WO2007014023A1 - Thiazolidinones, oxazolidinones, and pyrrolidinones for hbv - Google Patents

Thiazolidinones, oxazolidinones, and pyrrolidinones for hbv Download PDF

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WO2007014023A1
WO2007014023A1 PCT/US2006/028343 US2006028343W WO2007014023A1 WO 2007014023 A1 WO2007014023 A1 WO 2007014023A1 US 2006028343 W US2006028343 W US 2006028343W WO 2007014023 A1 WO2007014023 A1 WO 2007014023A1
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compound
formula
provides
subgeneric embodiment
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Huanming Chen
Anneke K. Raney
Matthew J. Allan
Jianlan Song
Stanley A. Lang
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Valeant Research & Development
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to pyrrazol-4-yl derivatives of thiazolidinones, oxazolidinones, and pyrrolidinones which are useful in the treatment of Hepatitis B virus.
  • HBV Hepatitis B virus
  • interferon alpha has been widely used for the treatment of chronic HBV infection.
  • interferon is effective only in certain subpopulations of chronic hepatitis B patients, and even in such patients it is poorly tolerated.
  • lamivudine (3'-thia-2',3'-dideoxycytidine), a particularly strong inhibitor of HBV replication, is used to treat HBV infection.
  • resistance to lamivudine is increasingly common and has limited its efficacy in a high proportion of patients.
  • adefovir dipivoxil (9-(2-((-bis((pivaloyloxy)methoxy)phosphinyl) methoxy)ethyl)adenine).
  • this nucleoside analog is active against the lamivudine- resistant viruses, its sustained viral response rate is poor (below 20%), and its maximum tolerated dose and treatment duration are often limited by nephrotoxicity. More recent developments in HBV research have led to clinical trials for several compounds with promising antiviral activity.
  • nucleoside analogs have been reported to exhibit significant anti-HBV activity (e.g., 2'-fluoro-5-methyl-beta-L- arabinofuranosyluracil (Bukwang) and 2'-deoxy-5-fluoro-3'-thiacytidine (Gilead); 2'-deoxy- L-thymidine and 2'-deoxy ⁇ L-cytidine (both Idenix)).
  • anti-HBV activity e.g., 2'-fluoro-5-methyl-beta-L- arabinofuranosyluracil (Bukwang) and 2'-deoxy-5-fluoro-3'-thiacytidine (Gilead); 2'-deoxy- L-thymidine and 2'-deoxy ⁇ L-cytidine (both Idenix)).
  • carbocyclic nucleoside analogs (6H-purin-6-one, 2-amino- 1 ,9-dihydro-9-(( 1 S,3R,4S)-4-hydroxy-3 -(hydroxymethyl)- 2-methylenecyclopentyl) monohydrate (Bristol-Myers Squibb), as well as acyclic nucleoside analogs with liver targeting properties (Remofovir; Ribapharm), were reported as having anti- HBV activity in clinical trials.).
  • R 4 is F or Cl
  • R 5 is H, F, or Cl
  • R 5 is H, F, or Cl
  • this invention provides compounds of formula I-R below, in which the chiral carbon is in the R configuration,
  • the invention provides a compound of formula II, which is a compound of formula I where A is S, n is 1 or 2, and other substituents are as defined above for formula I.
  • this invention provides compounds of formula H-R below, in which the chiral carbon is in the R configuration,
  • the invention provides a compound of formula III, where A is O, n is 1 or 2, and other substituents are as defined above for formula I.
  • the invention provides a compound of formula IV, where A is CH 2 , n is 1 or 2, and other substituents are as defined above for formula I.
  • This invention also provides the R isomers of fo ⁇ nulas III and IV.
  • the invention provides a compound of formula I, where R 2 is F or Cl.
  • the invention provides a compound of formula I, where R 2 is Cl.
  • the invention provides a compound of formula I, where Ri and R 3 are both F.
  • the invention provides a compound of formula I, where Ri is methyl and R 2 is F.
  • this invention provides a compound of formula I, where A is S and n is 1.
  • this invention provides a compound of formula I, where A is S and n is 2.
  • this invention provides a compound of formula I, where A is O and n is 1.
  • this invention provides a compound of formula I, where A is O and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 3-thienyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 3-thienyl, and n is 2.
  • this invention provides a compound of formula I 3 where A is S, Q is 3-furyl, and n is 1.
  • this invention provides a compound of fo ⁇ nula I, where A is S, Q is 3-furyl, and n is 2.
  • this invention provides a compound of fo ⁇ nula I, where A is S, Q is 3-pyrrolyl, and n is 1.
  • this invention provides a compound of fo ⁇ nula I, where A is S, Q is 3-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 4-fluorophenyl, and n is 1.
  • this invention provides a compound of fonnula I, where A is S, Q is 4-fluorophenyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 4-chlorophenyl, and n is 1.
  • this invention provides a compound of fo ⁇ nula I, where A is S, Q is 4-chlorophenyl, and n is 2.
  • tin ' s invention provides a compound of formula I, where A is S, Q is 5-fluoro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 5-fluoro-2-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 2-fluoro-5-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 2-fiuoro ⁇ 5-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 2-chloro-5-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 2-chloro-5-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 2-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
  • this invention provides a compound of fo ⁇ nula I, where A is S, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 2-thienyl, and n is 1.
  • JLn a lurther subgene ⁇ c embodiment this invention provides a compound of formula I, where A is S, Q is 2-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 3-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 3-thienyl, and n is 2.
  • this invention provides a compound of formula I 3 where A is O, Q is 3-furyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 3-furyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 3-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 3-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 4-fluorophenyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 4-fluorophenyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 4-chlorophenyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 4-chlorophenyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 5-fluoro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 5-fluoro-2-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 2-fluoro-5-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 2-fluoro-5-pyridyl, and n is 2.
  • this invention provides a compound of fo ⁇ nula I, where A is O, Q is 2-chloro-5-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 2-chloro-5-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 2-pyrrolyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 2-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 2-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-thienyl or 5-fluoro-2 ⁇ thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 3-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 3-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 3-furyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 3-furyl, and n is 2. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH 2 , Q is 3-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 3-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 4-fluorophenyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 4-fluorophenyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 4-chlorophenyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 4-chlorophenyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-fluoro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-fluoro-2-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-pyridyl, and n is 2.
  • this invention provides a compound of fo ⁇ nula I, where A is CH 2 , Q is 2-fluoro-5-pyridyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH 2 , Q is 2-fluoro-5-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-chloro-5-pyridyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-chloro-5-pyridyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 2-thienyl, and n is 2.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 1.
  • this invention provides a compound of formula I, where A is CH 2 , Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2.
  • Speccific embodiments of the invention include the compounds whose structures are shown below, as well as in the Table 1 in the next section.
  • CODEN CHRGB7 ISSN:0009-5893.
  • CODEN CHRGB7 ISSN:0009-5893.
  • the Berger procedure may be summarized as follows: The racemic mixture (60 mg) is dissolved in methanol (2 ml) and injected into a preparative chiral column (ChiralPak AD- H SFC, i.d. lcm x 25 cm).
  • the SFC conditions are as follows: mobile phase, 65% CO 2 and 35% methanol: flow rate, 10 ml/min; detection wavelength, 220 run. Two pools of material were isolated with different retention times.
  • R F or H 3-Furoyl chloride
  • a solution of 30.6 g of diethyl malonate inl6.5 ml of anhydrous ethanol and 20 ml of anhydrous ether is added with stirring at such a rate that rapid boiling is maintained; heat is supplied when necessary.
  • the mixture is heated under reflux at 70 0 C on an oil bath for 4-5 hours, at which time most of the magnesium has dissolved.
  • To the gray solution is added 21.4 g of furan-3-carbonyl chloride dissolved in 50 ml of ether in a period of 15 minutes. Heating under reflux at 70 0 C on the oil bath is continued throughout the addition of the furan-3-carbonyl chloride and until the solution becomes too viscous to stir.
  • reaction mixture is cooled (ice-bath) and shaken with dilute sulfuric acid (20.4 ml of concentrated sulfuric acid in 160 ml of water) until all the solid has dissolved and the reaction mixture become clear solution.
  • dilute sulfuric acid (20.4 ml of concentrated sulfuric acid in 160 ml of water)
  • the ether phase is separated and the aqueous layer extracted with 60 ml of ether.
  • the ether extracts are combined and washed with water, and the solvent is removed by distillation to give crude intermediates diethyl 2- (Furan-3-carbonyl) ⁇ malonate as an yellow oily product.
  • POCl 3 (3.0ml, 33mmol) was slowly added to anhydrous DMF (7.65ml, 66mmol) at O 0 C (ice-bath) with stirring. After stirring for 5 min, the semicarbazone (2.5g, 15mmol) was added portionwise to the above mixture with well-stirring. The mixture was heated to 60 0 C for 5 hours and poured onto 2Og of ice. It was neutralized with NaOH (6g in 24 ml of water) and heated at 60 0 C for 20 min, then cooled to room temperature and neutralized with ION HCl to pH 6. The resulting white precipitates were filtered and washed with water. After drying in vacuo at 60 0 C, 2 of the aldehyde as yellow solid was obtained.
  • HepG2 cells are transduced using a baculovirus to deliver the HBV genome essentially as previously described (Delaney, W.E., and Isom, H.C. Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus. Hepatology 1998; 28: 1134-1146.).
  • Transduced cells are cultured in supplemented EMEM media with 10% fetal bovine serum in a 5% CO 2 incubator at 37°C for three days in the presence of test compounds. The cells are lysed in a buffer containing 0.5% NP-40 and 500 microgram/ml proteinase K.
  • a solid-phase hybridization is performed to capture the viral DNA and to label the target DNA with Digoxigenin-labeled DNA probes.
  • the captured viral DNA is detected by ELISA using horseradish peroxidase-conjugated anti-digoxigenin antibodies.
  • the EC 50 values are determined using ExcelFit software from the inhibition values of a titration curve for each compound.
  • test compounds are co-cultured with non-transduced HepG2 for three days under the conditions described above.
  • the Promega CellTiter 96 AQ Ueous One Solution Cell Proliferation Assay is used to measure cell proliferation/viability.
  • the CC 50 values are determined using ExcelFitTM software from the inhibition values of the titration curve for each compound.
  • the dextrorotatory form is more than 250 fold more active than the levorotatory enantiomer.
  • the assignment of absolute configuration is based crystal structure of 2-(3, 5- di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3, 4-methylenedioxy)phenoxy] ethyl]amino]propyl]-l,3-thiazolidin-4-one. Kato, T., et ah, 1999, J.Med. Chem 42, 3134-46.
  • the R absolute configuration is intended to denote the dextrorotatory form.
  • substantially free of the levorotatory form should be construed by reference to examples 15, 32 and 19, which are substantially free of the levorotatory form.
  • the invention encompasses both mixtures of the dextrorotatory and levorotatory forms and compositions comprising the dextrorotatory form substantially free of the levorotatory form.
  • substantially free means a greater than 90% enantiomeric excess of one isomer.
  • Table 1 below lists selected compounds with their structures and corresponding antiviral activity.
  • Antiviral activity was determined using assay systems as described above. ND means not determined.

Abstract

The present invention relates to certain single-enantiomer pyrrazol-4-yl derivatives of thiazolidinones, oxazolidinones, and pyrrolidinones which are useful in the treatment of Hepatitis B virus.

Description

THIAZOLIDINONES, OXAZOLIDINONES, AND PYRROLIDINONES FOR HBV
Cross Reference to Related Applications
This application claims priority to U.S. Provisional Application Ser. No. 60/701,819, filed July 21, 2005, and to U.S. Provisional Application Ser. No. 60/706,602, filed August 8, 2005, both of which are hereby incorporated herein by reference in their entirety.
Field of the Invention
The present invention relates to pyrrazol-4-yl derivatives of thiazolidinones, oxazolidinones, and pyrrolidinones which are useful in the treatment of Hepatitis B virus.
Background of the Invention
Despite various treatment options available for patients infected with Hepatitis B virus (hereafter "HBV"), sustained treatment success as evidenced by decrease of HBV DNA in serum and anti-HBe or HBs seroconversion is frequently limited to a relatively small patient population.
For example, for several years interferon alpha has been widely used for the treatment of chronic HBV infection. However, interferon is effective only in certain subpopulations of chronic hepatitis B patients, and even in such patients it is poorly tolerated. Similarly, lamivudine (3'-thia-2',3'-dideoxycytidine), a particularly strong inhibitor of HBV replication, is used to treat HBV infection. However, resistance to lamivudine is increasingly common and has limited its efficacy in a high proportion of patients. The most recently-approved treatment for HBV is adefovir dipivoxil (9-(2-((-bis((pivaloyloxy)methoxy)phosphinyl) methoxy)ethyl)adenine). Although this nucleoside analog is active against the lamivudine- resistant viruses, its sustained viral response rate is poor (below 20%), and its maximum tolerated dose and treatment duration are often limited by nephrotoxicity. More recent developments in HBV research have led to clinical trials for several compounds with promising antiviral activity. For example, certain nucleoside analogs have been reported to exhibit significant anti-HBV activity (e.g., 2'-fluoro-5-methyl-beta-L- arabinofuranosyluracil (Bukwang) and 2'-deoxy-5-fluoro-3'-thiacytidine (Gilead); 2'-deoxy- L-thymidine and 2'-deoxy~L-cytidine (both Idenix)). Similarly, carbocyclic nucleoside analogs (6H-purin-6-one, 2-amino- 1 ,9-dihydro-9-(( 1 S,3R,4S)-4-hydroxy-3 -(hydroxymethyl)- 2-methylenecyclopentyl) monohydrate (Bristol-Myers Squibb), as well as acyclic nucleoside analogs with liver targeting properties (Remofovir; Ribapharm), were reported as having anti- HBV activity in clinical trials.).
However, while most of the recently discovered drugs with anti-HBV activity exhibited promising in vitro antiviral activity, low response rates and the emergence of resistance limit the efficacy of these clinical candidates. Therefore, although various compositions and methods for HBV treatment are known in the art, there is still a need to provide new and improved compositions and methods for treatment of HBV infections in human patients.
Thus, in light of the limited efficacy, resistance profiles, and toxicity of current anti- HBV drugs, there is a strong need for novel anti-HBV drugs that are more effective and less toxic and that exhibit a different resistance profile.
Brief Description of the Invention
Figure imgf000004_0001
where n is 1 or 2; R1, R2, and R3 are, independently, H, F, Cl, Br, or CF3 and Ri may also be methyl; A is O, S, or CH2; and Q is selected from the following:
Figure imgf000004_0002
where Q' is O, S, or NH
where R4 is F or Cl
Figure imgf000004_0003
where R5 is H, F, or Cl
Figure imgf000004_0004
where R5 is H, F, or Cl
Figure imgf000004_0005
where R4 is F or Cl
Figure imgf000004_0006
If
Figure imgf000005_0001
where R4 is F or Cl
Additionally, this invention provides compounds of formula I-R below, in which the chiral carbon is in the R configuration,
Figure imgf000005_0002
I-R
In one subgeneric embodiment, shown below, the invention provides a compound of formula II, which is a compound of formula I where A is S, n is 1 or 2, and other substituents are as defined above for formula I.
Figure imgf000005_0003
Additionally, this invention provides compounds of formula H-R below, in which the chiral carbon is in the R configuration,
Figure imgf000006_0001
In another subgeneric embodiment, shown below, the invention provides a compound of formula III, where A is O, n is 1 or 2, and other substituents are as defined above for formula I.
Figure imgf000006_0002
In another subgeneric embodiment, the invention provides a compound of formula IV, where A is CH2, n is 1 or 2, and other substituents are as defined above for formula I.
Figure imgf000006_0003
This invention also provides the R isomers of foπnulas III and IV.
In another subgeneric embodiment, the invention provides a compound of formula I, where R2 is F or Cl.
In another subgeneric embodiment, the invention provides a compound of formula I, where R2 is Cl.
In another subgeneric embodiment, the invention provides a compound of formula I, where Ri and R3 are both F.
In another subgeneric embodiment, the invention provides a compound of formula I, where Ri is methyl and R2 is F.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2 and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2 and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 3-thienyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 3-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I3 where A is S, Q is 3-furyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is S, Q is 3-furyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is S, Q is 3-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is S, Q is 3-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 4-fluorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of fonnula I, where A is S, Q is 4-fluorophenyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 4-chlorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is S, Q is 4-chlorophenyl, and n is 2.
In a further subgeneric embodiment, tin's invention provides a compound of formula I, where A is S, Q is 5-fluoro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-fluoro-2-pyridyl, and n is 2. In a lurther subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-fluoro-5-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-fiuoro~5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-chloro-5-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-chloro-5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is S, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 2-thienyl, and n is 1. JLn a lurther subgeneπc embodiment, this invention provides a compound of formula I, where A is S, Q is 2-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is S, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 3-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 3-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I3 where A is O, Q is 3-furyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 3-furyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 3-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 3-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 4-fluorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 4-fluorophenyl, and n is 2. In a rurtner subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 4-chlorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 4-chlorophenyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-fluoro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-fluoro-2-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-fluoro-5-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-fluoro-5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is O, Q is 2-chloro-5-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-chloro-5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-pyrrolyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 2-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-thienyl or 5-fluoro-2~thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is O, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-furyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-furyl, and n is 2. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 3-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 4-fluorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 4-fluorophenyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 4-chlorophenyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 4-chlorophenyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-fluoro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-fluoro-2-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of foπnula I, where A is CH2, Q is 2-fluoro-5-pyridyl, and n is 1. In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-fluoro-5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-chloro-5-pyridyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-chloro-5-pyridyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-pyrrolyl or 5-fluoro-2-pyrrolyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 2-thienyl, and n is 2.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 1.
In a further subgeneric embodiment, this invention provides a compound of formula I, where A is CH2, Q is 5-chloro-2-thienyl or 5-fluoro-2-thienyl, and n is 2. Speccific embodiments of the invention include the compounds whose structures are shown below, as well as in the Table 1 in the next section.
Figure imgf000015_0001
Figure imgf000015_0002
Figure imgf000015_0003
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0003
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003

Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
Figure imgf000019_0002
Figure imgf000019_0003
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
Figure imgf000021_0001
Detailed Description ol tne invention
Synthesis
Compounds of this invention can be prepared according to the schemes below. Chiral separations are performed by supercritical fluid chromatography (SFC) according to the method of Berger. Berger, T. A. "Practical advantages of packed column supercritical fluid chromatography in supporting combinatorial chemistry," ACS Symposium Series (2000), 748(Unified Chromatography), 203-233. CODEN: ACSMC8 ISSN:0097-6156. CAN 132:216255 AN 2000:154567 CAPLUS; Berger, T. A.; Todd, B. S. "Packed column supercritical fluid chromatography of oligoethers using pure carbon dioxide with flame ionization and ultraviolet detection" Chromatographic! (2001), 54(11/12), 777-781. CODEN: CHRGB7 ISSN:0009-5893. CAN 136:296563 AN 2002:67904 CAPLUS; Berger, T. A.; Todd, B. S. "Packed column supercritical fluid chromatography of polysiloxanes using pure and hexane modified carbon dioxide with flame ionization and ultraviolet detection," Chromatographia (2001), 54(11/12), 771-775. CODEN: CHRGB7 ISSN:0009-5893. CAN 136:295293 AN 2002:67903 CAPLUS
The Berger procedure may be summarized as follows: The racemic mixture (60 mg) is dissolved in methanol (2 ml) and injected into a preparative chiral column (ChiralPak AD- H SFC, i.d. lcm x 25 cm). The SFC conditions are as follows: mobile phase, 65% CO2 and 35% methanol: flow rate, 10 ml/min; detection wavelength, 220 run. Two pools of material were isolated with different retention times. The absolute configuration was assigned by comparison based on the crystallographic results of CP0601 (CP060-(R)-(+), [α]D = +33.3°; CP060-(S)-(-), [α]D = -33.5°) (Kato, Tatsuya; Ozaki, Tomokazu; Tamura, Kazuhiko; Suzuki, Yoshiyuki; Akima, Michitaka; Ohi, Nobuhiro, "Novel Calcium Antagonists with Both Calcium Overload Inhibition and Antioxidant Activity. 2. Structure-Activity Relationships of Thiazolidinone Derivatives," Journal of Medicinal Chemistiy (1999), 42(16), 3134-3146. Representations of the R form are made on that basis.
1 2-(3, 5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3, 4- (methylenedioxy)phenoxy] ethyl]amino]propyl]- 1 ,3-thiazolidin-4-one. Synthesis of 2-(3-pyrrolylpyrazol-4-yl)thiazolidinone
Figure imgf000023_0001
A mixture of l-(4-fluorophenyl)-3-(lH-pyrrol-2-yl)-lH-pyrazole-4-carbaldehyde (128 mg, 0.5mmol) and tyramine (82 mg, O.βmmol) in 20 ml of methanol was refluxed for 3 hours, then the solvent was removed in vacuo and the residue was dried in oven under reduced pressure. The residue was dissolved in 20 ml of toluene and mercaptoacetic acid (92 mg, lmmol) was added. The mixture was refluxed with condenser equipped with molecular sieves for 10 hours. The solvent was removed in vacuo and the resulting oily residue was dissolved in chloroform and washed with saturated sodium bicarbonate twice and water twice. The chloroform solution was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by column (chloroform) to give a racemic product as white solid. syntnesis of 2-(3-phenylpyrrazol-4-yl)oxazolidinones
Figure imgf000024_0001
A mixture of l,3-diphenyl-lH-pyrazole-4-carbaldehyde (0.5g, 2mmol), 2-hydroxy-N- [2-(4-methoxy-phenyl)-ethyl]-acetamide (0.46g, 2.2mmol), and p-toluenesulfonic acid (5mg) in 40 ml of toluene was refluxed with condenser equipped with molecular sieves for 24 hours. The solvent was removed in vacuo and the resulting residue was dried in vacuo and dissolved in 20 ml of anhydrous dichloromethane under argon. The mixture was cooled to -7O0C in a acetone-dry ice bath and 5 ml of IM boron tribromide in dichloromethane was added dropwise with stirring. The reaction mixture was stirred at room temperature overnight, then 20 ml of water was added with stirring until two clear layer solution formed. The organic layer was separated and the water layer was extracted with dichloromethane twice. The combined organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel column (chloroform/methanol, 40:1) to give pure product as a white solid. The pure isomer was obtained by following the above resolution method with the same conditions. Synthesis of (2-3-furfurylpyrrazolyl)-4-oxazoIidinone
Figure imgf000025_0001
R = F or H 3-Furoyl chloride
A mixture of 25 g of 3-furoic acid and 65 ml of thionyl chloride was heated to reflux for 6 hours. Then excess thionyl chloride was removed, and the residue was distilled under reduced pressure to give 25 g of 3-furoyl chloride as a colorless oil.
3-Acetylfuran
In a 500-ml. three-necked round-bottomed flask equipped with a mercury-sealed stirrer, a dropping funnel, and a reflux condenser (protected by a drying tube) is placed 4.4 g of magnesium turnings 4 ml of anhydrous ethanol and 0.6 ml of carbon tetrachloride are added under argon. If the reaction does not start immediately, the flask is heated for a short time at 700C on an oil bath. After the reaction has proceeded for several minutes, 120 ml of anhydrous ether is added cautiously with stirring. A solution of 30.6 g of diethyl malonate inl6.5 ml of anhydrous ethanol and 20 ml of anhydrous ether is added with stirring at such a rate that rapid boiling is maintained; heat is supplied when necessary. The mixture is heated under reflux at 700C on an oil bath for 4-5 hours, at which time most of the magnesium has dissolved. To the gray solution is added 21.4 g of furan-3-carbonyl chloride dissolved in 50 ml of ether in a period of 15 minutes. Heating under reflux at 700C on the oil bath is continued throughout the addition of the furan-3-carbonyl chloride and until the solution becomes too viscous to stir. The reaction mixture is cooled (ice-bath) and shaken with dilute sulfuric acid (20.4 ml of concentrated sulfuric acid in 160 ml of water) until all the solid has dissolved and the reaction mixture become clear solution. The ether phase is separated and the aqueous layer extracted with 60 ml of ether. The ether extracts are combined and washed with water, and the solvent is removed by distillation to give crude intermediates diethyl 2- (Furan-3-carbonyl)~malonate as an yellow oily product.
To the crude oily 2~(Furan-3-carbonyl)-malonic acid diethyl ester is added a solution of 40 ml of glacial acetic acid, 4 ml of concentrated sulfuric acid, and 20 ml of water, and the mixture is heated under reflux for 6 hours or until no more carbon dioxide is evolved. The reaction mixture is chilled in an ice-salt bath (-200C), made alkaline with cold 20% sodium hydroxide solution, The yellow oil layer was extracted with ether three times, the combined ether solution was washed with brine twice and dried over anhydrous sodium sulfate and evaporated to dryness at about 100C under reduced pressure to give 13.9g of the crude product as yellow solid.
Semicarbazone
A mixture of 3-acetylfuran (11. Og, O.lmol) and semicarbazide hydrochloride (11.2g, O.lmol), and sodium acetate (27.6g, 0.2mol) in 350 ml of methanol was refluxed for 2 hours, then 100 ml of water was added and the mixture was refluxed for another 2 hours. The methanol was removed in vacuo. The solid was filtered and washed with water to give 9.6 g of yellow solid after drying in vacuo.
3-(Furan-3-yl)-lH-pyrazole-4-carbaldehyde
POCl3 (3.0ml, 33mmol) was slowly added to anhydrous DMF (7.65ml, 66mmol) at O0C (ice-bath) with stirring. After stirring for 5 min, the semicarbazone (2.5g, 15mmol) was added portionwise to the above mixture with well-stirring. The mixture was heated to 60 0C for 5 hours and poured onto 2Og of ice. It was neutralized with NaOH (6g in 24 ml of water) and heated at 60 0C for 20 min, then cooled to room temperature and neutralized with ION HCl to pH 6. The resulting white precipitates were filtered and washed with water. After drying in vacuo at 60 0C, 2 of the aldehyde as yellow solid was obtained.
l-(4-Fluoro-phenyl)-3-furan-3-yl-lH-pyrazole-4-carbaldehyde
To a 25 ml round bottle flask was added in sequence: 4-fluorophenylboronic acid (84mg, 0.6mmol), 3-(furan-3-yl)-lH-pyrazole-4-carbaldehyde (49mg,0.3mmol), copper (II) acetate (81mg, 0.45mmol), 4A molecular sieves (250mg), pyridine (49μL), and 4 ml of anhydrous dichloromethane. The reaction mixture was stirred at ambient temperature for 2 days. The resulting mixture was filtered through Celite, washed with methanol and purified by silica gel column (hexane/ethyl acetate, 4:1) to give product as white solid.
2-[l-(4-Fluoro-phenyl)-3-furan-3-yl-lH-pyrazol-4-yl]-3-[2-(4-hydroxy-phenyl)-ethyl]- oxazolidin-4-one
A mixture of l-(4-fluoro-phenyl)-3-furan-3-yl-lH-pyrazole-4-carbaldehyde (0.51g, 2mmol), 2-hydroxy-N-[2-(4-methoxy-phenyl)-ethyl]-acetamide (0.46g, 2.2mmol), and p- toluenesulfonic acid (5mg) in 40 ml of toluene was refluxed with condenser equipped with molecular sieves for 24 hours. The solvent was removed in vacuo and the resulting residue was dried in vacuo and dissolved in 20 ml of anhydrous dichloromethane under argon. The mixture was cooled to -700C in an acetone-dry ice bath and 5 ml of IM boron tribromide in dichloromethane was added dropwise with stirring. The reaction mixture was stirred at room temperature overnight, then 20 ml of water was added with stirring until two clear layer solution formed. The organic layer was separated and the water layer was extracted with dichloromethane twice. The combined organic layer was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by preparative HPLC.
HBV Screening Assay
HepG2 cells are transduced using a baculovirus to deliver the HBV genome essentially as previously described (Delaney, W.E., and Isom, H.C. Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus. Hepatology 1998; 28: 1134-1146.). Transduced cells are cultured in supplemented EMEM media with 10% fetal bovine serum in a 5% CO2 incubator at 37°C for three days in the presence of test compounds. The cells are lysed in a buffer containing 0.5% NP-40 and 500 microgram/ml proteinase K. A solid-phase hybridization is performed to capture the viral DNA and to label the target DNA with Digoxigenin-labeled DNA probes. The captured viral DNA is detected by ELISA using horseradish peroxidase-conjugated anti-digoxigenin antibodies. The EC50 values are determined using ExcelFit software from the inhibition values of a titration curve for each compound.
For CC50 determinations, the test compounds are co-cultured with non-transduced HepG2 for three days under the conditions described above. The Promega CellTiter 96 AQUeous One Solution Cell Proliferation Assay is used to measure cell proliferation/viability. The CC50 values are determined using ExcelFit™ software from the inhibition values of the titration curve for each compound.
Three racemates were resolved by chiral chromatography. The activities of the dextro- and levorotatory fractions were determined. The structures and results given as the EC50 are presented in the table below.
Activities of Isolated Enantiomers
Figure imgf000029_0001
Figure imgf000029_0002
In each case the dextrorotatory form is more than 250 fold more active than the levorotatory enantiomer. The assignment of absolute configuration is based crystal structure of 2-(3, 5- di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3, 4-methylenedioxy)phenoxy] ethyl]amino]propyl]-l,3-thiazolidin-4-one. Kato, T., et ah, 1999, J.Med. Chem 42, 3134-46. As used herein the R absolute configuration is intended to denote the dextrorotatory form. As used herein the term substantially free of the levorotatory form should be construed by reference to examples 15, 32 and 19, which are substantially free of the levorotatory form. The invention encompasses both mixtures of the dextrorotatory and levorotatory forms and compositions comprising the dextrorotatory form substantially free of the levorotatory form. As used herein, "substantially free" means a greater than 90% enantiomeric excess of one isomer.
Test Results for Selected Compounds
Table 1 below lists selected compounds with their structures and corresponding antiviral activity. For EC50 determinations, the following legend applies: A: EC50 < 5OnM; B: EC50 = 5OnM - 175 nM; C: EC50 = 175 - 75OnM; D: > 750 nM). Antiviral activity was determined using assay systems as described above. ND means not determined.
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001

Claims

ClaimsWhat is claimed is
1. A compound of formula I
Figure imgf000040_0001
r where n is 1 or 2; R1, R2, and R3 are, independently, H, F, Cl, Br or CF3, and Ri may also be methyl; A is O, S or CH2; and Q is selected from the following:
Figure imgf000040_0002
where Q' is O, S or NH
Ib
Figure imgf000040_0003
where R4 is F or Cl
Ic
Figure imgf000040_0004
where R5 is H, F or Cl
Id
Figure imgf000040_0005
where R5 is H, F or Cl 1 e
Figure imgf000041_0001
V where R4 is F or Cl.
If
Figure imgf000041_0002
where R4 is F or Cl.
2. A compound of formula IR
Figure imgf000041_0003
IR where all substituents are defined as for formula I.
3. The compound of claim 1 or claim 2, where R1 is CF3.
4. The compound of claim 1 or claim 2, where R2 is Br.
5. The compound of claim 1 or claim 2, where R2 is I.
6. The compound of claim 1 or claim 2, where A is O.
7. The compound of claim 6, where Q is furan-3-yl or thiophen-3-yl.
8. The compound of claim 7, where n is 2 and Ri is H.
9. The compound of claim 7, where R2 is Br and R3 is H.
10. The compound of claim 8, where R2 is Cl or F, and R3 is CF3.
11. The compound of claim 6, where R2 is H, n is 2, and Ri is not methyl.
12. The compound of claim 1 or claim 2, where A is S.
13. The compound of claim 12, where Q is a furan-3-yl or thiophen-3-yl.
14. The compound of claim 13, where n is 2, and R\ is H.
15. The compound of claim 14, where R2 is Br, and R3 is H.
16. The compound of claim 15, where R2 is Cl or F, and R3 is CF3.
17. The compound of claim 13, where R2 is H, n is 2, and Rl is not methyl.
18. The compound of claim 1 or claim 2, where A is CH2.
19. The compound of claim 18, where Q is furan-3-yl or thiophen-3-yl.
20. The compound of claim 19, where n is 2, and Ri is H.
21. The compound of claim 20, where R2 is Br, and R3 is H.
22. The compound of claim 20, where R2 is Cl or F, and R3 is CF3.
21. The compound of claim 17, where R2 is H, n is 2, and Ri is not methyl.
22. A composition comprising a compound of any one of claims 1-21, which composition is substantially free of the levorotatory enantiomer of the compound.
23. A compound selected from those pictured below.
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
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CN109311865B (en) * 2016-04-06 2021-08-31 上海挚盟医药科技有限公司 Pyrazole-oxazolidinone compound for resisting hepatitis B virus
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WO2022135601A1 (en) * 2020-12-25 2022-06-30 杭州百新生物医药科技有限公司 5-alkyl-2-pyrazole-oxazolidine-4-ketone derivative and use thereof
WO2023001299A1 (en) * 2021-07-23 2023-01-26 上海挚盟医药科技有限公司 Crystal form of compound represented by formula i, and preparation therefor and application thereof

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