WO2003063771A2 - N4-acylcytosine nucleosides for treatment of viral iinfections - Google Patents

N4-acylcytosine nucleosides for treatment of viral iinfections Download PDF

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Publication number
WO2003063771A2
WO2003063771A2 PCT/US2002/040081 US0240081W WO03063771A2 WO 2003063771 A2 WO2003063771 A2 WO 2003063771A2 US 0240081 W US0240081 W US 0240081W WO 03063771 A2 WO03063771 A2 WO 03063771A2
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Prior art keywords
hydrogen
dideoxy
fluorine
pharmaceutically acceptable
fluorocytidine
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PCT/US2002/040081
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English (en)
French (fr)
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WO2003063771A3 (en
Inventor
Kyoichi A. Watanabe
Junxing Shi
Michael J. Otto
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Pharmasset Ltd.
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Priority to JP2003563467A priority Critical patent/JP2005519916A/ja
Priority to MXPA04005779A priority patent/MXPA04005779A/es
Priority to EP02804833A priority patent/EP1569652A4/en
Priority to BR0214944-3A priority patent/BR0214944A/pt
Priority to KR1020047009263A priority patent/KR100978904B1/ko
Priority to AU2002365234A priority patent/AU2002365234B2/en
Priority to CA2470255A priority patent/CA2470255C/en
Publication of WO2003063771A2 publication Critical patent/WO2003063771A2/en
Publication of WO2003063771A3 publication Critical patent/WO2003063771A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals

Definitions

  • the present invention is directed to compounds, methods and compositions for the treatment or prevention of viral infections using nucleoside analogues. More specifically, the invention describes N 4 -acyl-substituted cytosine nucleoside analogues, pharmaceutically acceptable salts, prodrugs, or other derivatives thereof, and the use thereof in the treatment of a viral infection, and in particular a human immunodeficiency virus (HIV) or hepatitis B virus (HBV) infection.
  • HIV human immunodeficiency virus
  • HBV hepatitis B virus
  • HIV human immunodeficiency virus
  • HBV HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection.
  • HBV infection can lead to acute hepatitis and liver damage, resulting in abdominal pain, jaundice and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which large sections of the liver are destroyed. Patients typically recover from the acute phase of HBV infection. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone, and worldwide, almost 300 million carriers. Chronic persistent hepatitis can cause fatigue, cirrhosis of the liver, and hepatocellular carcinoma, a primary liver cancer.
  • HBV is very similar to that of HIV/AIDS, which is a reason why HBV infection is common among patients infected with HIV or suffering from AIDS. However, HBV is more contagious than HIV.
  • DNA causing chain termination, because they lack a 3 '-hydroxyl group.
  • Some nucleosides also inhibit the viral enzyme reverse transcriptase.
  • 3TC (lamivudine) and interferon are currently the only FDA-approved drugs for the treatment of HBV infection. Viral resistance develops within 6 months of 3TC treatment in about 14% of patients.
  • Cis-2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane is currently in clinical trials for the treatment of HIV and separately for HBV by Triangle Pharmaceuticals, Inc. See Schinazi et al. (1992) Selective inhibition of human immunodeficiency viruses by racemates and enantiomers of cis-5-fluoro-l-[2- (hydroxymethyl)-l,3-oxathiolane-5-yl]cytosine. Antimicrob. Agents Chemother. 36,
  • A2 (Ajinomoto Co., Inc.). Netherlands Pat. No. 8901258 (Stichting Rega V.Z.W.) discloses generally 5-halogeno-2',3'-dideoxy-2',3'-didehydrocytidine derivatives for use in treating HIV and HBV. ⁇ -D- and ⁇ -L-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine were further described in US Pat. Nos. 5,703,058; 5.905,070; 6,232,300; and 5,561,120. US Pat. No.
  • 5,703,058 claims a method for the treatment of HIV and/or HBV infection that includes administering an effective amount of ⁇ -L-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin- 1 -yl)- 1 ,3-oxathiolane, cis-2-hydroxymethyl- 5-(cytosin- 1 -yl)- 1 ,3-oxathiolane, 9-[4-(hydroxymethyl)-2-cyclopenten- 1 -yl)-guanine
  • 5,905,070 claims a method for the treatment of HIV and HBV infection that includes administering an effective amount of ⁇ -D-d4FC in combination or alternation with cis-2-hydroxymethyl-5-(5-fluorocytosin-l-yl)-l,3-oxathiolane, cis-2- hydroxymethyl-5-(cytosin- 1 -yl)- 1 ,3-oxathiolane, 9-[4-(hydroxy-methyl)-2-cyclopenten- 1 - yl)-guanine (carbovir), 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir), interferon, 3'- deoxy-3 '-azido-thymidine (AZT), 2',3'-dideoxyinosine (ddl), 2',3'-dideoxycytidine (ddC), (-)-2'-fluoro-5-methyl- ⁇ -L-ara-uridine (L-FMAU) or 2
  • N 4 -acyl-cytosine nucleosides and in particular, N 4 - acyl-2',3'-dideoxy-5-fluorocytidine and N 4 -acyl-2',3'-didehydro-2',3'-dideoxy-5-fluoro- cytidine, show improved inhibitory activity against HIV and HBV. Therefore, a method for the treatment or prevention of HIV and/or HBV infection in a host, and in particular, a human, is provided that includes administering an effective amount of a N 4 -acyl-cytosine nucleoside.
  • the active compound is of formula (I) or (II):
  • R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C ,O5, and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), haloalkyny
  • R 2 is chosen from alkyl (including but not limited to , C 2 , C 3 , C , C 5 , C 6 , C 7 , C 8 , C 9 , C]Q, C ⁇ , C ⁇ , C ⁇ 3 , C ⁇ 4 , C15, C ⁇ 6 , C ⁇ , C 18 , C 1 9, C 2 o, C 21 , and C 22 ), alkenyl (including but not limited to
  • R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to Ci, C 2 , C 3 , C , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), and aryl (including but not limited to C 6 , C 7 , C 8 , C 9 , and C10); v) R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to Ci, C 2 , C 3 , C
  • R 2 cannot be an alkyl, alkoxyalkyl (such as methoxymethyl), aralkyl (such as benzyl or substituted benzyl), aryloxyalkyl (such as phenoxymethyl) or aryl (including but not limited to a phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to C t , C 2 , C 3 , and C 4 ) or alkoxy (including but not limited to , C 2 , C 3 , and C )).
  • alkoxyalkyl such as methoxymethyl
  • aralkyl such as benzyl or substituted benzyl
  • aryloxyalkyl such as phenoxymethyl
  • aryl including but not limited to a phenyl optionally substituted with halogen (F, CI, Br, I)
  • alkyl including but not limited to C t , C 2 , C 3 , and C 4
  • the compound of the present invention can be in the form of the isolated ⁇ -L- or ⁇ -D- configuration, or a mixture thereof, including but not limited to a racemic mixture.
  • Y is CH 2 and both R 3 and R 3 groups are hydrogen, forming a d2 nucleoside (i.e., a 2',3'-dideoxy nucleoside).
  • the active compound is ⁇ -D-N 4 -p-iodobenzoyl-2',3'-dideoxy- 5-fluorocytidine.
  • active compounds include ⁇ -D-N 4 -p-fluoro- benzoyl-2',3'-dideoxy-5-fluorocytidine, ⁇ -D-N -p-chlorobenzoyl-2',3'-dideoxy-5-fluoro- cytidine, ⁇ -D-N 4 -p-bromobenzoyl-2',3'-dideoxy-5-fluorocytidine, ⁇ -D-N 4 -p-ethyl- benzoyl-2 ' ,3 ' -dideoxy-5 -fluorocytidine, and ⁇ -D-N 4 -p-t-butylbenzoyl-2 ' ,3 '-dideoxy-5 - fluoro-cytidine.
  • the active compound is ⁇ -D- ⁇ -p-bromobenzoyl ⁇ ' ⁇ '- didehydro-2',3'-dideoxy-5-fluorocytidine.
  • active compounds include ⁇ -D-N 4 -p-fluorobenzoyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, ⁇ -D-N 4 - ⁇ -chlorobenzoyl-2',3 '-didehydro-2'3 '-dideoxy-5 -fluorocytidine, ⁇ -D- ⁇ 4 -p-iodobenzoyl- 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, ⁇ -D-N 4 -p-ethylbenzoyl-2',3'-didehydro- 2',3'-dideoxy-5-fluorocytidine, and ⁇ -D-N 4 -p-
  • 2',3'-dideoxy-N 4 -acyl-cytosinenucleosides and 2',3'-didehydro- 2',3'-dideoxy-N 4 -acyl-cytosinenucleosides are inhibitors of HBV. Therefore, these compounds can also be used to treat patients that are co-infected with both HIV and HBV.
  • the present invention provides a compound, method and composition for treating an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for treating an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a compound, method and composition for preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient for the treatment of a host infected with HIV or HBV.
  • a compound, method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • Figure 1 is a non-limiting example of the synthesis of active compounds of the present invention, and in particular, the synthesis of ⁇ -D-N 4 -acyl-2',3'-dideoxy-5- fluorocytidine and ⁇ -D-N 4 -acyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine nucleosides.
  • Figure 2 is a graphic representation of the anti-HBV activity of selected N 4 -acyl- substituted ⁇ -D-2 ',3 '-dideoxy- and ⁇ -D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine analogues.
  • N 4 -acyl-cytosine nucleosides and in particular, N 4 -acyl-
  • a method for the treatment or prevention of a host, and in particular, a human, infected with HIV and/or HBV includes administering an effective amount of an N 4 - acyl-cytosine nucleosides.
  • the present invention also provides a method and composition for treating an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a method and composition for preventing an HIV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a method and composition for treating an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • the present invention provides a method and composition for preventing an HBV infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
  • a pharmaceutical formulation comprising a compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
  • a method and composition for treating or preventing an HIV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • a method and composition for treating or preventing an HBV infection in a host comprising administering to the subject a combination comprising at least one compound of the invention and at least one further therapeutic agent.
  • the active compound is of formula (I) or (II):
  • R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to Q, C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), haloalkenyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), alkynyl
  • R 2 is chosen from alkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), cycloalkyl (including but not limited to C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 ), CN, CF 3 , N 3 , NO 2 , aryl (including but not limited to C 6 , C , C 8 , C9, and C 10 ), heteroaryl (including but not limited to C 4 , C 5 , C 6 , C 7 , Cs, C9, C 1 0, C ⁇ , and C 12 ) and acyl (including but not limited to C , C 3 , C 4 , C 5 , and C 6 ); iv) R 2 is chosen from alkyl (including but not limited to C ⁇ , C 2
  • R 6 is chosen from halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to Cj, C 2 , C 3 , C 4 ,
  • C 5 , and C 6 aminoalkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkoxy (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), thioalkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), and aryl (including but not limited to C 6 , C 7 , C 8 , C 9 , and
  • R 3 and R 3' are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to C ls C 2 , C 3 , C , C 5 , and C 6 ), alkenyl (including but not limited to C , C 3 , C 4 , C 5 , and C 6 ), and alkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ); vi) R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C , C 3 , C 4 , C 5 , and C 6 ), alkyny
  • R 5 is H, acyl, alkyl, alkenyl, alkynyl, or cycloalkyl.
  • the compound of the present invention can be in the form of the ⁇ -L- or ⁇ -D- configuration, or a racemic mixture.
  • R 2 cannot be an alkyl, alkoxyalkyl (such as methoxymethyl), aralkyl (such as benzyl or substituted benzyl), aryloxyalkyl (such as phenoxymethyl) or aryl (including but not limited to a phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to Ci, C 2 , C 3 , and C ) or alkoxy (including but not limited to Ci, C 2 , C 3 , and C 4 )).
  • alkoxyalkyl such as methoxymethyl
  • aralkyl such as benzyl or substituted benzyl
  • aryloxyalkyl such as phenoxymethyl
  • aryl including but not limited to a phenyl optionally substituted with halogen (F, CI, Br, I)
  • alkyl including but not limited to Ci, C 2 , C 3 , and C
  • alkoxy including but not
  • the active compound is of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) Y is CH 2 , CHF or CF 2 ; iii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and
  • C 6 haloalkenyl (including but not limited to C , C 3 , C 4 , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C 4 , Cs, and C 6 ), cycloalkyl (including but not limited to C 3 , C 4 , Cs, C 6 , C 7 , and Cs), CN, CF 3 , N3, NO , aryl (including but not limited to C ⁇ , C , C 8 , C 9 , and Cio), heteroaryl (including but not limited to C 4 , C 5 , C 6 , C 7 ,
  • R 2 is chosen from alkyl (including but not limited to Ci, C 2 , C3, C 4 , C 5 , C ⁇ , C 7 , C 8 , C 9 , Cio, C ⁇ , C 12 , Ci 3 , C 14 , C15, Ci6, C 17 , C 18 , C19, C 2 o, C 21 , and C 22 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C9, Cio, Cn, C ⁇ 2 , C ⁇ 3 ,
  • alkynyl including but not limited to C 2 , C 3 , C 4 , C5, C ⁇ , C , C 8 , C9, Cio, C ⁇ , C ⁇ 2 , C13, C ⁇ 4 , C15, Ci ⁇ , C ⁇ , C] 8 , C 1 9, C 2 o, C 2 ⁇ , and C 22
  • cycloalkyl including but not limited to C 3 , C 4 , C 5 , C ⁇ , C ⁇ , and C 8
  • aminoalkyl including but not limited to C ⁇ , C 2 , C 3 , C , C5, and C 6
  • hydroxyalkyl including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C ⁇
  • haloalkyl including but not limited to , C 2 , C 3 , C 4 , C
  • C 2 , C3, C , C 5 , and C ⁇ haloalkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C 5 , and Ce), aminoalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkoxy (including but not limited to d, C 2 , C 3 , C 4 , C 5 , and C ⁇ ), thioalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C , C 3 , C 4 , C 5 , and C 6 ), alkynyl (including but not limited to C 2s
  • R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C3, C , C5, and C 6 ), and alkynyl (including but not limited to C 2 , C3, C 4 , C 5 , and C 6 ); and vi) R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl (including but not limited to , C 2 , C 3 , C 4 , C5, and
  • a phospholipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol .
  • the active compound is of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) Y is CH 2 , CHF or CF 2 ; iii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to Ci, C 2 , C3, C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to C , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and
  • R 2 is chosen from cycloalkyl (including but not limited to C 3 , C 4 , C 5 , C 6 , C ⁇ , and C 8 ), aminoalkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C5, and Ce), haloalkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), thioalkyl (including but not limited to Ci, C 2 , C 3 , C 3 , C 3 , C 4 , C 5 , and C 6 ), thioalkyl (including but not limited to Ci, C 2 , C 3 , C
  • Ci Ci, C 2 , C 3 , C 4 , C 5 , and C ⁇
  • alkoxy including but not limited to Cj, C 2 , C 3 , C 4 , C 5 , and C 6
  • thioalkyl including but not limited to C ⁇ , C 2 , C3, C 4 , C 5 , and C 6
  • alkenyl including but not limited to C 2 , C 3 , C , C 5 , and C ⁇
  • alkynyl including but not limited to C 2 , C 3 , C 4 , C 5 , and C ⁇
  • aryl including but not limited to v
  • R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N3, NO 2 , alkyl (including but not limited to , C 2 , C3, C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5
  • a phospholipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) Y is CH 2 , CHF or CF 2 ; iii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C3, C 4 , Cs, and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ), haloal
  • R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) Y is CH 2 , CHF or CF 2 ; iii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to Cj, C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to Cj, C 2 , C 3 , C 4 , C 5 , and C ⁇ ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), alkynyl
  • R 2 is CeHtR 6 where R 6 is chosen from CN, CF 3 , N 3 , NO 2 , haloalkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C 5 , and C 6 ), aminoalkyl (including but not limited to , C 2 , C 3 , C , C 5 , and C 6 ), thioalkyl (including but not limited to Ci,
  • R 3 and R 3 are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to C 1? C 2 , C 3 , C , C 5 , and C ⁇ ), alkenyl
  • R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl (including but not limited to , C 2 , C3, C 4 , C 5 , and C 6 ), alkenyl
  • R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) Y is CH 2 , CHF or CF 2 ; iii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C ⁇ ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), alkynyl (including but not limited to C 2 , C3, C 4 , C 5 , and C ⁇ ), haloalky
  • R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl (including but not limited to C C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), aryl (including but not limited to C 6 ,
  • the active compound is of formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to C ⁇ , C 2 , C3, C , C5, and C 6 ), haloalkyl (including but not limited to Ci,
  • alkenyl including but not limited to C 2 , C 3 , C , C 5 , and C ⁇
  • haloalkenyl including but not limited to C , C 3 , C 4 , C 5 , and C 6
  • alkynyl including but not limited to C 2 , C3, C 4 , C 5 , and C ⁇
  • haloalkynyl including but not limited to C 2 , C 3 , C , C 5 , and C 6
  • cycloalkyl including but not limited to ⁇ C 3 , C 4 , C 5 , C ⁇ , C ⁇ , and C 8
  • aryl including but not limited to
  • R 2 is chosen from cycloalkyl (including but not limited to C 3 , C 4 , C 5 , C 6 , C 7 , and C 8 ), aminoalkyl (including but not limited to Ci, C 2 , C3, C 4 , C 5 , and C ⁇ ), haloalkyl (including but not limited to Ci, C 2 , C 3 , C , C5, and C 6 ), thioalkyl
  • R 6 is chosen from halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to C , C 2 , C 3 , C , C 5 , and C ⁇ ), haloalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), aminoalkyl (including but not limited to d, C 2 , C 3 , C 4 , C 5 , and C 6 ), alkoxy (including but not limited to , C 2 , C 3 , C 4 ,
  • thioalkyl including but not limited to C ⁇ , C 2 , C 3 , C , C 5 , and Ce
  • alkenyl including but not limited to C 2 , C 3 , C 4 , C5, and C 6
  • alkynyl including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6
  • aryl including but not limited to
  • R 3 and R 3' are chosen independently from H, halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl (including but not limited to , C , C 3 , C 4 , C 5 , and C ⁇ ), alkenyl (including but not limited to C 2 , C3, C 4 , C 5 , and C 6 ), and alkynyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C 6 ); and v) R 4 is H, phosphate (including but not limited to monophosphate, diphosphate, triphosphate, or a stabilized phosphate prodrug), carbonyl substituted with alkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C 5 , and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C
  • a phospholipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to Ci, C 2 , C 3 , C 4 , C5, and C 6 ), haloalkyl (including but not limited to C ⁇ , C 2 , C 3 , C , C 5 , and C ⁇ ), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ), alkynyl (including but not limited to C 2 , C , C , C 5 , and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C 4
  • a phospholipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and C 6 ), haloalkyl (including but not limited to C ⁇ , C 2 , C 3 , C 4 , C5, and C 6 ), alkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C 3 , C 4 , C 5 , and C ⁇ ), alkynyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), haloalkynyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), halo
  • R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • R 3 and R 3 are H or phosphate, sulfonate ester (including but not limited to alkyl or arylalkyl sulfonyl including but not limited to methanesulfonyl), benzyl (wherein the phenyl group is optionally substituted with one or more substituents as described in the definition or aryl given above), a lipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is * of - formula (II) or a pharmaceutically acceptable salt or prodrug thereof, wherein i) X is O; ii) R 1 is chosen from hydrogen, halogen (F, CI, Br, I), alkyl (including but not limited to , C 2 , C 3 , C , C 5 , and C 6 ), haloalkyl (including but not limited to , C 2 , C 3 , C 4 , C 5 , and Ce), alkenyl (including but not limited to C 2 , C 3 , C , C 5 , and C ⁇ ), haloalkenyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), alkynyl
  • R 2 is CeH t R 6 where R 6 is chosen from CN, CF 3 , N 3 , NO 2 , haloalkyl (including but not limited to C 2 , C 3 , C 4 , C5, and C 6 ), cycloalkyl (including but not limited to C 3 , C 4 , C 5 , C ⁇ , C ⁇ , and C 8 ), CN, CF 3 , N 3 , NO 2 , aryl (including but not limited to C 6 , C ⁇ , C 8 , C 9 , and Cio), heteroaryl (including but not limited to C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , do, C ⁇ , and C ⁇ 2 ) and acyl (including but not limited to C 2 , C 3 , C , C 5 , and C 6 ); iii) R 2 is CeH t R 6 where R 6 is chosen from CN, CF 3 , N 3 , NO 2 , halo
  • a phospholipid (including but not limited to a phospholipid), an amino acid, a peptide, or cholesterol.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the ortho position.
  • halogen F, CI, Br, I
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) ' R 2 is a phenyl moiety optionally substituted with Br in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with F in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; Y is CH 2 ; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and
  • R 2 is a phenyl moiety optionally substituted with methyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R is a phenyl moiety optionally substituted with n-propyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CN in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with N3 in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluorine; R is hydrogen; and iv) R is a phenyl moiety optionally substituted with alkoxy in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; R4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine ⁇ R 4 is hydrogen; and iv) R is a phenyl moiety optionally substituted with furanyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the ortho position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 ,
  • N 3 NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with Br in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with F in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein:
  • X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the meta position.
  • the active compound is of formula , its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CN in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is.hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically,.acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the meta position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the para position.
  • halogen F, CI, Br, I
  • the active compound is of formula
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with Br in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R3 and R3' are independently hydrogen or fluorine; R4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and .. iv) R 2 is a phenyl moiety optionally substituted with F in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the para position.
  • the active compound is of formula (I), its pharmaceutically. acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii). R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen;..and * > iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorin ⁇ ; R 4 is hydrogen; and
  • R is a phenyl moiety optionally substituted with n-butyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) ,'J R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and, ,•- iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine 1 , R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y js CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CN in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable, salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii): .; R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are Independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and ⁇ iv) R 2 is a phenyl .moiety optionally substituted with thioalkyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable, salts or prodrugs thereof, wherein: i) X is O; Y is GH 2 ; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and v) R 2 is a phenyl moiety optionally substituted with alkynyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii). -. :R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and ⁇ iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; . iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the para position.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; , iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; Y is CH 2 ; ii) R .1 i •s fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; Y is CH 2 ; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and v) R 2 is a phenyl moiety optionally substituted with 2,6-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorinej R 4 is hydrogen; and iv) R is a phenyl moiety optionally substituted with 3,4-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with 3,5-dihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y ⁇ CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 -and.R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R is a phenyl moiety optionally substituted with 3,4,5-trihalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and, iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.
  • the active compound is of
  • I' formula (I), its pharmaceutically acceptable salts or prodrugs thereof wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentahalo.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine ⁇ R 4 is hydrogen; and iv) R is a phenyl moiety optionally substituted with 3,4- dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with 3,5- dialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and t iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5- trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 . are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R are independently hydrogen or fluorine ⁇ R is hydrogen; and
  • R is a phenyl moiety optionally substituted with 3,4,5- trialkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; Y is CH 2 ; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , v) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetraalkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentaalkyl.
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-di-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- di-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R l is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- di-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- di-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; 1 R 4 is hydrogen; and iv) R 2 is a ph ' enyl moiety optionally substituted with 3,4- di-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with 3,5- di-NO .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4- tri-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5- tri-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- tri-NO .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- tri-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- tri-NO .
  • the active compound is of formula (I), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorinej R 4 is hydrogen; and
  • R 2 is a p 'henyl moiety optionally substituted with 3,4,5- tri-NO .
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N3, NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the ortho position.
  • halogen F, CI, Br, I
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein:
  • X is O; ii) R 1 is fluorine or hydrogen; iii) R and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with Br in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and v) R 2 is a phenyl moiety optionally substituted with F in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine 1 ; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with alkyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; , ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine;! R 4 is hydrogen; and
  • R is a phenyl moiety optionally substituted with sec-butyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine ⁇ R 4 is hydrogen; and
  • R is a phenyl moiety optionally substituted with a cyclohexyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and
  • R 2 is a phenyl moiety optionally substituted with CN in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O;
  • R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the ortho position.
  • the active compound is of
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; 'R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and , iv) R 2 is a phenyl, moiety optionally substituted with alkenyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the ortho position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF3, N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the meta position.
  • halogen F, CI, Br, I
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; i ⁇ ) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with Br in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with F in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; , iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the meta position,
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ⁇ ) R 1 is fluorine or hydrogen; iii) R 3 and R 3' are independently hydrogen or fluorine); R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine r hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and, iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; r ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the meta position.
  • the active compound is of , . , formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: . i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with neopentyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CN in the meta position.
  • the active compound is of ⁇ formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein:.. '-> ⁇ _ i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF 3 in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently, hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: ... ,. «.. . i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the meta position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I), CN, CF 3 , N 3 , NO 2 , alkyl, haloalkyl, aminoalkyl, alkoxy, thioalkyl, alkenyl, alkynyl, or aryl in the para position.
  • halogen F, CI, Br, I
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with halogen (F, CI, Br, I) in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with Br in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with I in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with F in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CI in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with NO 2 in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) , X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with methyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with ethyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-propyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with iso-propyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-butyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with sec-butyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with tert-butyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-pentyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with isopentyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and v) R 2 is a phenyl moiety optionally substituted with neopentyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with cyclopentyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with n-hexyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with a cyclohexyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CN in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with CF3 in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with N 3 in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with haloalkyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aminoalkyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkoxy in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thioalkyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 andR 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkenyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with alkynyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with aryl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with thiophenyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with furanyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with naphthyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with benzoyl in the para position.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,6-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,5-dihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5-trihalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetrahalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; i) R 1 is fluorine or hydrogen; ii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and v) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentahalo.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4- dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen;
  • R and R are independently hydrogen or fluorine; R is hydrogen; and iv) R is a phenyl moiety optionally substituted with 3,5- dialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4-trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5- trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; ⁇ i) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) .
  • X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5- trialkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5-tetraalkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4,5,6-pentaalkyl.
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3-di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4- di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5- di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,6- di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4- di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,5- di-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,4- tri-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,3,5- tri-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluorine; R is hydrogen; and d iv) R 2 is a phenyl moiety optionally substituted with 2,4,5- tri-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,4,6- tri-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 2,5,6- tri-NO 2 .
  • the active compound is of formula (II), its pharmaceutically acceptable salts or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a phenyl moiety optionally substituted with 3,4,5- tri-NO 2 .
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2- position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 3- position or the 4-position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a benzothiophenyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the benzene ring.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a benzothiophenyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the thienyl ring.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a cyclohexyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or 3- position.
  • the active compound is of formula (I), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; Y is CH 2 ; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a cyclohexyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 4- position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or 3 position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R and R are independently hydrogen or fluorine; R is hydrogen; and iv) R 2 is a thienyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 4- position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a benzothiophenyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the benzene ring.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a benzothiophenyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl on the thienyl ring.
  • the active compound is of formula
  • R 1 is fluorine or hydrogen
  • R 3 and R 3 are independently hydrogen or fluorine
  • R 4 is hydrogen
  • R 2 is a cyclohexyl optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 2 or 3 position.
  • the active compound is of formula (II), its pharmaceutically acceptable salt or prodrugs thereof, wherein: i) X is O; ii) R 1 is fluorine or hydrogen; iii) R 3 and R 3 are independently hydrogen or fluorine; R 4 is hydrogen; and iv) R 2 is a cyclohexyl moiety optionally substituted with alkyl, halo, alkenyl, alkynyl, cycloalkyl, aminoalkyl, hydroxyalkyl, haloalkyl, thioalkyl, aryl, or heteroaryl in the 4 position.
  • the active compound is ⁇ -D-2',3'-dideoxy-5-fluoro- N 4 -(4-iodobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-2',3'-dideoxy-5- fluoro-N ⁇ 4 -(4-fluorobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(4- chlorobenzoyl)-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(4-bromobenzoyl)- 2 ',3 '-dideoxy-5 -fluorocytidine of the structure:
  • the active compound is ⁇ -D-2',3 '-dideoxy-5- fluoro-N 4 -(3-fluorobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(3- chlorobenzoyl)-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(3-bromobenzoyl)- 2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-2',3'-dideoxy-5- fluoro-N 4 -(4-nitrobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-2',3 '-dideoxy- 5-fluoro-N 4 - »-toluoylcytidine of the structure:
  • the active compound is ⁇ -D-2',3 '-dideoxy-5-fluoro-
  • the active compound is ⁇ -D-2',3'-dideoxy-N 4 - (4-ethylbenzoyl)-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-2',3 '-dideoxy- 5-fluoro-N 4 -(4-propylbenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(4-tert- butylbenzoyl)-2', 3 '-dideoxy-5 -fluorocytidine of the structure:
  • the active compound is ⁇ -D-2',3'-dideoxy- 5-fluoro-N -(2-thiophenecarbonyl)cytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(benzo-[b]-thiophene-2- carbonyl)-2',3'-dideoxy-5-fluorocytidine of the structure: or a pharmaceutically acceptable salt or prodrug thereof.
  • the active compound is ⁇ -D-N 4 -(cyclohexane-carbonyl)-
  • the active compound is ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluoro-N 4 -(4-iodobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-2',3'-didehydro-2',3'-dideoxy- 5-fluoro-N 4 -(4-fluorobenzoyl)cytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(4-chlorobenzoyl)-2',3'- didehydro-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 -(4- bromobenzoy ⁇ )-2 ' ,3 ' -didehydro-2 ' ,3 '-dideoxy-5 -fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 -p-anisoyl-2',3'- didehydro-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-2 ',3'- didehydro-2 ' ,3 ' -dideoxy-5 -fluoro-N 4 -(3 -nitrobenzoy l)cytidine of the structure:
  • the active compound is ⁇ -D-2',3'-didehydro-2',3'- dideoxy-5-fluoro-N 4 -j9-toluoylcytidine of the structure:
  • the active compound is ⁇ -D-2',3 '-didehydro-
  • the active compound is ⁇ -D-N 4 -(4-t-butylbenzoyl)- 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 - cyclopentanecarbonyl-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the active compound is ⁇ -D-N 4 - (cyclohexanecarbonyl)-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine of the structure:
  • the compounds of the present invention have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers or enantiomers, with all isomeric forms being included in the present invention. Some compounds may exhibit polymorphism.
  • the present invention encompasses racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein.
  • the optically active forms can be prepared by, for example, resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase or by enzymatic resolution.
  • Examples of methods to obtain optically active materials include at least the following. i) physical separation of crystals: a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist, i.e., the material is a conglomerate, and the crystals are visually distinct; ii) simultaneous crystallization: a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions: a technique whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis: a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis:
  • first- and second-order asymmetric transformations a technique whereby diastereomers from the racemate equilibrate to yield a preponderance in solution of the diastereomer from the desired enantiomer or where preferential crystallization of the diastereomer from the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer from the desired enantiomer.
  • kinetic resolutions this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors: a synthetic technique whereby the desired enantiomer is obtained from non- chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography: a technique whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase (including but not limited to via chiral HPLC).
  • the stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the differing interactions;
  • chiral gas chromatography a technique whereby the racemate is volatilized and enantiomers are separated by virtue of their differing interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
  • extraction with chiral solvents a technique whereby the enantiomers are separated by virtue of preferential dissolution of one enantiomer into a particular chiral solvent;
  • xiii) transport across chiral membranes a technique whereby a racemate is placed in contact with a thin membrane barrier.
  • the barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane that allows only one enantiomer of the racemate to pass through.
  • Chiral chromatography including but not limited to simulated moving bed chromatography, is used in one embodiment.
  • a wide variety of chiral stationary phases are commercially available.
  • the term “substantially free of or “substantially in the absence of refers to a nucleoside composition that includes at least 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the designated enantiomer of that nucleoside.
  • the compounds are substantially free of enantiomers.
  • isolated refers to a nucleoside composition that includes at least 85 or 90% by weight, preferably 95% to 98 % by weight, and even more preferably 99% to 100% by weight, of the nucleoside, the remainder comprising other chemical species or enantiomers.
  • alkyl refers to a saturated straight, branched, or cyclic, primary, secondary, or tertiary hydrocarbon. The term includes both substituted and unsubstituted alkyl groups.
  • the alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that provides an improvement in the process, including but not limited to but limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfmyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, either unprotected, or protected as necessary, as known to those skilled
  • C(alkyl range) independently includes each member of that class as if specifically and separately set out.
  • C ⁇ -2 independently represents each species that falls within the scope.
  • Alkyl groups include, but are not limited to the radicals of methane, ethane, propane, cyclopropane, 2-methylpropane (isobutane), «-butane, 2,2- dimethylpropane (neopentane), cytobutane, 1,1 dimethylcyclopropane, 2-methylbutane, trans- 1,2-dimethylcyclopropane, ethylcyclopropane, n-pentane, methylcyclobutane, cis- 1,2-dimethylcyclopropane, spiropentane, cyclopentane, 2,2-dimethylbutane, 1,1,2- trimethylcyclopropane, 2,3-dimethylbutane, 2-methylpentane,
  • alkenyl refers to an unsaturated, hydrocarbon radical, linear or branched, in so much as it contains one or more double bonds.
  • the alkenyl group disclosed herein can be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to alkyl, halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxi
  • Non-limiting examples of alkenyl groups include methylene, ethylene, methylethylene, isopropylidene, 1,2-ethane-diyl, 1,1-ethane-diyl, 1,3- propane-diyl, 1,2-propane-diyl, 1,3-butane-diyl, and 1,4-butane-diyl.
  • alkynyl refers to an unsaturated, acyclic hydrocarbon radical, linear or branched, in so much as it contains one or more triple bonds.
  • the alkynyl group may be optionally substituted with any moiety that does not adversely affect the reaction process, including but not limited to but not limited to hydroxyl, halo (F, CI, Br, I), perfluoro alkyl including but not limited to trifluoromethyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, acyl, amido, carboxamido, carboxylate, thiol, alkylthio, azido, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene et al, Protective Groups in Organic Synthesis. John Wiley & Sons, Second
  • alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylburyn-l-yl, hexyn-1-yl, hexyn- 2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-l-yl radicals.
  • alkylamino or "arylamino” refers to an amino group that has one or two alkyl or aryl substituents, respectively.
  • aryl alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused.
  • Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or the following aromatic group that remains after the removal of a hydrogen from the aromatic ring: benzene, toluene, ethylbenzene, 1,4-xylene, 1,3-xylene, 1,2- xylene, isopropylbenzene (cumene), ra-propylbenzene, l-ethyl-3-methylbenzene (m- ethyltoluene), l-ethyl-4-methylbenzene (p-ethyltoluene), 1,3,5-trimethylbenzene (mesitylene), l-ethyl-2-methylbenzene (o-ethyltoluene), tert-butylbenzene, 1,2,4- trimethylbenzene (pseudodocumene), isobutylbenzene, ⁇ 'ec-butyl
  • 1,2,3,4-tetrahydronaphthalene 6,7-dimethyl- 1,2,3,4-tetrahydronaphthalene, 5,7-dimethyl- 1,2,3,4-tetrahydrona ⁇ hthalene, 2-ethylnaphthalene, 1-7-dimethylnaphthalene, 1,6- dimethylnaphthalene, 1,3-dimethylnaphthalene, n-octylbenzene, 1-allylnaphthalene, 1- isopropylnaphthalene, 1,4-dimethylnaphthalene, 1,1-diphenylethane, 2- isopropylnaphthalene, 2-propylnaphthalene, 1-propylnaphthalene, 1,3,7- trimethylnaphthalene, l-isopropyl-7-methylnaphthalene, n-nonylbenzene, 2- butylnaphthalene, 2-tert-butylnaphthalen
  • 1,4-dimethylphenanthrene bibenzyl, methylenefluorene, 3,5-dimethylphenanthrene, 1,3- dimethylazulene, 7-methyl-3,4-benzphenanthrene, pentamethylbenzene, 1,2,4- trimethylnaphthalene, 3,3-dimethylstilbene, 1,4,5,7-tetramethylnaphthalene, 1,2,4,8- tetramethylnaphthalene, 2,9-dimethylphenanthrene, 1,5 -dimethylphenanthrene, 2- benzylnaphthalene, 1-benzylnaphthalene, 1-benzylnaphthalene, 1,2-dimethylazulene, 9- propylphenanthrene, l,7-dimethyl-4-isopropylnaphthalene, 3 -methylphenanthrene, 3,4- dimethylphenanthrene, 1-ethylphenanthrene, ,sym-diphenylacetylene, 9-e
  • aryl includes both substituted and unsubstituted moieties.
  • the aryl group may be optionally substituted with any moiety that does not adversely affect the process, including but not limited to but not limited to halo, haloalkyl, hydroxyl, carboxyl, acyl, acyloxy, amino, amido, carboxyl derivatives, 5 alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide, anhydride, oxime, hydrozine, carbamate, phosphonic acid, phosphonate, or any other viable functional
  • Non-limiting examples of substituted aryl include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, 5 arylsulfonamido, diarylamidosulfonyl, monoaryl amidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydoxyheteroaralkyl, haloalkoxyalkyl
  • halo includes chloro, bromo, iodo and fluoro.
  • acyl refers to a carboxylic acid ester in which the non-carbonyl moiety 5 of the ester group is selected from straight, branched, or cyclic alkyl or lower alkyl, alkoxyalkyl including but not limited to methoxymethyl, aralkyl including but not limited to benzyl, aryloxyalkyl such as phenoxymethyl, aryl including but not limited to phenyl optionally substituted with halogen (F, CI, Br, I), alkyl (including but not limited to C ⁇ , C 2 , C 3 , and C ) or alkoxy (including but not limited to C ⁇ , C 2 , C 3 , and C 4 ), sulfonate esters 0 such as alkyl or aralkyl sulphonyl including but not limited to methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl,
  • alkoxy and alkoxyalkyl embrace linear or branched oxy-containing radicals having alkyl moieties, such as methoxy radical.
  • alkoxyalkyl also embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.
  • the "alkoxy” radicals may be further substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide "haloalkoxy" radicals.
  • radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.
  • alkylamino denotes “monoalkylamino” and “dialkylamino” containing one or two alkyl radicals, respectively, attached to an amino radical.
  • arylamino denotes “monoarylamino” and “diarylamino” containing one or two aryl radicals, respectively, attached to an amino radical.
  • aralkylamino embraces aralkyl radicals attached to an amino radical.
  • aralkylamino denotes
  • aralkylamino and “diaralkylamino” containing one or two aralkyl radicals, respectively, attached to an amino radical.
  • aralkylamino further denotes “monoaralkyl monoalkylamino” containing one aralkyl radical and one alkyl radical attached to an amino radical.
  • heteroatom refers to oxygen, sulfur, nitrogen and phosphorus.
  • heteroaryl or “heteroaromatic,” as used herein, refer to an aromatic that includes at least one sulfur, oxygen, nitrogen or phosphorus in the aromatic ring.
  • heterocyclic refers to a nonaromatic cyclic group wherein there is at least one heteroatom, such as oxygen, sulfur, nitrogen, or phosphorus in the ring.
  • heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4- thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazo
  • the heteroaromatic group can be optionally substituted as described above for aryl.
  • the heterocyclic or heteroaromatic group can be optionally substituted with one or more substituent selected from halogen (F, CI, Br, I), haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amido, amino, alkylamino, dialkylamino.
  • the heteroaromatic can be partially or totally hydrogenated as desired.
  • dihydropyridine can be used in place of pyridine. Functional oxygen and nitrogen groups on the heterocyclic or heteroaryl group can be protected as necessary or desired.
  • Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl.
  • the heterocyclic or heteroaromatic group can be substituted with any moiety that does not adversely affect the reaction, including but not limited to but not limited to those described above for aryl.
  • the term "host,” as used herein, refers to a unicellular or multicellular organism in which the virus can replicate, including but not limited to cell lines and animals, and preferably a human. Alternatively, the host can be carrying a part of the viral genome, whose replication or function can be altered by the compounds of the present invention.
  • the term host specifically refers to infected cells, cells transfected with all or part of the viral genome and animals, in particular, primates (including but not limited to chimpanzees) and humans. In most animal applications of the present invention, the host is a human patient. Veterinary applications, in certain indications, however, are clearly anticipated by the present invention (such as chimpanzees).
  • pharmaceutically acceptable salt or prodrug is used throughout the specification to describe any pharmaceutically acceptable form (such as an ester, phosphate ester, salt of an ester or a related group) of a nucleoside compound which, upon administration to a patient, provides the nucleoside compound.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium and magnesium, among numerous other acids well known in the pharmaceutical art.
  • Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form the compound of the present invention.
  • prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound.
  • Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound.
  • the compounds of this invention possess antiviral activity against
  • Flaviviridae or are metabolized to a compound that exhibits such activity.
  • Prodrugs also include natural or unnatural amino acid esters of the disclosed nucleosides (see, e.g., European Patent Specification No. 99493, the text of which is inco ⁇ orated by reference, which describes amino acid esters of acyclovir, specifically the glycine and alanine esters which show improved water-solubility compared with acyclovir itself, and US Pat. No. 4,957,924 (Beauchamp), which discloses the valine ester of acyclovir, characterized by side-chain branching adjacent to the ⁇ -carbon atom, which showed improved bioavailability after oral administration compared with the alanine and glycine esters).
  • a process for preparing such amino acid esters is disclosed in US Pat. No.
  • Suitable inorganic salts may also be formed, including but not limited to, sulfate, nitrate, bicarbonate and carbonate salts.
  • nucleosides described herein can be administered as a nucleotide prodrug to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside.
  • a number of nucleotide prodrug ligands are known.
  • alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide.
  • substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including but not limited to sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones & N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides to achieve' a desired effect.
  • the active nucleoside can also be provided as a 5'-phosphoether lipid or a 5'-ether lipid, as disclosed in the following references, which are incorporated by reference: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi, "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation," AIDS Res. Hum. Retroviruses, 1990, 6, 491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles,
  • the active compound or its prodrug or salt can be administered in combination or alternation with another antiviral agent, such as another active anti-HIV or anti-HBV agent, including but not limited to those of the formulae above, others listed below or known in the art.
  • another antiviral agent such as another active anti-HIV or anti-HBV agent, including but not limited to those of the formulae above, others listed below or known in the art.
  • effective dosages of two or more agents are administered together, whereas during alternation therapy, an effective dosage of each agent is administered serially.
  • the dosage will depend on absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • antiviral agents that can be used in combination with the compounds disclosed herein include those in the tables below.
  • MCC 478 nucleoside analogue Eli Lilly valLdC (valtorcitabine) nucleoside analogue Idenix
  • NRTIs Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
  • NRTIs Transcriptase Inhibitors
  • the compounds of the invention may be employed together with at least one other antiviral agent chosen from reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, entry inhibitors and polymerase inhibitors.
  • compounds according to the present invention can be administered in combination or alternation with one or more anti-retrovirus, anti-HBV, anti-HCV or anti- herpetic agent or interferon, anti-cancer or antibacterial agents, including but not limited to other compounds of the present invention.
  • Certain compounds according to the present invention may be effective for enhancing the biological activity of certain agents according to the present invention by reducing the metabolism, catabolism or inactivation of other compounds and as such, are co-administered for this intended effect.
  • Host including but not limited to humans, infected with a human immunodeficiency virus, a hepatitis virus, or a gene fragment thereof, can be treated by administering to the patient an effective amount of the active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form.
  • a preferred dose of the compound for an HIV or HBV infection will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day.
  • the effective dosage range of the pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent nucleoside to be delivered. If the salt or prodrug exhibits activity in itself, the effective dosage can be estimated as above using the weight of the salt or prodrug, or by other means known to those skilled in the art.
  • the compound is conveniently administered in unit any suitable dosage form, including but not limited to but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form.
  • An oral dosage of 50-1000 mg is usually convenient.
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 ⁇ M, preferably about 1.0 to 10 ⁇ M. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient.
  • the concentration of active compound in the drug composition will depend on abso ⁇ tion, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like.
  • a syrup may contain, in addition to the active compound(s), sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compound or a pharmaceutically acceptable prodrug or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti- inflammatories or other antivirals, including but not limited to other nucleoside compounds.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates or phosphates, and agents for the adjustment of tonicity, such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • PBS physiological saline or phosphate buffered saline
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including but not limited to implants and microencapsulated delivery systems.
  • a controlled release formulation including but not limited to implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
  • enterically coated compounds can be used to protect cleavage by stomach acid. Methods for preparation of such formulations will be apparent to those skilled in the art. Suitable materials can also be obtained commercially.
  • Liposomal suspensions including but not limited to liposomes targeted to infected cells with monoclonal antibodies to viral antigens are also preferred as pharmaceutically acceptable carriers.
  • liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container.
  • An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container.
  • the container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension.
  • a method for the facile preparation of N -acyl-substituted 2',3'-dideoxy-5- fluorocytidine and 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine nucleosides is also provided.
  • the method includes condensation of a 5'-O-silyl protected 2',3'-dideoxy-5- fluorocytidine or a 5'-O-silyl protected 2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, with either a carboxylic acid chloride, or carboxylic acid anhydride, or a carboxylic acid, followed by desilylation.
  • the other N 4 -acyl-substiruted cytosine nucleosides can be synthesized using the similar approaches.
  • N 4 -acyl-substituted 2',3'-dideoxy-5-fluorocytidine and 2',3'-didehydro-2',3'- dideoxy-5-fluorocytidine nucleosides disclosed herein can be prepared as described in detail below, or by other assays known to those skilled in the art.
  • Anti-HIV-1 activity of the compounds was determined in human peripheral blood mononuclear (PBM) cells as described previously (Schinazi R.F., McMillan A., Cannon D., Mathis R., Lloyd R.M. Jr., Peck A., Sommadossi J.-P., St. Clair M., Wilson J., Furman P.A., Painter G., Choi W.-B., Liotta D.C. Antimicrob. Agents Chemother. 1992, 36, 2423; Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D., Xie M.-Y., Hart G., Smith G., Hahn E.
  • Stock solutions (20-40 mM) of the compounds were prepared in sterile DMSO and then diluted to the desired concentration in growth medium.
  • Cells were infected with the prototype HIV-I AI at a multiplicity of infection of 0.01.
  • Virus obtained from the cell supernatant was quantified on day 6 after infection by a reverse transcriptase assay using (rA) n *(dT)j 2 -i 8 as template- primer.
  • the DMSO present in the diluted solution ( ⁇ 0.1 %) had no effect on the virus yield.
  • AZT was included as positive control.
  • the antiviral EC 50 and EC 90 were obtained from the concentration-response curve using the median effective method described previously (Chou T.-C. & Talalay P. Adv. Enzyme Regul 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F . Antiviral Res. 1994, 25, 1-11).
  • the potency of the compounds was determined by measurement of viral RNA accumulation in HIV-1 RF infected MT-2 cells (Bacheler LT, Paul M, Otto MJ, Jadhav PK, Stone BA & Miller JA (1994) An assay for HIV RNIn infected cell lysates, and its use for rapid evaluation of antiviral efficacy.
  • the virus titer was established to determine the dilution producing 15 to 30 ng/RNA per well of HIV RNIn 3 days of infection.
  • HIV-1 RNA was quantified using biotinylated capture and alkaline phosphatase-derivatized reporter oligonucleotides as described previously (Charvet A-S, Camplo M, Faury P, Graciet JC,
  • the anti-HBV activity of the compounds was determined by treating the AD-38 cell line carrying wild type HBV under the control of tetracycline (Ladner S.K careful Otto M.J., Barker C.S., Zaifert K., Wang G.H., Guo J.T., Seeger C. & King R.W. Antimicrob. Agents Chemother. 1997, 41, 1715-1720). Removal of tetracycline from the medium [Tet (-)] results in the production of HBV. The levels of HBV in the culture supernatant fluids from cells treated with the compounds were compared with that of the untreated controls.
  • the toxicity of the compounds was assessed in Vero, human PBM, CEM (human lymphoblastoid), MT-2, and HepG2 cells, as described previously (Schinazi R.F., Sommadossi J.-P., Saalmann V., Cannon D.L., Xie M.-Y., Hart G.C., Smith G.A. & Hahn
  • Cycloheximide was included as positive cytotoxic control, and untreated cells exposed to solvent were included as negative controls.
  • the cytotoxicity IC 50 was obtained from the concentration-response curve using the median effective method described previously (Chou T.-C. & Talalay P. Adv. Enzyme Regul. 1984, 22, 27-55; Belen'kii M.S. & Schinazi R.F. Antiviral Res. 1994,
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US6914054B2 (en) 2000-05-23 2005-07-05 Idenix Pharmaceuticals, Inc. Methods and compositions for treating hepatitis C virus
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US10525072B2 (en) 2002-11-15 2020-01-07 Idenix Pharmaceuticals Llc 2′-branched nucleosides and flaviviridae mutation
US8658616B2 (en) 2006-11-24 2014-02-25 University College Cardiff Consultants Limited Nucleoside aryl phosphoramidates and their use as anti-viral agents for the treatment of hepatitis C virus

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US20090176730A1 (en) 2009-07-09
AU2002365234B2 (en) 2009-01-29
WO2003051306A2 (en) 2003-06-26
US8114997B2 (en) 2012-02-14
EP1569652A4 (en) 2008-07-02
KR100978904B1 (ko) 2010-08-31
EP1569652A2 (en) 2005-09-07
CN1617726A (zh) 2005-05-18
AU2002364730A8 (en) 2003-06-30
BR0214944A (pt) 2005-06-07
CA2470255C (en) 2012-01-17
US20120202766A1 (en) 2012-08-09
US7105527B2 (en) 2006-09-12
US20030176319A1 (en) 2003-09-18
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US6908924B2 (en) 2005-06-21
CN100560073C (zh) 2009-11-18
US20040214844A1 (en) 2004-10-28
US20070078080A1 (en) 2007-04-05
JP2005519916A (ja) 2005-07-07
WO2003051306A3 (en) 2003-12-18

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