-amine, Benzothiazol-5-yl-[5-(4-chloro- phenyl)-oxazol-2-yl]-amine, Benzothiazol-6-yl-[5-(4-chloro-phenyl)-oxazol-2-yl]- amine, ( 1 H-Indol-7-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol- 2-yl]-(lH-indol-7-yl)-amine!, (1 H-Indol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4- Chloro-phenyl)-oxazol-2-yl]-(l H-indol-5-yl)-amine, (1 H-Benzotriazol-5-yl)-(5- phenyl-oxazol-2-yl)-amine, (lH-Benzotriazol-5-yl)-[5-(4-chloro-phenyl)-oxazol-2yl]- amine, Benzooxazol-6-yl-(5-phenyl-oxazol-2-yl)-amine, Benzooxazol-6-yl-[5-(4- chloro-phenyl)-oxazol-2-yl]-amine, 5-(5-Phenyl-oxazol-2-ylamino)-benzoimidazole- 1-carboxylic acid tert-butyl ester, 5-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]- benzoimidazole-1-carboxylic acid tert-butyl ester, (lH-Benzoimidazol-5-yl)-[5-(4- chloro-phenyl)-oxazol-2-yl]-amine, ( 1 H-Benzoimidazol-5-y l)-(5-phenyl-oxazol-2-yl)- amine, 6-(5-Phenyl-oxazol-2-ylamino)-benzothiazole-2-thiol, 6-[5-(4-Chloro-phenyl)- oxazol2-ylamino]-benzothiazole-2-thiol, (2-Methylsulfanyl-benzothiazol-6-yl)-(5- ρhenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyI)-oxazol-2-yl]-(2-methylsulfanyl- benzothiazol-6-yl)-amine, N-[2-Methoxy-4-(5-ρhenyl-oxazol-2-ylamino)-phenyl]- acetamide, 6-(5-Phenyl-oxazol-2-ylamino)-3H-benzooxazol-2-one, 6-[5-(4-Chloro- phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 6-Chloro-7-(5-phenyl-oxazol-2- ylamino)-4H-benzo[l,4Joxazin-3-one, 6-Chloro-7-[5-(4-chloro-phenyl)-oxazol-2- ylamino]-4H-benzo[l ,4]oxazin-3-one, 5-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-l ,3- dihydro-benzoimidazol-2-one, 5-(5-Phenyl-oxazol-2-ylamino)- 1 ,3-dihydro- benzoimidazol-2-one, [4-(5-Phenyl-oxazol-2-ylamino)-plienyl]-carbamic acid methyl ester, {4-[5-(4-Chloro-pheπyl)-oxazol-2-ylamino]-phenyl}-carbamic acid methyl ester, 6-(5-Phenyl-oxazol-2-ylaτnino)-3H-benzothiazol-2-one56-[5-(4-Chloro- phenyl)-oxazol-2-ylamino]-3H-benzothiazol-2-one, N-{6-[5-(4-Chloro-phenyl)- oxazol-2-ylamino]-benzothiazol-2-yl}-acetamide, N-[6-(5-Phenyl-oxazol-2-ylamino)- benzothiazol-2-yl]-acetamide, Compound Example No. 109, [5-(4-Chloro-ρhenyl)- oxazol-2-yl]-(lH-pyrazolo[3,4-b]pyridin-5-yl)-amine, (5-Phenyl-oxazol-2-yl)-(lH- pyrazoIo[3,4-b]pyridin-5-yl)-amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH- pyrazolo[3,4-b]pyridin-5-yl)-amine, 6-(5-Phenyl-oxazol-2-ylamino)-lH-quinoxaIin-2- one, Isoquinolin-5-yl-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2- yl]-isoquinoIin-5-yl-amine, 7-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-3-oxo-3,4- dihydro-quinoxaline-2-carboxylic acid methyl ester, 7-(5-Benzo[l,3]dioxol-5-yl- oxazol-2-ylamino)-4H-benzo[ 1 ,4]oxazin-3-one, 7-[5-(3,4-Dimethoxy-phenyl)-oxazol- 2-ylamino]-4H-benzo[l,4]oxazin-3-one, [5-(4-Chloro-phenyl)-oxazol-2-yl]-pyridin-3- yl-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-pyridin-4-yl-amine, [5-(4-Chloro- phenyl)-oxazol-2-yl]-pyridin-2-yl-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(3,4- dimethoxy-phenyl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(4-methoxy-phenyl)- amine, 3-[5-(3,4-Dimethoxy-phenyl)-oxazol-2-ylamino]-lH-pyrazole-4-carbonitrile, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-pyridin-3-ylmethyl-amine, [5-(3,4- Dimethoxy-phenyl)-oxazol-2-yl]-pyridin-4-ylmethyl-amine, 6-(5-Phenyl-oxazol-2- ylamino)-4H-benzo[l,4]oxazin-3-one, 6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-4H- benzo[l ,4]oxazin-3-one, Indan-5-yl-(5-phenyl-oxazol-2-yl)-amine, 7-[5-(4-Chloro- phenyl)-oxazol-2-ylamino]-4H-benzo[ 1 ,4]oxazin-3-one, 7-(5-Phenyl-oxazol-2- ylamino)-4H-benzo[l,4]oxazin-3-one, (2,3-Dihydro-lH-indol-5-yl)-(5-phenyl-oxazol- 2-yl)-amine, 7-[5-(4-Fluoro-phenyl)-oxazol-2-ylamino]-4H-benzo[ 1 ,4]oxazin-3-one5 7- [5 -(4-Trifluoromethoxy-phenyl)-oxazol-2-ylamino]-4H-benzo [ 1 ,4] oxazin-3 -one, 7- [5-(4-Diethylamino-phenyl)-oxazol-2-ylamino]-4H-benzo[l,4]oxazin-3-one, 5-(5- Phenyl-oxazoI-2-ylamino)-3-[l-pyridin-4-yI-meth-(Z)-ylidene]-l,3-dihydro-indol-2- one, 5-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-l,3-dihydro-indol-2-one, (4-
Imidazol- 1 -yl-phenyl)-(5-phenyl-oxazol-2-yl)-amine, 6-[5~(4-Chloro-phenyl)-oxazol- 2-ylamino]-2-methyl-3H-quinazolin-4-one, 6- [5-(3 ,4-Dimethoxy-phenyl)-oxazol-2- ylamino]-3H-benzooxazol-2-one, 6-[5-(4-Fluoro-phenyl)-oxazol-2-ylamino]-3H- benzooxazol-2-one, 6-(5-Benzo[l,3]dioxol-5-yl-oxazol-2-ylamino)-3H-benzooxazol- 2-one,6-(5-p-Tolyl-oxazol-2-ylamino)-3H-benzooxazol-2-one, 6-[5-(2,5-Dimethoxy- phenyl)-oxazol-2-ylaτnino]-3H-benzooxazol-2-one, 6-[5-(2,3-Dihydro- benzo[l,4]dioxin-6-yl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 6-[5-(4- Trifluoromethoxy-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 2-[2-Oxo-5-(5- phenyl-oxazol-2-ylamino)-benzooxazol-3-yl]-acetamide, 2-{5-[5-(4-Chloro-phenyl)- oxazol-2-ylamino]-2-oxo-benzooxazol-3-yl}-acetamide, 6-[5-(3,4-Dihydro-2H- benzo[b][l,4]dioxepin-7-yl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 6-[5-(3- Methoxy-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 6-[5-(3,5-Dimethoxy- phenyl)-oxazol-2-ylamino]-3H-benzooxazo]-2-one, ( 1 H-Indazol-5-yl)-[5-(3-methoxy- phenyl)-oxazol-2-yl]-amine, [5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-oxazol-2-yI]- (lH-indazol-5-yl)-amine, [5-(3,4-Dihydro-2H-benzo[b][l ,4]dioxepin-7-yl)-oxazol-2- yl]-(lH-indazol-5-yl)-amine, [5-(2,3-Dihydro-benzo[l,4]dioxin-5-yl)-oxazol-2-yl]- (1 H-indazol-5-yl)-amine, [5-(2,4-Dimethoxy-phenyl)-oxazol-2-yl]-(l H-indazol-5-yl)- amine, [5-(5-Bromo-2-methoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, N-{4- [2-( 1 H-Indazol-5-ylamino)-oxazol-5-yl]-phenyl} -acetamide, 4-[2-( 1 H-IndazoJ-5- ylarnino)-oxazol-5-yl]-2-methoxy-benzene-l ,3-diol, (1 H-Indazol-5-yl)-[5-(4- methylsulfanyl-phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5-yl)-(5-{3-methoxy-4-[2- (4-methoxy-phenyl)-ethoxy]-phenyl}-oxazol-2-yl)-amine, (5-{4-[2-(4-Fluoro- phenyl)-ethoxy]-3-methoxy-phenyl}-oxazol-2-yl)-(lH-indazol-5-yl)-amine> (IH- Indazol-5-yl)-[5-(3-iodo-4-methoxy-phenyl)-oxazol-2-yl]-amine, N-{5-[2-(lH- Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenyl}-acetamide, 2-Hydroxy-5-[2- (lH-indazol-5-ylamino)-oxazol-5-yl]-benzoic acid methyl ester, 4-[2-(lHIndazoI-5- ylamino)-oxazol-5-yl]-benzoic acid, N-((R)-1 - {4-[2-(lH-Indazol-5-ylamino)-oxazol- 5-yl]-phenyl}-ethyl)-acetamide, 3-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-benzoic acid, N-((S)-1 - {4-[2-(l H-Indazol-5-ylamino)-oxazoI-5-yl]-phenyl} -ethyl)-acetamide, [5-(3-Benzyloxy-4-methoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, {5-[3-(4- Chloro-benzyloxy)-4-methoxy-phenyl]-oxazol-2-yl}-(lH-indazol-5-yl)-amine, [5-(3- Ethoxy-4-methoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)- [5-(4-methoxy-3-propoxy-phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5-yl)-{5-[4- methoxy-3-(2-methoxy-ethoxy)-phenyl]-oxazol-2-yl}-amine, (lH-Indazol-5-yl)-(5- {4-methoxy-3-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-oxazol-2-yl)-amine, (R)-2-(4- {4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenoxy}-butyrylamino)-4- methyl-pentanoic acid tert-butyl ester, {4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2- methoxy-phenoxy} -acetic acid ethyl ester, [5-(4-Ethoxy-3-methoxy-phenyl)-oxazol- 2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(4-isobutoxy-3-methoxy- phenyl)-oxazol-2-yl] -amine, ol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-(5- {3-methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-oxazol-2-yl)-amine, [5-(4- Ethyl-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (5-Indan-5-yl-oxazol-2-yl)-(lH- indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(5,6,7,8-tetrahydro-naphthalen-2-yl)- oxazol-2-yl]-amine, (5-Biphenyl-4-yl-oxazol-2-yl)-(lH-indazol-5-yl)-amine, 2- Amino-5-[5-(4-chloro-phenyl)-oxazol-2-ylamino]-phenol, [5-(4-Chloro-phenyl)- oxazol-2-yl]-(2,2-dioxo-2,3-dihydro-21ambda*6*-benzo[l,2,3]oxathiazol-6-yl)- amine, (1 H-Indazol-5-yl)-[5-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-amine, [5-(4- Difluoromethoxy-phenyl)-oxazol-2-yl] -( 1 H-indazol-5-yl)-amine, [5-(4-Amino- phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3,4-Diethyl-phenyl)-oxazol-2-yl]- (lH-indazol-5-yl)-amine, {5-[4-(2-Chloro-ethyl)-phenyl]-oxazol-2-yl}-(lH-indazol-5- yl)-amine, Benzo[l ,3]dioxol-5-yl-(5-phenyl-oxazol-2-yl)-amine, Benzothiazol-6-yl- (5-phenyl-oxazol-2-yl)-amine, -phenyl)-oxazol-2-yl]-amine, (1 H-Indol-6-yl)-(5- phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indol-6-yl)- amine, l-{6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-2,3-dihydro-indol-l-yl}- ethanone, (lH-Indazol-5-yl)-(5-thiophen-2-yl-oxazol-2-yl)-amine, (1 -Methyl-1H- indazol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(2- methyl-2H-indazol-5-yl)-amine, 5-(5-Phenyl-oxazol-2-ylamino)-l,3-dihydro-indol-2- one, (3-Methyl-lH-indazol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, 2-Amino-6-[5-(4- chloro-phenyl)-oxazol-2-ylamino]-quinazolin-4-ol, [5-(4-Chloro-phenyl)-oxazol-2- yl]-quinolin-6-yl-amine, 7-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-2-methyl-3H- quinazolin-4-one, [5-(3 ,4-Dimethoxy-phenyl)-oxazol-2-yl]-(l H-indazol-6-yl)-amine, (1 H-Indazol-5-yl)- {5-[4-methoxy-3-(2-methoxy-ethoxy)-phenyl]-oxazol-2-yl} -amine, 3-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-ρhenoxymethyl}-benzoic acid, 4-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenoxymethyl}- benzoic acid methyl ester, 4-{4-[2-(lH-Indazol-5-ylarnino)-oxazol-5-yl]-2-methoxy- phenoxyτnethyl}-benzoic acid, 3-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2- methoxy-phenoxymethyl}-benzoic acid, (5-{3,4-Bis-[2-(2-methoxy-ethoxy)-ethoxy]- phenyl}-oxazol-2-yl)-(lH-indazol-5-yl)-amine, {5-[3,4-Bis-(2-methoxy-ethoxy)- phenyl]-oxazol-2-yl}-(lH-indazol-5-yl)-amine} (lH-Indazol-5-yl)-[5-(3- trifluoromethyl"phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5-yl)-{5-[3-methoxy-4-(2- morpholin-4-yl-ethoxy)-phenyl]-oxazol-2-yl}-amine, (l H-Benzotriazol-5-yl)-[5-(3,4- dimethoxy-ρhenyl)-oxazol-2-yl]-amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]- (lH-indol-6-yl)-amine, Benzothiazol-5-yl-[5-(3,4-dimethoxy-phenyl)-oxazol-2-yl]- amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indol-7-yl)-amine, [5-(3,4- Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indol-5-yl)-amine, [5-(3,4-Dimethoxy-phenyl)- oxazol-2-yl]-(lH-indazol-7-yl)-amine5 [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH- indol-4-yl)-amine, Benzooxazol-6-yl-[5-(3,4diτnethoxy-phenyl)-oxazol-2-yl]-amine, Compound Example number 226, Compound Example number 227, Compound
Example number 228, Compound Example number 229, Compound Example number 230, and Compound Example number 231. These compound names were derived from the compound examples using Autonom 2000.
As is understood by the skilled artisan, certain variables in the list of substituents are repetive (different name for the same substituent), generic to other terms in the list, and/or partially overlap in content with other terms. For example, pyridyl (pyridinyl) is generic to 2-pyridyl, 3-pyridyl, and 4-pyridyl, which are all listed together in some lists of R-groups disclosed herein. In some lists of R-groups disclosed herein, some groups are not listed as the — yl form, but rather as the free, unbonded form (e.g., imidazole and imidazolyl, which are considered equivalent in this disclosure when listed as an R-group). In the compounds of the invention, the skilled artisan recognizes that substituents (R-groups) may be attached to the remainder of the molecule via a number of positions and the preferred positions are as illustrated in the Examples.
Specific examples of the compounds of Formula I are given in the Examples.
The invention also includes pharmaceutical compositions having one or more compounds of Formula I and one or more pharmaceutically acceptable carrier. As used herein, "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-β acylamino groups, e.g., benzoylamido, and pentafluorobenzoylamido.
As used herein, "acyloxy" groups are any Ci -6 acyl (alkanoyl) as definided herein, attached to an oxy (— O— ) group, e.g., formyloxy, acetoxy, propionoyloxy, butaπoyloxy, pentaπoyloxy and hexanoyloxy.
As used herein, the term "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. Typical non-limiting examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl and 2-butenyl. As used herein, the term "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 Ci-io 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. As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon including straight chain and branched chain groups. In one aspect, 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). In another aspect, it is a medium size alkyl having 1 to 10 carbon atoms. In yet another aspect, 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. When substituted, the substituent group(s) can be one or more independently chosen 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. Typical non-limiting examples of Ci-io alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/-butyl, 3-pentyl, hexyl and octyl groups, which may be optionally substituted.
As used herein, the term "alkylthio" group 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 Ci-1O alkyl groups mentioned above, which may be optionally substituted. Also included are the sulfoxides and sulfones of such alkylthio groups.
As used herein, the term "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, 1 -methyl -2-propynyl, 2-propynyl, 1- butynyl and 2-butynyl.
As used herein, the term "amino" refers to an -NRi7 Rig group, with Rn and RiS being hydro to give an -NH2 group. Independently, Rn and Ri8 may also be hydro, Ci-io alkyl or cycloalkyl groups, or R17 and Rn are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Rιs are combined with the N to form a ring, such as a piperazine. One of Rn and Ris can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "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 Cg-I4 aryl, preferably CO-1O aryl. Typical Cβ-14 aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylenyl and fluorenyl groups.
As used herein, the term "arylalkyl" refers to any of the CLIO alkyl groups substituted by any of the above-mentioned C6-I4 aryl groups as defined herein. Non- limiting examples of arylalkyl group include benzyl, phenethyl, and naphthylmethyl.
As used herein, the term "arylalkenyl" is used herein to mean any of the above-mentioned C2-10 alkenyl groups substituted by any of the above-mentioned Cβ-14 aryl groups. As used herein, the term "arylalkynyl" refers to any of C2-io alkynyl groups substituted by any of the above-mentioned C6-14 aryl groups as defined herein.
As used herein, the term "arylalkoxy" refers to any of the Ci.10 alkoxy groups substituted by any of the aryl groups as defined herein, which may be optionally substituted. Examples of arylalkoxy groups include benzyl oxy and phenethyloxy. As used herein, the term "aryloxy" refers to oxygen substituted by any of the Cβ-i4 aryl groups defined herein, which may be optionally substituted. Examples of aryloxy groups include phenoxy and 4-methylphenoxy.
As used herein, the term "arylthio" group refers to both an -S-aryl and an -S- heteroaryl group, as defined herein.
As used herein, the term "carbocycle" or "carbocyclic" refers to cycloalkyl and partially saturated carbocyclic groups. Non-limiting carbocyclic groups are C3-8 cycloalkyl and cycloalkenyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexy], cyclohexenyl, and cycloheptyl. As used herein, the term "cyano" refers to a -C ≡=N group.
As used herein, the term "cyanato" refers to a -CNO group.
As used herein, the term "halo" or "halogen group" refers to a fluoro, chloro, bromo and iodo group.
As used herein, the term "haloalkyl" refers to Ci.10 alkyl groups substituted by one or more fluoro, chloro, bromo or iodo groups, e.g., fluoromethyl, difluoromethyl, trifiuoromethyl, pentafluoroethyl, 1,1-difluoroethyl, chloromethyl, chlorofluoromethyl and trichloromethyl groups. The halo groups can be independently chosen.
As used herein, the term "halophenyl" refers to a phenyl group substituted with one or more fluoro, chloro, bromo or iodo groups. The halo groups can be independently chosen, e.g., a di halo substituted phenyl can have a fluoro and a chloro substituent.
As used herein, the term "hydro" refers to an -H group.
As used herein, the term "hydroxyl" refers to an -OH group. As used herein, the term "heteroaryl" refers to groups having 5 to 14 ring atoms; 6, 10 or 14 π electrons shared in a cyclic array; and containing carbon atoms and 1, 2 or 3 oxygen, nitrogen or sulfur heteroatorns. Non-limiting heteroaryl groups include thienyl (thiophenyl), benzo[&]thienyl, naphtho[2,3-δ]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, isoindolyU 3//-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalzinyl, naphthyridinyl, quinozalinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acrindinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, l,4-dihydroquinoxaline-2,3-dione, 7-amino- isocoumarin, pyrido[l,2-α]pyrimidin-4-one, pyrazolo[l,5-α]pyrimidinyl, including without limitation pyrazolo[l,5-α]pyrimidin-3-yl, l,2-benzoisoxazol-3-yl, benzimidazolyl, 2-oxindolyl and 2-oxobenziτnidazolyl. Where the heteroaryl group contains a nitrogen atom in a ring, such nitrogen atom may be in the form of an N- oxide, e.g., a pyridyl ΛT-oxide, pyrazinyl iV-oxide and pyrimidinyl N-oxide. Heteroaryl groups can be monocyclic, bicyclic, tricyclic, and/or polycyclic. As used herein, the term "heteroaryloxy" refers to oxygen substituted by a heteroaryl group as defined herein, which may be optionally substituted. Νon- limiting heteroaryloxy groups include pyridyloxy, pyrazinyloxy, pyrrolyloxy. pyrazolyloxy, imidazolyloxy and thiophenyloxy.
As used herein, the term "heterocycle" or heterocyclic" refers to a saturated or partially saturated 3-7 membered monocyclic, 7-10 membered bicyclic ring system, or 7-14 membered polycyclic ring system, which carbon atoms and from one to five heteroatoms independently selected from the group consisting of O, Ν, 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 (as is readily recognized by the skilled artisan). Νon-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.
As used herein, the term "heteroarylalkoxy" refers to a C MO alkoxy groups substituted by a heteroaryl group as. defined herein, which may be optionally substituted. As used herein, the term "isocyanato" refers to a -ΝCO group.
As used herein, the term "isothiocyanato" refers to a -ΝCS group. As used herein, the term "nitro" refers to a -ΝO2 group. As used herein, the term "sulfinyl" refers to a -S(=O)R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "sulfonyl" refers to a -S(=O)2R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "sulfonamido" refers to a -S(=O)2 NRj7RiS. Independently, Rj7 and Ri8 may be hydro, Ci-io alkyl or cycloalkyl groups, or Ri7 and Ris are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Rig are combined with the N and to form a ring, such as a piperazine. One OfRi7 and Ri 8 can be hydro and the other alkyl oτ cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "thiocarbonyl" group refers to a -C(=S)R" group. R" can be a cycloalkyl or alkyl group. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "thiocyanato" refers to a -CNS group.
As used herein, the term "trihalomethanesulfonamido" refers to a XaCSC=O)2 NRi7 -group with X being independently chosen from -Br, -Cl, -F, and -I groups and Ri7 is as defined herein. As used herein, the term "O-carbamyl" refers to a -OC(=O)NRi7 Rig group.
Ri7 and R18 may be hydro, CMO alkyl or cycloalkyl groups, or Ri7 and Ri8 are combined with the N to form a ring structure, such as a piperidine, or Rj7 and Ri8 are combined with the N and to form a ring, such as a piperazine. One OfRi7 and Ri8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "N-carbamyl" refers to a Ri8θC(=O)NRi7- group. Ris may be hydro; Ri7 and R]8 may be CMO alkyl or cycloalkyl groups, or R]7 and Rjg are combined with the N to form a ring structure, such as a piperidine, or Rn and R^ are combined with the N and to form a ring, such as a piperazine. One of Ri7 and Rj8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "O-thiocarbamyl" refers to a -OC(=S)NRi7R]8 group. Ri7 and Rt8 may be hydro, CMO alkyl or cycloalkyl groups, or Rj7 and Rig are combined with the N to form a ring structure, such as a piperidine, or Ri7 and Ri8 are combined with the N and to form a ring, such as a piperazine. One of Ri7 and Rj8 can be hydro and the other alkyl or cycloalkyl. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "N-thiocarbamyl" refers to a Ri7OC(=S)NRis- group. Ri7 may be hydro; R17 and R18 may \>e Cn0 alkyl or cycloalkyl groups. The alkyl or cycloalkyl group may be optionally substituted.
As used herein, the term "C-amido" refeis to a
Figure imgf000029_0001
group. An "N-amido" refers to a Ri7C(=O)NRi8- group (Rj8 is not hydro). Rj7 and Ri8 may be hydro, Ci-io alkyl or cycloalkyl groups, or Rn and R18 are combined with the N to form a ring structure, such as a piperidine, or Rn and Rig are combined with the N and to form a ring, such as a piperazine. One of Rn and R]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-Ce acylamino, Ci-C6 acyloxy, Ci-C6 alkoxy, aryloxy, alkylthio, C6-CiO aryl, C4-C7 cycloalkyl, d-Cβ alkenyl, C2-C6 alkynyl, C6-C10 aryl(C2-C6)alkenyl, C6-CiO aryI(C2-C6)alkynyl, saturated and unsaturated heterocyclic or heteroaryl unless otherwise specified. Optional substituents on the aryl, arylalkyl, arylalkenyl, arylalkynyl and heteroaryl and heteroarylalkyl groups include one or more halo, Ci-Ce haloalkyl, C6-Ci0 aryl, C4-C7 cycloalkyl, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-Ci0 aryl(Cι-C6)alkyl, C6-Ci0 aryl(C2-C6)alkenyl, C6-C]0 aryl(C2-C6)alkynyl, Ci-C6 hydroxyaϊkyl, nitro, amino, ureido, cyano, Ci-C6 acylamino, hydroxy, thiol, Ci-C6 acyloxy, azido, Ci-C6 alkoxy, carboxy or Ci-2 alkylenedioxy (e.g., methylenedioxy) unless otherwise specified.
The invention also provides pharmaceutically accceaptable salts of the compounds of Formula I. 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. Their hydrates (1 hydrate, 2 hydrate, 3 hydrate, 1/2 hydrate, 3/2 hydrate, 1/4 hydrate, 4/5 hydrate, 1/5 hydrate, 3/4 hydrate, 1/3 hydrate, 5/3 hydrate, 5/4 hydrate etc.), solvates and the like are also encompassed in the compound of the present invention. In addition, N-oxide compounds are also encompassed in the compound of the present invention.
In addition, 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", Ca+"1" or Ba+4), 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 thriethylamine, N,N-diethylamine, N,N-dicyclohexylamine, pyridine, N5N- 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-ene (DBU).
Additionally, the compounds of Formula I can contain asymmetric carbon atoms and can therefore exist in racemic and optically active forms. Thus, 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. The inventors have discovered that the compounds of Formula I are 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.
Thus, in one aspect, 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. For example, 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 a compound of Formula I, preferably in a pharmaceutical composition having a pharmaceutically acceptable carrier.
In another aspect, 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. Alternatively, 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. Consequently, 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. Such 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), SIV5 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 tyρe-7). 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, fϊloviruses, coxachievirus, coronavirus (such as SARS-associated coronavirus), Dengue viruses, yellow fever virus, hantaviruses, regional hemorrhagic fever viruses, molluscum virus, poliovirus, rabiesvirus, etc. In preferred embodiments, 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. In more preferred embodiments, the methods are used in treating or preventing infections by enveloped viruses. In specific embodiments, as described below, particular viruses known to infect humans and cause disease are treated by the methods of the present invention.
HIV:
As used herein, the term "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 III (also known as LAV-2), and the like. "HTV" can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV family. Thus, 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 AIDS5 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. For example, a person can be identified as HIV carrier on the basis that the person is anti-HTV 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-defming illnesses and/or a decline in the circulating CD4 T-cell count to below a level that is compatible with effective immune function). As used herein, 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 HP/ 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. As is known in the art, 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.
In addition, 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/μl) 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. The term "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/μl). 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.
HBV:
As used herein, the term "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. Thus, 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. For example, 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. Hence, "treating HBV infection" should be understood as treating a patient who is at any one of the several stages of HBV infection progression. In addition, the term "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. The term "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.
In yet another aspect, 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. Particularly, 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. Particularly, the compounds are especially effective in inhibiting HBV infection and/or egress. Moreover, 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. Thus, in accordance with the present invention, 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.
The term "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:
As used herein, the term "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. Thus, 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. For example, 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). Hence, "treating HCV infection" should be understood as treating a patient who is at any one of the several stages of HCV infection progression. In addition, the term "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. The term "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. The term of "preventing HCV" as used herein 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.
Importantly, about one quarter of all HIV-infected persons in the United States, or an estimated 200,000 people, are infected with both HCV and HIV (See National Center for HIV, STD and TB Prevention report at http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm and Thomas, D.L. Hepatology 36:S201 -S209 (2002)). As the lives of HIV-infected persons have been prolonged by use of highly active antirerroviral therapy, liver disease has emerged as an important, and in some settings, the leading cause of morbidity and mortality.
HIV infection appears to adversely affect all stages of HCV infection. Particularly, HIV infection is associated with a significant increase in the development of persistent hepatitis C, with higher titers of HCV3 more rapid progression to HCV- related liver disease, and an increased risk for HCV-related cirrhosis (scarring) of the liver. In turn, 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.htnϊ). In the United States, two different treatment regimens have been approved as therapy for chronic hepatitis C: monotherapy with alpha interferon and combination therapy with alpha interferon and ribavirin. Among HIV-negative persons with chronic hepatitis C, combination therapy consistently yields higher rates (30%-40%) of sustained response than monotherapy (10%-20%). Combination therapy is more effective against viral genotypes 2 and 3, and requires a shorter course of treatment; however, viral genotype 1 is the most common among U.S. patients. Combination therapy is associated with more side effects than monotherapy, but, in most situations, it is preferable. At present, interferon monotherapy is reserved for patients who have contraindications to the use of ribavirin. (See, http://www.cdc.gov/hiv/pubs/facts/HIV-HCV_Coinfection.htm)
Hence, in yet another aspect, 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. Particularly, the compounds are especially effective in inhibiting HCV infection and/or egress from host cells. Moreover, the compounds are also effective in inhibiting HIV entry into and/or egress (particularly budding) from host cells. In contrast to the combination therapy described above, the compounds according to the present invention are significantly less toxic, and are less like to result in evolved viral resistance. Thus, in accordance with the present invention, 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: 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 rype-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 HSV-2. After an initial infectious cycle, HSV-I and HSV-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.
In addition to oral and genital herpes, HSV-I and HSV-2 can cause other diseases. Examples of such 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). Thus, 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. Currently there is no known cure for HSV-I infection. The available antiviral therapies are not completely effective and there is a chance that the virus will become resistant to the treatment. Thus, there is a clear need for improved methods and compositions for treating HSV-I .
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). 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.
Scientists are finding it difficult to explain why the virus causes a relatively mild disease like glandular fever in some people and malignant tumors in others.
Genetic factors may play a role. Regardless, treatments are needed to combat EBV. As used herein, the terms "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). Thus, "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.
As used herein, the term "HSV infection" generally encompasses infection of a human by any strain of herpes simplex virus, and includes both active and latent infections. Thus, "treating HSV infection" means the treatment of a person who is a carrier of any strain of HSV. For example, 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. Hence, "treating HSV infection" should be understood as treating a patient who is at any one of the several stages of HSV infection progression. In addition, the term "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. The term "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.
In yet another aspect, 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. Particularly, 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. Particularly, the compounds are especially effective in inhibiting HSV infection and/or egress. Moreover, 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. Thus, in accordance with the present invention, 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.
The term "delaying the onset of HSV-associated symptoms" as used herein 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:
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.
All three types of influenza virus have genomes composed of eight different RNA helices, which encodes a single gene and are bound by a nucleoprotem that determines the viral type: A, B, or C. In effect, 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 KNA 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 viτal 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. However, since the genetic makeup of viral strains is dynamic and ever-changing, 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.
Epidemics of influenza are thought to result when viral strains change over time by the process of antigenic drift. Antigenic drift (caused by mutations in the principal viral antigen genes, especially in the hemagglutinin or neuramidase genes) 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. Influenza pandemics (or worldwide epidemics) occur as a result of "antigenic shift." 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. In support of the antigenic shift hypothesis presented above, 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. Two categories of treatment/preventative strategies are available for influenza infection: vaccination with "the flu shot" and administration of antiviral drugs. The flu shot involves vaccination with killed or inactivated influenza viruses. The antiviral drugs available for treating influenza infection include 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.
Despite the numerous drugs and vaccinations available, there is a need for improved methods and compositions for both treating and preventing influenza infection.
As used herein, the term "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.
Poxviruses:
As used herein, the terms "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 15th Edition Principles of Internal Medicine, Braunwald et al. EDS. McGraw-Hill, United States, and Genbank accession no. NC_001611). Skilled artisans are capable of diagnosing individuals infected or suspected of being infected with smallpox. The term "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. The term of "delaying the onset of symptoms associated with smallpox infection" as used herein 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. The term "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).
An outbreak of monkeypox occurred for the first time in the United States ih June of 2003. The causative agent is the monkeypox virus, which belongs to the group of viruses that includes the smallpox virus (variola), the virus used in the smallpox vaccine (vaccinia), and the cowpox virus. In humans, 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. In Africa, where most cases of monkeypox are known to occur, infections result in deaths of between 1% and 10% of infected individuals. As used herein, 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.
Coronaviruses:
As used herein, the terms "SARS-CoV", "SARS" or "SARS-associated Coronavirus" refers to any strain of coronavirus associated with severe acute respiratory syndrome. Examples of such 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. The term "treating SARS" or "treating SARS associated Comoavirus" 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. The term of "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).
West Nile 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. In one embodiment, 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.
In one particular embodiment, 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/μl). For example, 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). In one aspect, 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. Examples of such other antiviral compounds include, but are not limited to, protease inhibitors, nucleoside reverse transcriptase inhibitors, non- nucleoside reverse transcriptase inhibitors, iπtegrase 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. As used herein, "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. For example, in the case of HIV, 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. Other indications for non-responding patients may include, e.g., persistent decline of CD4 T-cell numbers, adverse drug reaction or toxicity, and clinical deterioration. Thus, 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.
In another embodiment, 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.
In addition, 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. For example, in delaying the onset of 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. Preferably, an amount is used sufficient to delay the onset of acute viral infection by at least 12 months, 18 months or 24 months.
In addition, 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. For purposes of preventing viral infection, treating asymptomatic viral infection, delaying the onset of symptomatic viral infection, or treating symptomatic viral infection, 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. Examples of such other 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. Additionally, 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. However, it is to be understood that 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 provide a method according to this aspect of the invention.
Accordingly, the present invention also provides pharmaceutical compositions or medicaments useful for the above treatment and prevention purposes and having (1) a therapeutically effective amount of a compound according to Formula I and (2) a therapeutically effective amount of one or more other antiviral compounds.
Preferably, such other antiviral compounds have a different mode of action than that of the compounds according to Formula I. More preferably, 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. Preferably, 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.
Other Disease Indications 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 other diseases where the compounds show activity. Cancer includes, but is not limited to, bone marrow leukemia, lymphocytic leukemia, gastric cancer, breast cancer, prostate cancer, brain cancer, colon cancer, lung cancer, pancreatic cancer, liver cancer, cancer of esophangus, ovarian cancer, skin cancer, cervical cancer, orchioncus, neuroblastoma, urinary epithelial cancer, multiple myeloma, uterine cancer, melanoma, cerebral tumors 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, Paτkinson'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. Generally, the toxicity profile and therapeutic efficacy of the therapeutic agents can be determined by standard pharmaceutical procedures in suitable cell models or animal models. As is known in the art, the LD50 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 LD50 and ED50 can be determined in cell models and animal models. In addition, the IC50, 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. Typically, as will be apparent to skilled artisans, the dosage range for human use should be designed such that the range centers around the ED50 and/or IC50, but significantly below the LD50 obtained from cell or animal models.
Typically, compounds according to Formula I can be effective at an amount of from about 0.01 μg/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 μg to about 2000 mg, preferably from about 5 μg to about 1000 mg. In the case of combination therapy, 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. It should be understood that the dosage ranges set forth above are exemplary only and are not intended to limit the scope of this 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.
In the pharmaceutical compositions, the active agents can be in any pharmaceutically acceptable salt form. As used herein, the term "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. Examples of salts of basic active ingredient compounds include, but are not limited to, hydrochloride salts, hydrobrorhide 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. See, e.g., Berge, et al. J. Pharm. Set, 66:1-19 (1977). Examples of salts of acidic active ingredient compounds include, e.g., alkali metal salts, alkaline earth salts, and ammonium salts. Thus, suitable salts may be salts of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. In addition, organic salts may also be used including, e.g., salts of lysine, N,N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine and tris.
For oral delivery, 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). The formulation can be orally delivered in the form of enclosed gelatin capsules or compressed tablets. Capsules and tablets can be prepared in any conventional techniques. The capsules and tablets can also be coated with various coatings known in the art to modify the flavors, tastes, colors, and shapes of the capsules and tablets. In addition, liquid carriers such as fatty oil can also be included in capsules.
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. In addition, for convenient administration by enteral feeding tube in patients unable to swallow, the active compounds can be dissolved in an acceptable lipophilic vegetable oil vehicle such as olive oil, corn oil and saffϊower 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. In such formulations, 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. For example, 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. Routes of topical administration include nasal, bucal, mucosal, rectal, or vaginal applications. For topical administration, the active compounds can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols. Thus, 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. For purposes of this invention, hydrogels made of polyethylene glycols, collagen, or poly(glycolic-co-L-lactic acid) may be useful. See, e.g., Phillips et al., J. Pharmaceut. ScL, 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. For example, an active compound is covalently linked to polyethylene glycol to form a conjugate. Typically, such a conjugate exhibits improved solubility, stability, and reduced toxicity and immunogenicity. Thus, when administered to a patient, the active compound in the conjugate 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. For example, PEGylated interferon (PEG- INTRON A®) is clinically used for treating Hepatitis B. PEGylated adenosine deaminase (ADAGEN®) is being used to treat severe combined immunodeficiency disease (SCIDS). 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. Such other 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.
EXAMPLES
ABBREVIATIONS AND ACRONYMS
Figure imgf000053_0001
Figure imgf000054_0001
General Experimental for Synthetic Methods
Chemicals were purchased from standard commercial vendors. Abbreviations are consistent with those in the ACS Style Guide., plus: satd (saturated), DCM (dichloromethane), "dry" glassware means oven/desiccator dried. Solvents were ACS grade unless otherwise noted. Analytical TLC plates (Silica Gel 60 F254, EM Science, Gibbstown, NJ, or Merck # 5715) were used to follow the course of reactions, and the MPLC system used for purifications was from Isco (Foxy Jr fraction collector, UA-6 detector), using Isco silica gel flash columns (10 or 40 g). 1H NMR spectra in CDCl3, CD3OD, and/or d6-DMSO were recorded on either a Varian Mercury 400 MHz or Brucker ARX-300 MHz instrument and chemical shifts are expressed in parts per million (ppm, δ) relative to TMS as the internal standard. Mass spectra were obtained on a Thermo Finnigan LCQ-Deca (injection volume 5 uL, XTerra MS-Ci8 3.5 μm 2.1 x 50mm column, XTerra MS-Ci8 5 μm 2.1 x 20mm guard column), ESI source, analytical HPLC was performed on an HP 1050 (injection volume 5 μl, XTerra RP-C is 5 μm 4.6 x 250 mm column, with an XTerra MS-Ci8 5 μm 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. GCMS was performed on either an Agilent Technology 6890N or Shimadzu
QP5000/17A instrument. Yields are not optimized. Chemical reagents used to create the novel products of the invention listed in the table are all available commercially. Otherwise their preparation is facile and known to one of ordinary skill in the art or it is referenced.
General Synthetic Route to Examples 1-225
Scheme 1
Figure imgf000056_0001
Example 1 Step l:
5-isothiocyanato-l /7-indazole
To a solution of 5-aminoindazole (2.0 g, 15 mmol) in CH2Cl2 (120 mL) was added thiocarbodiimidazole (2.7 g, 15 mmol) or l ',l '-thiocarbonyldi-2(lH)-pyridone. After stirring for 2 h at it, the mixture was concentrated and the residue was purified by coulumn chromatography on SiO2 (3:7 ethyl acetate:hexane) to afford the isothiocyanate 2 (1.7 g, 64%) as pale yellow solid; 1H NMR (DMSO-^j) δ 13.37 (s, IH), 7.61 (d, J = 8.8 Hz, IH), 7.40 (dd, J = 8.8, 2.0 Hz, IH), 8.13 (s, IH), 7.91 (d, J = 2.0 Hz, IH).
Step 2:
2-azido-l-phenylehanone (4)
To a solution of 2 (1.0 g, 5.0 mmol) in acetone (6 mL) and H2O (3 mL) was added
NaN3 (0.326 g, 5.02 mmol). The mixture was stirred at 50 °C for 30 min and concentrated. The residue was diluted with EtOAc (30 mL), and the product portion was washed with H2θ/brine. The organic layer was dried (Na2SO4) and concentrated to provide the azide 4 (0.938 g, 92%); 1H NMR (DMSO-^) δ 7.95 (m, IH), 7.93 (m, IH), 7.69 (tt, J = 7.6, 1.2 Hz, IH), 7.58-7.53 (m, 2H), 4.90 (s, 2H).
Step 3: iV-(5-phenyloxazol-2-yl)-lH-indazo-5-amine
Figure imgf000057_0001
A mixture of 2 (0.200 g, 1.14 mmol), 4 (0.183 g, 1.14 mmol) and PPh3 (0.229 g, 1.14 mmol) or PPh3-polymer bound in dioxane (2 mL) was heated at 90 0C for 30 min. After cooling to rt, the reaction mixture was filtered. The cake was washed with CH2Cl2/ether and air-dried to afford the product (0.196 g, 62%). (Alternative work-up method: The reaction mixture was acidified with 6 N HCl (5 mL) and washed with EtOAc (10 mL x 3). The aqueous layer was neutralized with 20% KOH and the product portion was extracted with EtOAc in several times. The combined organic layers were concentrated in vacuum. The residue was washed with CH2Cl2 and dried to provide the title product.
1H NMR (DMSO-d6) δ 10.27 (s, IH), 8.21 (s, IH)5 8.02 (s, IH), 7.61-7.57 (m, 2H), 7.51-7.41 (m, 5H), 7.27 (t, J= 7.2 Hz, IH); LC-MS m/z 277 [M+H]+.
Various isothiocyanates were prepared according to the procedure described in step 1 of Example 1 from the corresponding amines. Substituted ot- haloketones were purchased commercially or prepared from substituted acetophenones (J. Med. Chem., 17, 49 (1974); J. Org. Chem., 29, 3459(1964; , J. Org. Chem, 65, 583 (2000); Chem. Commun., 488 (2002) ). The acyl azides were prepared analogously to the procedure described in step 2 of Example 1.
Examples 2 - 225 listed in the Table 1 were prepared analogously to the procedure described for Example 1 using appropriate starting materials. It is noted that some of the compounds in Table 1 are depicted as the TFA (trifiuoroacetic acid) salts. The skilled artisan readily recogonizes that these TFA salts can be converted to the free bases or other salt forms using standard organic chemistry techniques. The compounds in Table 1 that are listed as TFA salts are also meant to indicate the free base.
Table 1
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
General Synthetic Route to Examples 226-231 Scheme 2
Figure imgf000095_0001
Example 226
{4-[5-(4-chlorophenyl)-oxazole-2-ylamino]-phenyI}carbamic acid tert-butyl ester} To a solution of (4-isothiocyanato-phenyl)-carbamic acid tert-butyl ester (9.06 g, 36.2 mmole) and 2-azido-l-(4-chlorophenyl)-ethanone (7.08 g, 36.2 mmol) in dioxane (181 mL) was added triphenylphosphine polymer-bound resin (14.5 g, 43.4 mmol; ~3 mmol/g). After 5 min, the resulting mixture was heated at 85 0C for 1.5 h. After cooling to rt, the mixture was diluted with THF (—500 mL), filtered, and washed with THF (~300 mL). The combined fϊlterates were concentrated in vacuo. The residue was purified by tritulation with CH2Cl2 (~70 mL) to afford the title product .(7.64 g, 55%). LC-MS m/z 386 [M+H]+ Example 227 N-f5-(4-chIorophenyI)-oxazol-2-yl]beπzene)-4-diamine To a suspension of {4-[5-(4-chlorophenyl)-oxazole-2-ylamino]-phenyl}carbamic acid tert-butyl ester (7.64 g, 19.8 mmol) in CH2Cl2 (76 mL) was added TFA (30.5 mL) at 0 0C. The resulting mixture was allowed to rt and stirred for 1O h. The solvent was concentrated in vacuo. The title compound (10.11 g, quantitative) was obtained by an azeotropic removal of residual TFA with toluene followed by trituration with Et2O. 1H NMR (DMSOd6) δ 9.79 (s, IH), 7.54 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.44 (s, IH), 7.27 (d, J = 8.4 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H); LC-MS m/z 286 [M+H]+
2-bromo-N-{4-[5-(4-chIorophenyl)-oxazol-2-ylamino]-phenyIacetamide To a suspension of N-[5-(4-chlorophenyl)-oxazol-2-yl]benzene)-4-diamine (2.16 g, 4.20 mmol) in CH2Cl2 (28 mL) was added bromacetyl bromide (549 μL, 6.31 mmol) and NEt3 (1.75 mL, 12.6 mmole) at 00C. The resulting mixture was stirred at the same temperature for 1 h. Two batches were combined, quenched with water, and extracted with ethyl acetate. The organic layers were washed with water/brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the product (2.70 g). The crude product was used in the next step. Example 228
N-{4-f5-(4-chIorophenyI)-oxazol-2-ylamino]-phenyl}-2-(4-methylpiperazin-l-lyI)- acetamide To a suspension of 2-bromo-N-{4-[5-(4-chlorophenyl)-oxazol-2-ylamino]-phenylacetamide (2.70 g, 6.64 mmol) in dioxane (17 mL) was added N-methyl piperazine (2.95 mL, 26.5 mmol) dropwise at rt. The resulting mixture was stirred for 15 h at rt. After concentration in vacuo, the product portion was extracted with CH2Cl2. The extracts were washed with satd. NH4CI, brine, dried (Na2SO4), filtered, and concentrated. The two samples were combined and were purified in two batches by column chromatography (95:5 CH2Cl2/MeOH, SiO2) to provide the title compound (1.06 g, 25%); 1H NMR (DMSO-d6) δ 10.30 (s, IH), 9.58 (s, IH), 7.60-7.55 (m, 6H), 7.51- 7.48 (m, 3H), 3.08 (s, 2H), 2.51-2.49 (m, 4H), 2.40-2.33 (m, 4H), 2.17 (s, 3H); LC- MS m/z 426 [M+H]+.
Using the method described above for Example 228 and substituting the appropriate starting materials Examples 229-231 similarly prepared and are shown in Table 2 Table 2
Figure imgf000097_0001
Results from the MT-4 cytoprotection assay described in Example 236 are listed in table 3 below. These reulsts indicate that the compounds of Formula I have antiviral activity.
Table 3 MT4 Cytoprotection Assay Results
Figure imgf000097_0002
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Example 232: VLP Assay 5 x 104 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. On the day of transfection, 0.6 μg of pEGFP-Gag(HIV-l) plasmid DNA is diluted with 50 μl of Opti-MIM I medium. The same amount of a plasmid with HIV GAG mutated at the p6 late domain motif [pEGFP-Gag(Hl V-I /LIRL)] is diluted in the same manner. Each of the diluted plasmid DNA is combined with 2 μl of LipofectAmine 2000 reagent (Invitrogen) in 50 μl 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)-amiπe) are added to the transfec ted cells.
An aliquot of post-transfection cell culture medium is collected and passed through a 0.45 μm syringe filter and centrifuged in 20% sucrose 14,000 rpm at 4°C for 90 minutes. The supernatant is removed but for about 20 μl. The residue is resuspended with Hank's Balanced Salt Solution (Invitrogen, Carlsbad, CA) and is used in the p24 ELISA assay described below.
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. For HIV-I p24 ELISA assays, kits 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 370C 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 μl of Stop Solution to all wells. The plate is read at 490 nm within 15 minutes after stop.
For immunoblot assay to detect protein expression, cell lysates as described above are subjected to electrophoresis in 4-12% NuPAGE Bis-Tris acrylamide gel.
The proteins are then transferred from the gel to a nitrocellulose membrane. The blot is blocked with 5% milk in 1 X TBST for 60 min at room temperature, and then incubated in primary antibody diluted in 1 x TBST for 1 hour at room temperature.
The membrane is then washed and incubated for 30 min at room temperature with horseradish peroxidase (HRP) conjugated secondary antibody. The membrane is washed again and incubated in ECL reagent for 1 minute at room temperature. The signal is detected by exposing the membrane to a film or by BioChemi system of '
UVP Biolmaging Systems. Rabbit anti-GFP from Invitrogen is used as primary antibody.
Example 233: Anti-HI V Assays
In an acute infection assay, fresh PBMCs (peripheral blood mononuclear cells) are isolated from human blood and stimulated to grow with PHA-P and IL-2 in RPMI culture medium. To cells growing in 96 well plates, dilutions of each compound are added followed by an aliquot of HIV-I (ROJO isolate) virus stock at an MOI of 0.1. Wells with cells and virus alone, along with a titration of AZT are used as controls. A duplicate plate without virus is identically prepared for cytotoxicity (MTS assay) studies. At the end of 7 days, cell-free supernatant samples are collected and assayed for reverse transcriptase activity. For these studies, serial dilutions of the compounds are tested for antiviral activity.
A microliter based reverse transcriptase (RT) reaction is utilized. See Buckheit et al, AIDS Research and Human Retroviruses 7:295-302 (1991). Tritiated thymidine triphosphate (TTP; New England Nuclear) is resuspended in distilled H2O at 5 Ci/ml. Poly rA and oligo dT are prepared as a stock solution, which is kept at - 200C. The RT reaction buffer is prepared fresh on a daily basis and consists of 125 μl IM EGTA, 125 μl dH2O, 1 10 μl 10% SDS, 50 μl IM Tris (pH 7.4), 50 μl IM DTT, and 40 μl 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 ju.1 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. Following the reaction, the entire reaction volume is spotted onto pieces of DE81 paper, washed 5 times 5 min each in a 5% sodium phosphate buffer, 2 times 1 min each in distilled water, 2 times for 1 min each in 70% ethanol, and then dried. Opti- Fluor-O (Packard) is added to each sample and incorporated radioactivity is quantified utilizing a Wallac 1450 MicroBeta Plus liquid scintillation counter.
At assay termination 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. At termination of the assay, 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.
In addition, 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.
Example 234: Inhibition of EIAV Infectivity with Compounds of Formula I
Plasmid construct
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 10s 293 T 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 μg of pEV53 plasmid DNA is combined with 100 μl of Opti-MIM I medium. 3 μl of LipofectAmine 2000 reagent (Invitrogen) is then added to 100 μl 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. 200 μl of DNA/Lipofectamine 2000 solution is then added to the 293 T cells in each well of the plate and mixed gently by rocking. The plate is then placed at 37°C, 5% CO2 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.
Reverse Transcription Assay
1.0 ml of post-transfection cell culture medium is collected, passed through a 0.45 μm syringe filter and layered on top of 200 μl of 20% sucrose. This discontinuous gradient is then centrifuged at 14,000 rpm (4°C) for 90 minutes. The supernatant is carefully removed leaving ~20μl in the tube. The pellet contained in the remaining ~20μl is resuspended in 150 μl of HBSS (Hank's Balanced Salt Solution, Invitrogen) and used for the Reverse Transcriptase Assay.
Reverse Transcriptase Assay (Ouan-T-RT assay from Amersham Biosciences. Piscataway. ND 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.
1. Preparation of [3H]TTP solution 1.1. Mix 10 μl of [3H]TTP stock solution with 190 μl of 5.25x assay buffer (this amount is sufficient for 10 assays using 20 μl per assay).
2. Assay procedure 2.1. Pipette 10 μl of primer/template on SPA bead into each tube.
2.2. Add 20 μl of TTP/[3H]TTP solution from 1.1 into each tube.
2.3. Add appropriate volume of sample and mix by pipette up and down.
2.4. Finally add ddH2O to final volume of 100 μl.
2.5. Incubate the tubes for 2 h at 37°C. 2.6. Terminate the reaction by adding 200 μl of stop reagent into each tube.
2.7. Count the tubes in a scintillation counter with the window settings fully open.
The results of these studies indicate whether the compounds according to Formula I reduce or inhibit the infectivity of the virus EAIV.
Example 235: 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.
Example 236: MT-4 Cytoprotection Assay
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. This assay was used to obtain the results liste din Table 3.
MT-4 Cvtoprotection 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 HTV-induced cytopathic effect. In this assay, 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.
Briefly, exponentially growing 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).
All publications, patents and patent application publications cited above are herein incorporated by reference to the same extent as if each individual publication, patent or patent application publication was specifically and individually indicated to be incorporated by reference. The mere mentioning of the publications and patent applications does not necessarily constitute an admission that they constitute prior art to the instant invention or application.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced within the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
Claims 1. A compound of the following formula, or a pharmaceutically acceptable salt thereof,
Figure imgf000110_0001
wherein Rl and R2 are independently chosen from hydro, or an optionally substituted -L-aryl, -L-heteroaryl, -L-heterocyclic, or -L-cycloalkyl group;
R3 is an optionally substituted -L-aryl, -L-heterocyclic, or —L-heteroaryl group; and L can be saturated, partially saturated, or unsaturated, and is chosen from -(CKb)n- (CH2V, -(CH2)nC(=O)(CH2)n-, -(CH2)nC(O)N(CH2)π-, -(CH2)nNC(=O)O(CH2)n-, - (CH2)nNC(=O)N(CH2)n-, -(CH2)nNC(=S)S(CH2)n-, -(CH2)nOC(=O)S(CH2)n-, - (CH2)nNH(CH2)n-s -(CH2)nO(CH2)n-, -(CH2)nS(CH2)n-, and -(CH2)nNC(=S)N(CH2)n-, where each n is independently chosen from 0, 1, 2, 3, 4, 5, 6, 7, and 8, and wherein each carbon and/or nitrogen can be optionally substituted with one or more substituents independently chosen from hydroxyl, halo, alkoxy, Cι-3 alkyl, and C3.6 cycloalkyl groups; and wherein said compound is chosen from (lH-Indazol-5-yl)-(5-pyridin-2-yl-oxazol- 2-yl)-amine, (1 H-Indazol-5-yl)-(5-pyridin-3-yl-oxazol-2-yl)-amine, [5-(2-Chloro- phenyl)-oxazol-2-yl]-(l H-indazol-5-yl)-amine, [5-(3-Chloro-phenyl)-oxazol-2-yl]- (1 H-indazol-5-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(l H-indazol-5-yl)- amine, [5-(3,4-Dichloro-phenyl)-oxazol-2-yl]-( lH-indazol-5-yl)-amine, [5-(3-Fluoro- phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-(5-p-tolyl-oxazol-2- yl)-amine, (1 H-Indazol-5-yl)-[5-(4-methoxy-phenyl)-oxazol-2-yl]-amine, [5-(4- Bromo-phenyl)-4-methyl-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (4,5-Diphenyl- oxazol-2-yl)-(lH-indazol-5-yl)-amine, [5-(4-Bromo-phenyl)-oxazol-2-yl]-(lH- indazol-5-yl)-amine, [5-(4-Fluorophenyl)-oxazol-2-yl]-(l H-indazol-5-yl)-amine, [5- (4-Fluoro-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(4-Bromo-phenyl)- oxazol-2-yl]-(lH-indazol-5-yl)-amine, 4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]- benzoic acid methyl ester, (lH-Indazol-5-yl)-[5-(4-methanesulfonyI-phenyl)-oxazol- 2-yl]-amine, (1 H-Indazol-5-yl)-[5-(3-nitro-phenyl)~oxazol-2-yl]-amme, (1H-Indazol- 5-yl)-[5-(2-methoxy-phenyl)oxazol-2-yl]-amine, (lH-Indazol-5-yl)~(4-methyl-5- phenyl-oxazol-2-yl)-amine, 5-[5-(3-Nitro-phenyl)-oxazol-2-ylamino]-indazoIe-l- carboxylic acid tert-butyl ester, 5-[5-(4-Methanesulfonyl-phenyl)-oxazol-2-ylamino]- indazole-1-carboxylic acid tert-butyl ester, 5-[5-(4-Bromo-phenyl)-oxazol-2- ylamino]-indazole-l-carboxylic acid tert-butyl ester, {4~[2-(lH-Indazol-5-ylamino)- oxazol-5-yl]-phenyl} -methanol, {4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-phenyl}- (4-methyl-piperazin-l-yl)-methanone, {4-[2-(lH Indazol-5-ylamino)-oxazol-5-yl]- phenyl}-morpholin-4-yl-methanone, {4-[2-(lH-Indazol-5-ylaτnino)-oxazol-5-yl]- phenyl} -pyrrolidin-1 -yl-methanone, N,N-Diethyl-4-[2-(lH-indazol-5-ylamino)- oxazoI-5-yl]-benzamide, 5-[5-(4-Vinyl-phenyl)-oxazol-2-ylamino]-indazole-l- carboxylic acid tert-butyl ester, 5-[5-(4-Vinyl-phenyl)-oxazol-2-ylamino]-indazole-l- carboxylic acid tert-butyl ester, 5-{5-[4-((E)-2-Methoxycarbonyl-vinyl)-phenyl]- oxazol-2-ylamino}-indazole-l-carboxylic acid tert-butyl ester, 5-[5-(4- Methoxycarbonyl-phenyl)-oxazol-2-ylamino]-indazole-l -carboxylic acid tert-butyl ester, (1 H-Indazol-5-yl)-(5-naphthalen-2-yl-oxazol-2-yl)-amine, (1 H-Indazol-5-yl)-[5- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-oxazol-2-yl]-amine, [5-(4- Chloro-phenyl)-oxazol-2-yl]-(3-phenyl-lH-indazol-5-yl)-amine, 4-[2-(lH-Indazol-5- ylamino)-oxazol-5-yl]-phenol, (3-Bromo-lH-indazol-5-yl)-[5-(4-chloro-phenyl)- oxazol-2-yl]-amine, N*5*-[5-(4-Chloro-phenyl)-oxazol-2-yl]-lH-indazole-3,5- diamine, (lH-Indazol-5-yl)-[5-(2,3,4-trimethoxy-phenyl)-oxazol-2-yl]-amine, [5-(3^ Dimethoxy-phenyl)-oxazol-2- yl]-(lH-indazol-5-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-[3-((E)-styryl)-lH- indazol-5-yl]-amine, (5-Benzo[l ,3]dioxol-5-yl-oxazol-2-yl)-(l H-indazol-5-yl)-amine, Acetic acid 4-[2-(lH-indazol-5-ylam ino)-oxazol-5-yl]-2-methoxy-phenyl ester, 3-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]- benzonitrile, 4-[2-(l H-Indazol-5-ylamino)-oxazol-5-yl]-benzonitrile, (5-Benzofuran- 2-yl-oxazol-2-yl)-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(lH-indol-2-yl)- oxazol-2-yl]-amine, (5-Benzo[b]thiophen-2-yl-oxazol-2-y l)-(lH-indazol-5-yl)-amine, 4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-benzene-l,2- diol, (lH-Indazo]-5-yl)-[5-(3,4,5-trimethoxy-phenyl)-oxazol-2-yl]-amine, [5-(2,3- Dihydro-benzofuran-5-yl)-oxazol-2-yl]-(lH-mdazol-5-yI)-amiπe, 4-[2-(lH-Iπdazol-5- ylamino)-oxazol-5-yl]-2-methoxy-phenol, [5-(4-Benzyloxy-phenyl)-oxazol-2-yl]- (lH-indazol-5-yl)-amine, [5-(4-Difluoromethoxy-phenyl)-oxazol-2-yl]-(lH-indazol- 5-yl)-amine, [S-CόJ^JO.l^lS.lS.ld^δ^P-Decahydro-S.S^ ^M^T^O-hexaoxa- benzo cyclooctadecen-2-yl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3,4-Diethoxy- phenyl)-oxazol-2-yl] -(I H-indazol-5-yl)-amine, 4- {4-[2-( 1 H-Indazol-5-ylamino)- oxazol-5-yl]-2-methoxy-phenoxy}-butyric acid methyl ester, 4-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy- phenoxy} -butyric acid, {5-[4-(4-Chloro-benzyloxy)-3-methoxy-phenyl]-oxazol-2-yl} - (lH-indazol-5-yl)-amine, {5-[4-(3-Chloro-betizyloxy)-3-methoxy-phenyl]-oxazol-2- yl} -( 1 H-indazol-5-yl)-amine, [5-(4-Benzyloxy-3-τnethoxyphenyl)-oxazol-2-yl]-( IH- indazol-5-yl)-amine, ( 1 H-Indazol-6-yl)-(5 -phenyl-oxazol-2-yl)-amine, ( 1 H-Indazol-6-yl) -(5 -pyridin-2-yl-oxazol-2-yl)-amine, ( 1 H-Indazol-6 -yl)-(5-pyridin- 3-yl-oxazol-2-yl)-amine, [5-(3-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-6-yl)-amine, (lH-Indazol-6-yl)-(5-p-tolyl-oxazol-2-yl)-amine, [5-(2-Chloro-phenyl)-oxazol-2-yl]- (1 H-indazol-6-yl)-amine, (1 H-Indazol-6-yl)-[5-(4-methoxy-phenyl)-oxazol-2-yl]- amine, (lH-Indazol-6-yl)-(5-p-tolyl-oxazol-2-yl)-amine, (lH-Indazol-6-yl)-[5-(4- trifϊuoromethyl-phenyl)-oxazol-2-yl]-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH- indazol-6-yl)-amine, [5-(4-Diethylamino-phenyl)-oxazol-2-yl]-(lH-indazol-6-yl)- amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indazol-7-yl)-amine, l-(lH-Indazol-5- yl)-3 -(5-phenyl-oxazol-2-yl)-thiourea, 1 -(I H-Indazol-6-yl)-3-(5-phenyl-oxazol-2-yl)- thiourea, ( lH-Indol-4-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)- oxazol-2-yl]-(lH-indol-4-yl)-amine, Benzothiazol-5-yl-(5-phenyl-oxazol-2-yl)-amine, Benzothiazol-5-yl-[5-(4-chloro-phenyl)-oxazol-2-yl]-amine, Benzothiazol-6-yl-[5-(4- chloro-phenyl)-oxazol-2-yl]-amine, (lH-Indol-7-yl)-(5-phenyl-oxazol-2-yl)-amine,
[5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indol-7-yl)-amine, (lH-Indol-5-yl)-(5-phenyl- oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indol-5-yl)-amine, (1 H- Benzotriazol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, (lH-Benzotriazol-5-yl)-[5-(4- chloro-phenyl)-oxazol-2yl]-amine, Benzooxazol-6-yl-(5-phenyl-oxazol-2-yl)-amine, Benzooxazol-6-yl-[5-(4-chloro-phenyl)-oxazol-2-yl]-amine, 5-(5-Phenyl-oxazol-2- ylamino)-benzoimidazole-l-carboxylic acid tert-butyl ester, 5-[5-(4-Chloro-phenyl)- oxazol-2-ylamino]-benzoimidazole-l-carboxylic acid tert-butyl ester, (IH- Benzoimidazol-5-yl)-[5-(4-chloro-pheπyl)-oxazol-2-yl]-amine, (lH-Benzoimidazol-5- yl)-(5-phenyl-oxazol-2-yl)-amine, 6-(5-Phenyl-oxazol-2-ylamino)-benzothiazole-2- thiol, 6-[5-(4~Chloro-phenyl)-oxazol2-ylamino]-benzothiazole-2-thiol, (2- Methylsulfanyl-benzothiazol-6-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro- phenyl)-oxazol-2-yl]-(2-methylsulfanyl-benzothiazol-6-yl)-amine, N-[2-Methoxy-4- (5-phenyl-oxazol-2-ylammo)-phenyl]-acetamide, 6-(5~Phenyl-oxazol-2-ylamino)-3H- benzooxazol-2-one, 6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2- one, 6-Chloro-7-(5-phenyl-oxazol-2-ylamino)-4H-benzo[l ,4]oxazin-3-one, 6-Chloro- 7-[5-(4-chloro-phenyl)-oxazol-2-ylamino]-4H-benzo[l,4]oxazin-3-one, 5-[5-(4- Chloro-phenyl)-oxazol-2-ylamino]- 1 ,3 -dihydro-benzoiτmdazol-2-one, 5-(5-Phenyl- oxazol-2-ylamino)-l,3-dihydro-benzovrnidazol-2-one, [4-(5-Phenyl-oxazol-2- ylamino)-phenyl]-carbamic acid methyl ester, {4-[5-(4-Chloro-phenyl)-oxazol-2- ylamino]-phenyl}-carbamic acid methyl ester, 6-(5-Phenyl-oxazol-2-ylamino)-3H- benzothiazol-2-one, 6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-3H-benzothiazol-2- one, N- {6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-benzothiazol-2-yl}-acetamide, N- [6-(5-Phenyl-oxazol-2-ylamino)-benzothiazol-2-yl]-acetamide, Compound Example No. 109, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-pyrazolo[3,4-b]pyridin-5-yl)-amine, (5-Phenyl-oxazol-2-yl)-( 1 H-pyrazolo
[3,4-b]pyridin-5-yl)-amine, [5-(3 ,4-Dimethoxy-phenyl)-oxazol-2-yl] -( 1 H- pyrazolo[3,4-b]pyridin-5-yl)-amine, 6-(5-Phenyl-oxazol-2-ylamino)-lH-quinoxalin-2- one, Isoquinolin-5-yl-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2- yl]-isoquinolin-5-yl-amine, 7-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-3-oxo-3,4- dihydro-quinoxaline-2-carboxylic acid methyl ester, 7-(5-Benzo[l,3]dioxol-5-yl- oxazol-2-ylamino)-4H-benzo[l,4]oxazin-3-one, 7-[5-(3,4-Dimethoxy-phenyl)-oxazol- 2-ylamino]-4H-benzo[l,4]oxazin-3-one, [5-(4-Chloro-phenyl)-oxazol-2-yl]-pyridin-3- yl-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-pyridin-4-yl-amine, [5-(4-Chloro- phenyl)-oxazol-2-yl]-pyridin-2-yl-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(3,4- dimethoxy-phenyl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-ylJ-(4-methoxy-phenyl)- amine, 3-[5-(334-Diinethoxy-phenyl)-oxazol-2-ylamino]-lH-pyrazole-4-carbonitrile, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-pyridin-3-ylmethyl-amine, [5-(3,4- Dimethoxy-phenyl)-oxazol-2-yl]-pyridin-4-ylmethyl-amine3 6-(5-Phenyl-oxazol-2- ylamino)-4H-benzo[ 1 ,4]oxazin-3 -one, 6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-4H- benzo[ 1 ,4]oxazin-3-one, Indan-5-yl-(5-phenyl-oxazol-2-yl)-amine, 7-[5-(4-Chloro- phenyl)-oxazol-2-ylamino]-4H-benzo[ 1 ,4]oxazin-3-one, 7-(5-Phenyl-oxazol-2- ylamino)-4H-benzo[ 1 ,4]oxazin-3-one, (2,3-Dihydro- 1 H-indol-5-yl)-(5-phenyl-oxazol- 2-yl)-amine, 7-[5-(4-Fluoro-phenyl)-oxazol-2-ylamino]-4H-benzo[ 1 ,4]oxazin-3-one, 7-[5-(4-Trifluoromethoxy-phenyl)-ox azol-2-ylaτnino]-4H-benzo[l,4]oxazin-3-one, 7-[5-(4-Diethylamino-phenyl)-oxazol- 2-ylamino]-4H-benzo[l,4]oxazin-3-one, 5-(5-Phenyl-oxazol-2-ylamino)-3-[l-pyridin- 4-yl-meth-(Z)-ylidene]-l ,3-dihydro-indol-2-one, 5-[5-(4-Chloro-phenyl)-oxazol-2- ylamino]-l,3-dihydro-indol-2-one, (4-Imidazol-l-yl-phenyl)-(5-phenyl-oxazol-2-yl)- amine, 6-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-2-methyl-3H-quinazolin-4-one, 6- [5-(3,4-Dimethoxy-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, 6-[5-(4- Fluoro-phenyl)-oxazol-2-ylaτnino]-3H-benzooxazol-2-one, 6-(5-Benzo[l,3]dioxol-5- yl-oxazol-2-ylamino)-3H-benzooxazol-2-one,6-(5-p-Tolyl-oxazol-2-ylamino)-3H- benzooxazol-2-one, 6-[5-(2,5-Dimethoxy-phenyl)-oxazol-2-ylamino]-3H- benzooxazol-2-one, 6-[5-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-oxazol-2-ylamino]-3H- benzooxazol-2-one, 6-[5-(4-Trifluoromethoxy-phenyl)-oxazol-2-ylamino]-3H- benzooxazol-2-one, 2-[2-Oxo-5-(5-phenyl-oxazol-2-ylamino)-benzooxazol-3-yl]- acetamide, 2-{5-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-2-oxo-benzooxazol-3-yl}- acetamide, 6-[5-(3,4-Dihydro-2H-benzo[b][l,4]dioxepin-7-yl)-oxazol-2-ylamino]-3H- benzooxazol-2-one, 6-[5-(3-Methoxy-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2- one, 6-[5-(3,5-Dimethoxy-phenyl)-oxazol-2-ylamino]-3H-benzooxazol-2-one, (IH- Indazol-5-yl)-[5-(3-methoxy-phenyl)-oxazol-2-yl]-amine, [5-(2,3-Dihydro- benzo[l,4]dioxin-6-yl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3,4-Dihydro-2H- benzo[b][l,4]dioxepin-7-yl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(2,3-Dihydro- benzo[l,4]dioxin-5-yl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(2,4-Dimethoxy- phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(5-Bromo-2-methoxy-phenyl)- oxazol-2-yl]-(lH-indazol-5-yl)-amine, N-{4-[2-(lH-Indazol-5-ylamino)-oxaκol-5-yl]- phenyl} -acetamide, 4-[2-(l H-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-benzene- 1 ,3-diol, (lH-Indazol-5-yl)-[5-(4-metliylsulfanyl-phenyl)-oxazol-2-yl]-amine, (IH- Indazol-5-yl)-(5-{3-methoxy-4-[2-(4-methoxy-phenyl)-ethoxy]-phenyl}-oxazol-2-yl)- amine, (5- {4-[2-(4-Fluoro-phenyl)-ethoxy]-3-methoxy-phenyl } -oxazol-2-yl)-( 1 H- indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(3-iodo-4-methoxy-phenyl)-oxazol-2-yl]-amine, N-{5-[2-(lH- Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenyl}-acetamide, 2-Hydroxy-5-[2- (lH-indazol-5-ylamino)-oxazol-5-yl]-benzoic acid methyl ester, 4-[2-(lHIndazol-5- ylamino)-oxazol-5-yl]-benzoic acid, N-((R)- 1 - {4-[2-( 1 H-Indazol-5 -ylamino)-oxazol- 5-yl]-phenyl}-ethyl)-acetamide, 3-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-benzoic acid, N-((S)- 1 - {4- [2-(l H-Indazol-5-ylamino)-oxazol-5-yl]-phenyl } -ethyl)-acetamide, [5-(3-Benzyloxy-4-methoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, {5-[3-(4- Chloro-benzyloxy)-4-methoxy-phenyl]-oxazol-2-yl}-(lH-indazol-5-yl)-amine, [5-(3- Ethoxy-4-methoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)- [5-(4-methoxy-3-propoxy-phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5~yl)-{5-[4- methoxy-3-(2-methoxy-ethoxy)-phenyl]-oxazol-2-yl}-amine, (lH-Indazol-5-yl)-(5- {4-methoxy-3-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl}-oxazol-2-yl)-amine, (R)-2-(4- {4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-τnethoxy-phenoxy}-butyrylamino)-4- methyl-pentanoic acid tert-butyl ester, {4-[2-(lH-Indazol-5-ylamino)-oxazol-5.-yl]-2- methoxy-phenoxy} -acetic acid ethyl ester, [5-(4-Ethoxy-3-methoxy-phenyl)-oxazol- 2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(4-isobutoxy-3-methoxy- phenyl)-oxazol-2-yl]-amine, ol-2-yl]-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-(5- {3 -methoxy-4-[2-(2-methoxy-ethoxy)-ethoxy]-phenyl } -oxazol-2-yl)-amine, [5-(4- Ethyl-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, (5-Indan-5-yl-oxazol-2-yl)-(lH- indazol-5-yl)-amine5 (1 H-Indazol-5-yl)-[5-(5,6,7,8-tetrahydro-naphthalen-2-yl)- oxazol-2-yl]-amine, (5-Biphenyl-4-yI-oxazol-2-yl)-(l H-indazol-5-yl)-amine, 2- Amino-5-[5-(4-chloro-phenyl)-oxazol-2-ylamino]-phenol, [5-(4-Chloro-phenyl)- oxazol-2-yl]-(2,2-dioxo-2,3-dihydro-21ambda*6*-benzo[l,2,3]oxathiazol-6-yl)- amine, (1 H-Indazol-5-yl)-[5-(4-trifluoromethoxy-phenyl)-oxazol-2-yl]-arnine, [5-(4- Difluoromethoxy-phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(4-Amino- phenyl)-oxazol-2-yl]-(lH-indazol-5-yl)-amine, [5-(3,4-Diethyl-phenyl)-oxazol-2-yl]- (1 H-indazoI-5-yl)-amine, {5-[4-(2-Chloro-ethyl)-phenyl]-oxazol-2-yl} -(I H-indazol-5- yl)-amine, Benzo[l ,3]dioxol-5-yl-(5-phenyl-oxazol-2-yl)-amine, Benzothiazol-6-yl- (5-phenyl-oxazol-2-yl)-amine, -phenyl)-oxazol-2-yl]-amine, (1 H-Indol-6-yl)-(5~ phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(lH-indol-6-yl)- amine, 1 - {6-[5-(4-Cbloro-phenyl)-oxazol-2-ylamino]-2,3-dihydro-indol-l -yl}- ethanone, (lH-Indazol-5-yl)-(5-thiophen-2-yl-oxazol-2-yl)-amine, (1-Methyl-lH- indazol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, [5-(4-Chloro-phenyl)-oxazol-2-yl]-(2- methyl-2H-indazol-5-yl)-amine, 5-(5-Phenyl-oxazol-2-ylamino)-l,3-dihydro-indol-2- one, (3-Methyl-lH-indazol-5-yl)-(5-phenyl-oxazol-2-yl)-amine, 2-Amino-6-[5-(4- chIoro-phenyl)-oxazol-2-ylamino]-quinazolin-4-ol, [5-(4-Chloro-phenyl)-oxazol-2- yl]-quinolin-6-yl-amine, 7-[5-(4-Chloro-phenyl)-oxazol-2-ylamino]-2-methyl-3H- quinazolin-4-one, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indazol-6-yl)-amine, (lH-Indazol-5-yl)-{5-[4-methoxy-3-(2-rnethoxy-ethoxy)-phenyl]-oxazol-2-yl}-amine, 3-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenoxymethyl}-benzoic acid, 4-{4-[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy-phenoxymetliyl}- benzoic acid methyl ester, 4-{4~[2-(lH-Indazol-5-ylamino)-oxazol-5-yl]-2-methoxy- phenoxymethyl} -benzoic acid, 3- {4-[2-( lH-Indazol-5-ylamino)-oxazol-5-yl]-2- methoxy-phenoxy methyl} -benzoic acid, (5-{3,4-Bis-[2-(2-methoxy-ethoxy)-ethoxy]- phenyl}-oxazol-2-yl)-(lH-indazol-5-yl)-aπiine, {5-[3,4-Bis-(2-methoxy-ethoxy)- phenyl]-oxazol-2-yl}-(lH-indazol-5-yl)-amine, (lH-Indazol-5-yl)-[5-(3- trifluoromethyl-phenyl)-oxazol-2-yl]-amine, (lH-Indazol-5-yl)-{5-[3-methoxy-4-(2- morpholin-4-yl-ethoxy)-phenyl]-oxazol-2-yl} -amine, (lH-Benzotriazol-5-yl)-[5-(3,4- dimethoxy-phenyl)-oxazol-2-yl] -amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]- (lH-indol-6-yl)-amine, Benzothiazol-5-yl-[5-(3,4-dimethoxy-phenyl)-oxazol-2-yl]- amine, [5-(3,4-Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indol-7-yl)-amine, [5-(3,4- Dimethoxy-phenyl)-oxazol-2-yl]-(lH-indol-5-yl)-amine, [5-(3,4-Dimethoxy-phenyl)- oxazol-2-yl] -(I H-indazol-7-yl)-amine, [5-(3 ,4-Dimethoxy-phenyl)-oxazol-2-yl] -( 1 H- indol-4-yl)-amine, Benzooxazol-6-yl-[5-(3,4dimethoxy-phenyl)-oxazol-2-yl]-amine. Compound Example number 226, Compound Example number 227, Compound Example number 228, Compound Example number 229, Compound Example number 230, and Compound Example number 231.
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US20160159789A1 (en) * 2013-07-08 2016-06-09 Bayer Pharma Aktiengesellschaft Substituted pyrazolopyridines
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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
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282805A1 (en) * 2004-06-15 2005-12-22 Hangeland Jon J Five-membered heterocycles useful as serine protease inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282805A1 (en) * 2004-06-15 2005-12-22 Hangeland Jon J Five-membered heterocycles useful as serine protease inhibitors

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