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Title:
ANTIVIRAL COMPOUNDS AND THEIR USE
Document Type and Number:
WIPO Patent Application WO/2021/062482
Kind Code:
A1
Abstract:
The invention relates to compounds that have antiviral activity, particularly 4-oxochromane derivatives that have antiviral activity against viruses of the Family Flaviviridae. Methods of treating viruses with the 4-oxochromane compounds, particularly viruses of the Family Flaviviridae, are also described.

Inventors:
COLLET TRUDI ANNE (AU)
DIGHE SATISH NATHA (AU)
Application Number:
PCT/AU2020/051058
Publication Date:
April 08, 2021
Filing Date:
October 02, 2020
Export Citation:
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Assignee:
SALUT PRODUCTS PTY LTD (AU)
International Classes:
C07H17/07; A61K31/352; A61P31/14; C07D311/28
Attorney, Agent or Firm:
GRIFFITH HACK (AU)
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Claims:
Claims

1. A compound of formula (I): wherein one of R1 and R2 is hydrogen and the other is A; is a double or single bond;

X is O or S;

R3 is selected from -C1-6alkylR7, -C2-6alkenylR7, -C2-6alkynylR7, -OH, -OC1-6alkylR7, -OC2- 6alkenylR7, -OC2-6alkynylR7; -SH, -SC1-6alkylR7, -SC2-6alkenylR7, -SC2- 6alkynylR7, -N(R8)2, -N(R8)C1-6alkylR7, -N(R8)C2-6alkenylR7, -N(R8)C2-6alkynylR7, -C(O)OC1- 6alkylR7, -C(O)OC1-6alkenylR7, -C(O)OC1-6alkynylR7, -C(O)C1-6alkylR7, -C(O)C1-6alkenylR7, -C(O)C1-6alkynylR7, -S(O)C1-6alkylR7, -S(O)C2-6alkenylR7, -S(O)C2-6alkynylR7, -S(O)2C1- 6alkylR7, -S(O)2C2-6alkenylR7, -S(O)2C2-6alkynylR7, -S(O)2N(R8)2, -S(O)2N(R8)C1-6alkylR7, - S(O)2N(R8)C2-6alkenylR7, - S(O)2N(R8)C2-6alkynylR7, -N(R8)S(O)2C1-6alkylR7, - N(R8)S(O)2C2-6alkenylR7, -N(R8)S(O)2C2-6alkynylR7, -C1-6alkylOC1-6alkylR7, -C1-6alkylOC2- 6alkenylR7, -C1-6alkylOC2-6alkynylR7, -C1-6alkylSC1-6alkylR7, -C1-6alkylSC2-6alkenylR7, -C1- 6alkylSC2-6alkynylR7, -C1-6alkylN(R8)C1-6alkylR7, -C1-6alkylN(R8)C2-6alkenylR7, -C1- 6alkylN(R8)C2-6alkynylR7, -C1-6alkylC(O)OC1-6alkylR7, -C1-6alkylC(O)OC1-6alkenylR7, -C1- 6alkylC(O)OC1-6alkynylR7, -C1-6alkylC(O)C1-6alkylR7, -C1-6alkylC(O)C1-6alkenylR7, -C1- 6alkylC(O)C1-6alkynylR7, -C1-6alkylS(O)C1-6alkylR7, -C1-6alkylS(O)C2-6alkenylR7, -C1- 6alkylS(O)C2-6alkynylR7, -C1-6alkylS(O)2C1-6alkylR7, -C1-6alkylS(O)2C2-6alkenylR7, -C1- 6alkylS(O)2C2-6alkynylR7, -C1-6alkylS(O)2N(R8)2, -C1-6alkylS(O)2N(R8)C1-6alkylR7, -C1- 6alkylS(O)2N(R8)C2-6alkenylR7, -C1-6alkylS(O)2N(R8)C2-6alkynylR7, -C1-6alkylN(R8)S(O)2C1- 6alkylR7, -C1-6alkylN(R8)S(O)2C2-6alkenylR7 and -C1-6alkylN(R8)S(O)2C2-6alkynylR7;

R4 and R6 are each independently selected from hydrogen or R7;

R5 is selected from hydrogen, hydroxy and a cyclic monosaccharide;

R7 is selected from hydrogen, OR8, CO2R8, CON(R8)2, SR8, N(R8)2, N+(R8)3 and SON(R8)2; R8 is selected from hydrogen, -C1-6alkyl, -C2-6alkenyl and -C2-6alkynyl;

A is wherein B is a cycloalkyl group, an aryl group, a heterocyclyl group or aheteroaryl group, R9 is selected from -C1-6alkylR7, -C2-6alkenylR7, -C2-6alkynylR7, -OH, -OC1-6alkylR7, -OC2- 6alkenylR7, -OC2-6alkynylR7; -SH, -SC1-6alkylR7, -SC2-6alkenylR7, -SC2- 6alkynylR7, -N(R8)2, -N(R8)C1-6alkylR7, -N(R8)C2-6alkenylR7, -N(R8)C2-6alkynylR7, -C(O)OC1- 6alkylR7, -C(O)OC1-6alkenylR7, -C(O)OC1-6alkynylR7, -C(O)C1-6alkylR7, -C(O)C1-6alkenylR7, -C(O)C1-6alkynylR7, -S(O)C1-6alkylR7, -S(O)C2-ealkenylR7, -S(O)C2-ealkynylR7, -S(O)2C1- 6alkylR7, -S(O)2C2-6alkenylR7, -S(O)2C2-6alkynylR7, -S(O)2N(R8)2, -S(O)2N(R8)C1-6alkylR7, - S(O)2N(R8)C2-6alkenylR7, - S(O)2N(R8)C2-6alkynylR7, -N(R8)S(O)2C1-6alkylR7, - N(R8)S(O)2C2-6alkenylR7 and -N(R8)S(O)2C2-6alkynylR7; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 wherein R1 is A and ring B is an aryl group or a heteroaryl group substituted with one or two R9 substituents.

3. The compound according to claim 1 or claim 2 wherein R2 is hydrogen.

4. The compound according to any one of claims 1 to 3 wherein R3 is -C1-6alkylR7, -C1- 6alkylOC1-6alkylR7, -C1-6alkylSC1-6alkylR7, -C1-6alkylN(R8)C1-6alkylR7, -C(O)OC1-6alkylR7, - C(O)C1-6alkylR7, -C1-6alkylC(O)OC1-6alkylR7, -C1-6alkylC(O)C1-6alkylR7, -C1-6alkylS(O)C1- 6alkylR7, -C1-6alkylS(O)2C1-6alkylR7, -C1-6alkylS(O)2N(R8)C1-6alkylR7 and -C1- 6alkylN(R8)S(O)2C1-6alkylR7.

5. The compound according to claim 4 wherein R3 is -C1-6alkylOH, -C1-6alkylSH, -C1- 6alkylCO2H, -C1-6alkylCONH2, -C1-6alkylNH2, -C(O)OC1-6alkyl, -C(O)OC1-6alkylOH, - C(O)OC1-6alkylSH, -C(O)OC1-6alkylCO2H, -C(O)OC1-6alkylCONH2, -C(O)OC1-6alkylNH2, - C1-6alkylOC1-6alkylOH, -C1-6alkylOC1-6alkylSH, -C1-6alkylOC1-6alkylCO2H, -C1-6alkylOC1- 6alkylCONH2, -C1-6alkylOC1-6alkylNH2, -C1-6alkylSC1-6alkylOH, -C1-6alkylSC1-6alkylSH, -C1- 6alkylSC1-6alkylCO2 H, -C1-6alkylSC1-6alkylCONH2, -C1-6alkylSC1-6alkylNH2, -C1- 6alkylN(H)C1-6alkylOH, -C1-6alkylN(CH3)C1-6alkylOH, -C1-6alkylN(H)C1-6alkylSH, -C1- 6alkylN(CH3)C1-6alkylSH, -C1-6alkylN(H)C1-6alkylCO2H, -C1-6alkylN(CH3)C1-6alkylCO2H, -C1- 6alkylN(H)C1-6alkylCONH2, -C1-6alkylN(CH3)C1-6alkylCONH2, -C1-6alkylN(H)C1- 6alkylNH2, -C1-6alkylN(CH3)C1-6alkylNH2, -C1-6alkylC(O)OC1-6alkylOH, -C1-6alkylC(O)OC1- 6alkylSH, -C1-6alkylC(O)OC1-6alkylCO2H , -C1-6alkylC(O)OC1-6alkylCONH2 , -C1- 6alkylC(O)OC1-6alkylNH2 , -C1-6alkylS(O)C1-6alkylOH, -C1-6alkylS(O)C1-6alkylSH, -C1- 6alkylS(O)C1-6alkylCO2H, -C1-6alkylS(O)C1-6alkylCONH2, -C1-6alkylS(O)C1-6alkylNH2, -C1- 6alkylS(O)2N(H)C1-6alkylOH, -C1-6alkylS(O)2N(CH3)C1-6alkylOH, -C1-6alkylS(O)2N(H)C1- 6alkylSH, -C1-6alkylS(O)2N(CH3)C1-6alkylSH, -C1-6alkylS(O)2N(H)C1-6alkylCO2H, -C1- 6alkylS(O)2N(CH3)C1-6alkylCO2H, -C1-6alkylS(O)2N(H)C1-6alkylCONH2, -C1- 6alkylS(O)2N(CH3)C1-6alkylCONH2, -C1-6alkylS(O)2N(H)C1-6alkylNH2, -C1- 6alkylS(O)2N(CH3)C1-6alkylNH2, -C1-6alkylN(H)S(O)2C1-6alkylOH, -C1-6alkylN(CH3)S(O)2C1- 6alkylOH, -C1-6alkylN(H)S(O)2C1-6alkylSH, -C1-6alkylN(CH3)S(O)2C1-6alkylSH, -C1- 6alkylN(H)S(O)2C1-6alkylCO2H, -C1-6alkylN(CH3)S(O)2C1-6alkylCO2H, -C1-6alkylN(H)S(O)2C1- 6alkylCONH2H, -C1-6alkylN(CH3)S(O)2C1-6alkylCONH2, -C1-6alkylN(H)S(O)2C1-6alkylNH2 and -C1-6alkylN(CH3)S(O)2C1-6alkylNH2.

6. The compound according to any one of claims 1 to 5 wherein R4 is hydrogen, -OH, -SH, - CO2H, -N(R8)2 or -CONH2.

7. The compound according to any one of claims 1 to 6 wherein R5 is hydroxy or a cyclic monosaccharide selected from D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D- idose, D-galactose, D-talose and D-fructose.

8. The compound according to claim 7 wherein R5 is hydroxy or D-glucose.

9. The compound according to either one of claims 7 or 8 wherein the monosaccharide is attached to the chromone ring through an ether bond.

10. The compound according to any one of claims 1 to 9 wherein R6 is hydrogen, -OH, -SH, - CO2H, -N(R8)2 or -CONH2.

11. The compound according to any one of claims 1 to 10 wherein ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

12. The compound according to any one of claims 1 to 11 wherein X is O.

13. The compound according to any one of claims 1 to 12 wherein R9 is selected from -C1- 6alkylR7, -OH, -OC1-6alkylR7, -SH, -SC1-6alkylR7, -N(R8)2, -N(R8)C1-6alkylR7, -C(O)OC1- 6alkylR7, -C(O)C1-6alkylR7, -S(O)C1-6alkylR7, -S(O)2C1-6alkylR7, -

S(O)2N(R8)2, -S(O)2N(R8)C1-6alkylR7 and -N(R8)S(O)2C1-6alkylR7.

14. The compound according to claim 13 wherein R9 is selected from -C1-6alkylOH, -C1- 6alkylSH, -C1-6alkylCO2H, -C1-6alkylCONH2, -C1-6alkylNH2, -C1-6alkylN(CH3)2, -C1- 6alkylN+(CH3)3, OH, -OC1-6alkylOH, -OC1-6alkylSH, -OC1-6alkylCO2H, -OC1-6alkylCONH2, - OC1-6alkylNH2, -OC1-6alkylN(CH3)2, -OC1-6alkylN+(CH3)3, -SH, -SC1-6alkylOH, -SC1- 6alkylSH, -SC1-6alkylCO2H, -SC1-6alkylCONH2, -SC1-6alkylNH2, -NH2, -NH(CH3), -N(CH3)2, N+(CH3)3, -NHCl- 6alkylOH, -NHC1-6alkylSH, -NHC1-6alkylCO2H, -NHC1- 6alkylCONH2, -NHC1-6alkylNH2, -NHC1-6alkylN(CH3)2, -NHC1-6alkylN+(CH3)3, -N(CH3)C1- 6alkylOH, -N(CH3)C1-6alkylSH, -N(CH3)C1-6alkylCO2H, -N(CH3)C1-6alkylCONH2, -N(CH3)C1- 6alkylNH2, -N(CH3)C1-6alkylN(CH3)2, - N(CH3)C1-6alkylN+(CH3)3, -C(O)OC1-6alkylOH, - C(O)OC1-6alkylSH, -C(O)OC1-6alkylCO2H , -C(O)OC1-6alkylCONH2, -C(O)OC1-6alkylNH2, - C(O)OC1-6alkylN(CH3)2, -C(O)OC1-6alkylN+(CH3)3, -S(O)C1-6alkylOH, -S(O)C1-6alkylSH, - S(O)C1-6alkylCO2H, -S(O)C1-6alkylCONH2, -S(O)C1-6alkylNH2, -S(O)C1-6alkylN(CH3)2, - S(O)C1-6alkylN+(CH3)3, -S(O)2C1-6alkylOH, -S(O)2C1-6alkylSH, -S(O)2C1-6alkylCO2H, - S(O)2C1-6alkylCONH2, -S(O)2C1-6alkylNH2, -S(O)2C1-6alkylN(CH3)2, -S(O)2C1-6alkylN+(CH3)3, -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2, -S(O)2NHC1-6alkylOH, -S(O)2NHC1- 6alkylSH, -S(O)2NHC1-6alkylCO2H, -S(O)2NHC1-6alkylCONH2, -S(O)2NHC1-6alkylNH2, - S(O)2NHC1-6alkylN(CH3)2, -S(O)2NHC1-6alkylN+(CH3)3, -S(O)2N(CH3)C1- 6alkylOH, -S(O)2N(CH3)C1-6alkylSH, -S(O)2N(CH3)C1-6alkylCO2H, -S(O)2N(CH3)C1- 6alkylCONH2, -S(O)2N(CH3)C1-6alkylNH2, -S(O)2N(CH3)C1-6alkylN(CH3)2, -S(O)2N(CH3)C1- 6alkylN+(CH3)3, -NHS(O)2C1-6alkylOH, -NHS(O)2C1-6alkylSH, -NHS(O)2C1- 6alkylCO2H, -NHS(O)2C1-6alkylCONH2, -NHS(O)2C1-6alkylNH2, -NHS(O)2C1-6alkylN(CH3)2, - NHS(O)2C1-6alkylN+(CH3)3, -N(CH3)S(O)2C1-6alkylOH, -N(CH3)S(O)2C1- 6alkylSH, -N(CH3)S(O)2C1-6alkylCO2H, -N(CH3)S(O)2C1-6alkylCONH2, -N(CH3)S(O)2C1- 6alkylNH2, -N(CH3)S(O)2C1-6alkylN(CH3)2 and -N(CH3)S(O)2C1-6alkylN+(CH3)3.

15. The compound according to claim 13 or 14 wherein R9 is selected from -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -CH2SH, -CH2CH2SH, -CH2CH2CH2SH, -CH2CO2H, - CH2CH2CO2H, -CH2CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2CH2CONH2, -

CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2N(CH3)2, -CH2CH2N(CH3)2, - CH2CH2CH2N(CH3)2, -CH2N+(CH3)3, -CH2CH2N+(CH3)3, -CH2CH2CH2N+(CH3)3, -OCH2OH, -OCH2CH2OH, -OCH2CH2CH2OH, -OCH2SH, -OCH2CH2SH, -OCH2CH2CH2SH, - OCH2CO2H, -OCH2CH2CO2H, -OCH2CH2CH2CO2H, -OCH2CONH2, -OCH2CH2CONH2, -

OCH2CH2CH2CONH2, -OCH2NH2, -OCH2CH2NH2, -OCH2CH2CH2NH2, -OCH2N(CH3)2, - OCH2CH2N(CH3)2, -OCH2CH2CH2N(CH3)2, -OCH2N+(CH3)3, -OCH2CH2N+(CH3)3, - OCH2CH2CH2N+(CH3)3-SCH2OH, -SCH2CH2OH, -SCH2CH2CH2OH, -SCH2SH, - SCH2CH2SH, -SCH2CH2CH2SH,-SCH2CO2H, -SCH2CH2CO2H, -SCH2CH2CH2CO2H, - SCH2CONH2, -SCH2CH2CONH2, -SCH2CH2CH2CONH2, -SCH2NH2, -SCH2CH2NH2, -

SCH2CH2CH2NH2, -SCH2N(CH3)2, -SCH2CH2N(CH3)2, -SCH2CH2CH2N(CH3)2, - SCH2N+(CH3)3, -SCH2CH2N+(CH3)3, S-CH2CH2CH2N+(CH3)3, -NHCH2OH, -NHCH2CH2OH, -NHCH2CH2CH2OH, -NHCH2SH, -NHCH2CH2SH, -

NHCH2CH2CH2SH, -NHCH2CO2H, -NHCH2CH2CO2H, -NHCH2CH2CH2CO2H, -NHCH2CO NH2, -NHCH2CH2CONH2, -NHCH2CH2CH2CONH2, -NHCH2NH2, -NHCH2CH2NH2, -NHCH2 CH2CH2NH2, -NHCH2N(CH3)2, -NHCH2CH2N(CH3)2, -NHCH2CH2CH2N(CH3)2, - NHCH2N+(CH3)3, -NHCH2CH2N+(CH3)3, - NHCH2CH2CH2N+(CH3)3, -N(CH3)CH2OH, -N(CH3)CH2CH2OH,

N(CH3)CH2CH2CH2OH, -N(CH3)CH2SH, -N(CH3)CH2CH2SH, -N(CH3)CH2CH2CH2SH, -N(C H3)CH2CO2H, -N(CH3)CH2CH2CO2H, -N(CH3)CH2CH2CH2CO2H, -N(CH3)CH2CONH2, -N(C H3)CH2CH2CONH2, -N(CH3)CH2CH2CH2CONH2, -N(CH3)CH2NH2, -N(CH3)CH2CH2NH2, - N(CH3)CH2CH2CH2NH2, -N(CH3)CH2N(CH3)2, -N(CH3)CH2CH2N(CH3)2, - N(CH3)CH2CH2CH2N(CH3)2, -N(CH3)CH2N+(CH3)3, -N(CH3)CH2CH2N+(CH3)3, - N(CH3)CH2CH2CH2N+(CH3)3, -CO2CH2OH, -CO2CH2CH2OH, -CO2CH2CH2CH2OH, - CO2CH2SH, -CO2CH2CH2SH, -CO2CH2CH2CH2SH, -CO2CH2CO2H, -CO2CH2CH2CO2H, - CO2CH2CH2CH2CO2H, -CO2CH2CONH2, -CO2CH2CH2CONH2, CO2CH2CH2CH2CONH2, - CO2CH2NH2, -CO2CH2CH2NH2 and -CO2CH2CH2CH2NH2, -CO2CH2N(CH3)2, - CO2CH2CH2N(CH3)2, -CO2CH2CH2CH2N(CH3)2, -CO2CH2N+(CH3)3, -CO2CH2CH2N+(CH3)3 and -CO2CH2CH2CH2N+(CH3)3.

16. The compound according to any one of claims 1 to 15 wherein n is 1 or 2.

17. The compound of formula (I) according to claim 1 which is a compound of formula (II): wherein R2 is hydrogen, R5a is hydrogen or where m is 1 or 2 and X, B, R3, R4, R6, R9 and n are as defined for formula (I).

18. The compound of formula (I) according to claim 1 which is a compound of formula (III): wherein R2 is hydrogen, R5a is hydrogen or and X, B, R3, R4, R6, R9 and n are as defined for formula (I).

19. The compound of formula (I) according to claim 1 which is a compound of formula (IV): wherein R2 is hydrogen and X, R3, R4, R6, R9 and n are as defined in claim 1.

20. A compound of formula (I) according to claim 1, as shown in Table 1.

21. A compound of formula (I) which is compound 352, 377, 380, 381, 485, 486, 487 and 488.

22. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

23. A method of treating or preventing a viral infection caused by a virus of the Family Flaviviridae comprising administering to a subject a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition for use in treating or preventing a viral infection caused by a virus of the Family Flaviviridae, wherein the composition comprises a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof.

25. Use of a compound of formula (I) according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a viral infection caused by a virus of the Family Flaviviridae.

Description:
Antiviral Compounds and their Use

Field

[0001] The invention relates to compounds that have antiviral activity, particularly 4- oxochromane derivatives that have antiviral activity against viruses of the Family Flaviviridae. Methods of treating viruses with the 4-oxochromane compounds, particularly viruses of the Family Flaviviridae, are also described.

Background

[0002] Flaviviruses, from the Family Flaviviridae, cause serious infections including haemorrhagic fever and encephalitis. Flaviviruses are transmitted to humans by mosquitoes and ticks and some of these viruses are endemic in tropical and sub-tropical regions of the world.

[0003] Current estimates indicate that greater than 2.5 billion people, approximately 30% of the global population, in more than 100 countries, are at risk of infection with the dengue virus. Each year, approximately 390 million infections with the dengue virus occur world-wide. Of these infections, 500,000 develop dengue haemorrhagic fever resulting in 25,000 deaths per year globally. In India, it is estimated that about 33 million people have symptomatic dengue infection, whilst 100 million people have asymptomatic infection.

[0004] The 2015-16 outbreak of Zika virus in South America resulted in at least 172,830 confirmed cases of Zika virus and many thousands more suspected cases. The Zika virus is transmitted by mosquitoes such as Aedes aegpti and Aedes albopictus. The Zika virus can also be sexually transmitted between partners of any gender and transmitted from pregnant mother to foetus, thereby resulting in microcephaly and other severe brain abnormalities in infants.

[0005] Other flaviviruses are predominant in one or more regions of the world. For example, Kunjin virus, a subtype of West Nile virus, has been found in humans in Australia and is transmitted by the Culex annulirostris mosquito found in South East Asia.

[0006] There are no vaccines available at the present time for dengue virus, Zika virus or Kunjin virus and there are no effective antiviral therapies. There is a need for new antiviral therapies that treat flavivirus infections.

Summary

[0007] The present invention is predicated at least in part on the discovery of chromone derivatives that show antiviral activity, particularly against viruses of the Family Flaviviridae. [0008] In one aspect of the present invention there is provided a compound of formula (I): wherein one of R 1 and R 2 is hydrogen and the other is A; is a double or single bond;

X is O or S;

R 3 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2 .

6alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 , -C(O)OC 1-6 alkenylR 7 , -C(O)OC 1-6 alkynylR 7 , -C(O)C 1-6 alkylR 7 , -C(O)C 1-6 alkenylR 7 , -C(O)C 1-6 alkynylR 7 , -S(O)C 1-6 alkylR 7 , -S(O)C 2-6 alkenylR 7 , -S(O)C 2-6 alkynylR 7 , -S(O) 2 C 1- 6 alkylR 7 , -S(O) 2 C 2-6 alkenylR 7 , -S(O) 2 C 2-6 alkynylR 7 , -S(O) 2 N(R 8 ) 2 , -S(O) 2 N(R 8 )C 1-6 alkylR 7 , - S(O) 2 N(R 8 )C 2-6 alkenylR 7 , - S(O) 2 N(R 8 )C 2-6 alkynylR 7 , -N(R 8 )S(O) 2 C 1-6 alkylR 7 , - N(R 8 )S(O) 2 C 2-6 alkenylR 7 , -N(R 8 )S(O) 2 C 2-6 alkynylR 7 , -C 1-6 alkylOC 1-6 alkylR 7 , -C 1-6 alkylOC 2- 6 alkenylR 7 , -C 1-6 alkylOC 2-6 alkynylR 7 , -C 1-6 alkylSC 1-6 alkylR 7 , -C 1-6 alkylSC 2-6 alkenylR 7 , -C 1- 6 alkylSC 2-6 alkynylR 7 , -C 1-6 alkylN(R 8 )C 1-6 alkylR 7 , -C 1-6 alkylN(R 8 )C 2-6 alkenylR 7 , -C 1- 6 alkylN(R 8 )C 2-6 alkynylR 7 , -C 1-6 alkylC(O)OC 1-6 alkylR 7 , -C 1-6 alkylC(O)OC 1-6 alkenylR 7 , -C 1- 6 alkylC(O)OC 1-6 alkynylR 7 , -C 1-6 alkylC(O)C 1-6 alkylR 7 , -C 1-6 alkylC(O)C 1-6 alkenylR 7 , -C 1- 6 alkylC(O)C 1-6 alkynylR 7 , -C 1-6 alkylS(O)C 1-6 alkylR 7 , -C 1-6 alkylS(O)C 2-6 alkenylR 7 , -C 1- 6 alkylS(O)C 2-6 alkynylR 7 , -C 1-6 alkylS(O) 2 C 1-6 alkylR 7 , -C 1-6 alkylS(O) 2 C 2-6 alkenylR 7 , -C 1- 6 alkylS(O) 2 C 2-6 alkynylR 7 , -C 1-6 alkylS(O) 2 N(R 8 ) 2 , -C 1-6 alkylS(O) 2 N(R 8 )C 1-6 alkylR 7 , -C 1- 6 alkylS(O) 2 N(R 8 )C 2-6 alkenylR 7 , -C 1-6 alkylS(O) 2 N(R 8 )C 2-6 alkynylR 7 , -C 1-6 alkylN(R 8 )S(O) 2 C 1- 6 alkylR 7 , -C 1-6 alkylN(R 8 )S(O) 2 C 2-6 alkenylR 7 and -C 1-6 alkylN(R 8 )S(O) 2 C 2-6 alkynylR 7 ;

R 4 and R 6 are each independently selected from hydrogen or R 7 ;

R 5 is selected from hydrogen, hydroxy and a cyclic monosaccharide;

R 7 is selected from hydrogen, OR 8 , CO 2 R 8 , CON(R 8 ) 2 , SR 8 , N(R 8 ) 2 , N + (R 8 ) 3 and SON(R 8 ) 2 ; R 8 is selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl;

A is wherein B is a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group, R 9 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2 - 6alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 , -C(O)OC 1-6 alkenylR 7 , -C(O)OC 1-6 alkynylR 7 , -C(O)C 1-6 alkylR 7 , -C(O)C 1-6 alkenylR 7 , -C(O)C 1-6 alkynylR 7 , -S(O)C 1-6 alkylR 7 , -S(O)C 2 -ealkenylR 7 , -S(O)C 2 -ealkynylR 7 , -S(O) 2 C 1- 6 alkylR 7 , -S(O) 2 C 2-6 alkenylR 7 , -S(O) 2 C 2-6 alkynylR 7 , -S(O) 2 N(R 8 ) 2 , -S(O) 2 N(R 8 )C 1-6 alkylR 7 , - S(O) 2 N(R 8 )C 2-6 alkenylR 7 , - S(O) 2 N(R 8 )C 2-6 alkynylR 7 , -N(R 8 )S(O) 2 C 1-6 alkylR 7 , - N(R 8 )S(O) 2 C 2-6 alkenylR 7 and -N(R 8 )S(O) 2 C 2-6 alkynylR 7 ; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

[0009] In another aspect of the invention there is provided a pharmaceutical composition comprising a compound of formula (I) as described herein and a pharmaceutically acceptable carrier or excipient.

[0010] In another aspect of the present invention there is provided a method of treating or preventing a viral infection caused by a virus of the Family Flaviviridae comprising administering to a subject a compound of formula (I) as described herein.

[0011] In yet another aspect of the invention there is provided a pharmaceutical composition for use in treating or preventing a viral infection caused by a virus of the Family Flaviviridae, wherein the composition comprises a compound of formula (I) as described herein.

[0012] In a further aspect of the invention there is provided a use of a compound of formula (I) as described herein in the manufacture of a medicament for treating or preventing a viral infection caused by a virus of the Family Flaviviridae.

Brief Description of the Figure

[0013] Figure 1 is a photographic representation showing plaque formation in cells infected with Kunjin virus at concentrations of 10 -1 to 10 -6 and treated with 3.6 mM of Compound 381 at 24 hours after infection (plate a.) and 72 hours after infection (plate b.)

Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described. For the purposes of the present invention, the following terms are defined below.

[0015] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “an excipient” may include a plurality of excipients, and a reference to “a subject” may be a reference to one or more subjects, and so forth.

[0016] The term “(s)” following a noun contemplates the singular or plural form, or both. [0017] The term “and/or” can mean “and” or “or”.

[0018] Unless the context requires otherwise, all percentages referred to herein are percentages by weight of the composition.

[0019] Various features of the invention are described and/or claimed with reference to a certain value, or range of values. These values are intended to relate to the results of the various appropriate measurement techniques, and therefore should be interpreted as including a margin of error inherent in any particular measurement technique. Some of the values referred to herein are denoted by the term “about” to at least in part account for this variability. The term “about”, when used to describe a value, preferably means an amount within ±25%, ±10%, ±5%, ±1% or ±0.1% of that value.

[0020] In the claims which follow and in the preceding description of the invention, except where the context requires otherwise due to express language or necessary implication, the word “comprise” or variations such as “comprises” or “comprising” is used in an inclusive sense, i.e. to specify the presence of the stated features but not to preclude the presence or addition of further features in various embodiments of the invention.

[0021] As used herein, the term "alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms. Where appropriate, the alkyl group may have a specified number of carbon atoms, for example, C 1-6 alkyl which includes alkyl groups having 1 , 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n- pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, n-hexyl, 2-methylpentyl, 3-methyl pentyl, 4- methylpentyl, 5-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, heptyl, octyl, nonyl and decyl.

[0022] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group having one or more double bonds between carbon atoms and having 2 to 10 carbon atoms. Where appropriate, the alkenyl group may have a specified number of carbon atoms. For example, C 2 -C 6 as in " C 2 -C 6 alkenyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkenyl groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, octenyl, nonenyl and decenyl.

[0023] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group having one or more triple bonds and having 2 to 10 carbon atoms. Where appropriate, the alkynyl group may have a specified number of carbon atoms. For example, C 2- C 6 as in " C 2 -C 6 alkynyl" includes groups having 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement. Examples of suitable alkynyl groups include, but are not limited to ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0024] As used herein, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon. The cycloalkyl ring may include a specified number of carbon atoms. For example, a 3 to 10 membered cycloalkyl group includes 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Examples of suitable cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.

[0025] As used herein, the term "aryl" is intended to mean any stable, monocyclic, bicyclic or tricyclic carbon ring system of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, fluorenyl, phenanthrenyl, biphenyl and binaphthyl.

[0026] The term "heterocyclic" or "heterocyclyl" as used herein, refers to a cyclic hydrocarbon, such as a cycloalkyl or cycloalkenyl defined above, in which one to four carbon atoms have been replaced by heteroatoms independently selected from the group consisting of N, N(R), S, S(O), S(O) 2 and O where R may be hydrogen or alkyl. A heterocyclic ring may be saturated or unsaturated but not aromatic. Examples of suitable heterocyclyl groups include azetidine, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, 2-oxopyrrolidinyl, pyrrolinyl, pyranyl, dioxolanyl, piperidinyl, 2-oxopiperidinyl, pyrazolinyl, imidazolinyl, thiazolinyl, dithiolyl, oxathiolyl, dioxanyl, dioxinyl, dioxazolyl, oxathiozolyl, oxazolonyl, piperazinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, dithianyl, trithianyl and oxazinyl.

[0027] The term "heteroaryl" as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, quinazolinyl, pyrazolyl, indolyl, isoindolyl, 1H,3H-1- oxoisoindolyl, benzotriazolyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl, isothiazolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,4,5-tetrazinyl and tetrazolyl.

[0028] As used herein, the term “monosaccharide” refers to a furanose or pyranose monosaccharide. Suitable monosaccharides are furanose and pyranose monosaccharides of D-ribose, D-arabinose, D-xylose, D-lyxose, D-allose, D-altrose, D-glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose, D-ribulose, D-fructose and D-sedoheptulose.

[0029] Each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl and heteroaryl whether an individual entity or as part of a larger entity may be optionally substituted with one or more optional substituents selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, oxo (=O), -OH, -SH, C 1-6 alkylO-, C 2-6 alkenylO-, C 3-6 cycloalkylO-, C 1-6 alkylS-, C 2- ealkenylS-, C 3-6 cycloalkylS-, -CO 2 H, -CO 2 C 1-6 alkyl, -NH 2 , -NH(C 1-6 alkyl), -N(C 1- 6 alkyl)2, -NH(phenyl), -N(phenyl) 2 , oxo, -CN, -NO 2 , -halogen, -CF 3 , -OCF 3 , -SCF 3 , -CHF 2 , - OCHF 2 , -SCHF 2 , -phenyl, -heterocyclyl, -heteroaryl, -Oheteroaryl, -Oheterocyclyl, -Ophenyl, - C(=O)phenyl, -C (=O)C 1-6 alkyl. Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, vinyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio, butylthio, hydroxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, fluoro, chloro, bromo, iodo, cyano, nitro, -CO 2 H, -CO 2 CH 3 , trifluoromethyl, trifluoromethoxy, trifluoromethylthio, difluoromethyl, difluoromethoxy, difluoromethylthio, morpholino, amino, methylamino, dimethylamino, phenyl, phenoxy, phenylcarbonyl, benzyl and acetyl.

[0030] The compounds of the invention may be in the form of pharmaceutically acceptable salts. It will be appreciated however that non-pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, malonic, malic (L), lactic (DL), mandelic (DL), gluconic, carbonic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, camphorsulphonic, benezenesulphonic, salicylic, cinnamic, cyclamic, sulphanilic, aspartic, glutamic, glutaric, galactaric, gentisic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0031] Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, aluminium, zinc, lysine, histidine, meglumine, ammonium and alkylammonium.

[0032] It will also be recognised that compounds of the invention may possess asymmetric centres and are therefore capable of existing in more than one stereoisomeric form. The invention thus also relates to compounds in substantially pure isomeric form at one or more asymmetric centres eg., greater than about 90% ee, such as about 95% or 97% ee or greater than 99% ee, as well as mixtures, including racemic mixtures, thereof. Such isomers may be prepared by asymmetric synthesis, for example using chiral intermediates, or by chiral resolution. The compounds of the invention may exist as geometric isomers. The invention also relates to compounds in substantially pure cis (Z) or trans (E) or mixtures thereof.

Compounds of the invention

[0033] The present invention provides compounds of formula (I): wherein one of R 1 and R 2 is hydrogen and the other is A; is a double or single bond;

X is O or S;

R 3 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2- 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2- 6 alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 , -C(O)OC 1-6 alkenylR 7 , -C(O)OC 1-6 alkynylR 7 , -C(O)C 1-6 alkylR 7 , -C(O)C 1-6 alkenylR 7 , -C(O)C 1-6 alkynylR 7 , -S(O)C 1-6 alkylR 7 , -S(O)C 2-6 alkenylR 7 , -S(O)C 2-6 alkynylR 7 , -S(O) 2 C 1- 6 alkylR 7 , -S(O) 2 C 2-6 alkenylR 7 , -S(O) 2 C 2-6 alkynylR 7 , -S(O) 2 N(R 8 ) 2 , -S(O) 2 N(R 8 )C 1-6 alkylR 7 , - S(O) 2 N(R 8 )C 2-6 alkenylR 7 , - S(O) 2 N(R 8 )C 2-6 alkynylR 7 , -N(R 8 )S(O) 2 C 1-6 alkylR 7 , - N(R 8 )S(O) 2 C 2-6 alkenylR 7 , -N(R 8 )S(O) 2 C 2-6 alkynylR 7 , -C 1-6 alkylOC 1-6 alkylR 7 , -C 1-6 alkylOC 2- 6 alkenylR 7 , -C 1-6 alkylOC 2-6 alkynylR 7 , -C 1-6 alkylSC 1-6 alkylR 7 , -C 1-6 alkylSC 2-6 alkenylR 7 , -C 1- 6 alkylSC 2-6 alkynylR 7 , -C 1-6 alkylN(R 8 )C 1-6 alkylR 7 , -C 1-6 alkylN(R 8 )C 2-6 alkenylR 7 , -C 1- 6 alkylN(R 8 )C 2-6 alkynylR 7 , -C 1-6 alkylC(O)OC 1-6 alkylR 7 , -C 1-6 alkylC(O)OC 1-6 alkenylR 7 , -C 1- 6 alkylC(O)OC 1-6 alkynylR 7 , -C 1-6 alkylC(O)C 1-6 alkylR 7 , -C 1-6 alkylC(O)C 1-6 alkenylR 7 , -C 1- 6 alkylC(O)C 1-6 alkynylR 7 , -C 1-6 alkylS(O)C 1-6 alkylR 7 , -C 1-6 alkylS(O)C 2-6 alkenylR 7 , -C 1- 6 alkylS(O)C 2-6 alkynylR 7 , -C 1-6 alkylS(O) 2 C 1-6 alkylR 7 , -C 1-6 alkylS(O) 2 C 2-6 alkenylR 7 , -C 1- 6 alkylS(O) 2 C 2-6 alkynylR 7 , -C 1-6 alkylS(O) 2 N(R 8 ) 2 , -C 1-6 alkylS(O) 2 N(R 8 )C 1-6 alkylR 7 , -C 1- 6 alkylS(O) 2 N(R 8 )C 2-6 alkenylR 7 , -C 1-6 alkylS(O) 2 N(R 8 )C 2-6 alkynylR 7 , -C 1-6 alkylN(R 8 )S(O) 2 C 1- 6 alkylR 7 , -C 1-6 alkylN(R 8 )S(O) 2 C 2-6 alkenylR 7 and -C 1-6 alkylN(R 8 )S(O) 2 C 2-6 alkynylR 7 ;

R 4 and R 6 are each independently selected from hydrogen or R 7 ;

R 5 is selected from hydrogen, hydroxy and a cyclic monosaccharide;

R 7 is selected from hydrogen, OR 8 , CO 2 R 8 , CON(R 8 ) 2 , SR 8 , N(R 8 ) 2 , N + (R 8 ) 3 and SON(R 8 ) 2 ; R 8 is selected from hydrogen, -C 1-6 alkyl, -C 2-6 alkenyl and -C 2-6 alkynyl;

A is wherein B is a cycloalkyl group, an aryl group, a heterocyclyl group or a heteroaryl group, R 9 is selected from -C 1-6 alkylR 7 , -C 2-6 alkenylR 7 , -C 2-6 alkynylR 7 , -OH, -OC 1-6 alkylR 7 , -OC 2. 6 alkenylR 7 , -OC 2-6 alkynylR 7 ; -SH, -SC 1-6 alkylR 7 , -SC 2-6 alkenylR 7 , -SC 2. 6 alkynylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -N(R 8 )C 2-6 alkenylR 7 , -N(R 8 )C 2-6 alkynylR 7 , -C(O)OC 1- 6 alkylR 7 , -C(O)OC 1-6 alkenylR 7 , -C(O)OC 1-6 alkynylR 7 , -C(O)C 1-6 alkylR 7 , -C(O)C 1-6 alkenylR 7 , -C(O)C 1-6 alkynylR 7 , -S(O)C 1-6 alkylR 7 , -S(O)C 2-6 alkenylR 7 , -S(O)C 2-6 alkynylR 7 , -S(O) 2 C 1- 6 alkylR 7 , -S(O) 2 C 2-6 alkenylR 7 , -S(O) 2 C 2-6 alkynylR 7 , -S(O) 2 N(R 8 ) 2 , -S(O) 2 N(R 9 )C 1-6 alkylR 7 , - S(O) 2 N(R 8 )C 2-6 alkenylR 7 , - S(O) 2 N(R 8 )C 2-6 alkynylR 7 , -N(R 8 )S(O) 2 C 1-6 alkylR 7 , - N(R 8 )S(O) 2 C 2-6 alkenylR 7 and -N(R 8 )S(O) 2 C 2-6 alkynylR 7 ; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of formula (I) is a compound of formula (II): wherein R 2 is hydrogen, R 5a is hydrogen or , where m is 1 or 2 and X, B, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).

[0035] In some embodiments, the compound of formula (I) is a compound of formula (III): wherein R 2 is hydrogen, R 5a is hydrogen or and X, B, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).

[0036] In some embodiments, the compound of formula (I) is a compound of formula (IV): wherein R 2 is hydrogen and X, R 3 , R 4 , R 6 , R 9 and n are as defined for formula (I).

[0037] In some embodiments, is a double bond. In other embodiments, is a single bond.

[0038] In particular embodiments, of compounds of formula (I), one or more of the following applies: i) R 1 is A, where ring B is an aryl group or a heteroaryl group substituted with one or two R 9 substituents, especially one R 9 substituent, especially an aryl group substituted with one or two R 9 substituents, especially one R 9 substituent, and more especially a phenyl group substituted with one or two R 9 substituents, especially one R 9 substituent; ii) R 2 is hydrogen; iii) R 3 is -C 1-6 alkylR 7 , -C 1-6 alkylOC 1-6 alkylR 7 , -C 1-6 alkylSC 1-6 alkylR 7 , -C 1-6 alkylN(R 8 )C 1- 6 alkylR 7 , -C(O)OC 1-6 alkylR 7 , -C(O)C 1-6 alkylR 7 , -C 1-6 alkylC(O)OC 1-6 alkylR 7 , -C 1- 6 alkylC(O)C 1-6 alkylR 7 , -C 1-6 alkylS(O)C 1-6 alkylR 7 , -C 1-6 alkylS(O) 2 C 1-6 alkylR 7 , -C 1- 6 alkylS(O) 2 N(R 8 )C 1-6 alkylR 7 and -C 1-6 alkylN(R 8 )S(O) 2 C 1-6 alkylR 7 , especially -C 1- 6 alkylOH, -C 1-6 alkylSH, -C 1-6 alkylCO 2 H, -C 1-6 alkylCONH 2 , -C 1-6 alkylNH 2 , -C(O)OC 1- 6 alkyl, -C(O)OC 1-6 alkylOH, -C(O)OC 1-6 alkylSH, -C(O)OC 1-6 alkylCO 2 H , -C(O)OC 1- 6 alkylCONH 2 , -C(O)OC 1-6 alkylNH 2 , -C 1-6 alkylOC 1-6 alkylOH, -C 1-6 alkylOC 1-6 alkylSH, - C 1-6 alkylOC 1-6 alkylCO 2 H, -C 1-6 alkylOC 1-6 alkylCONH 2 , -C 1-6 alkylOC 1-6 alkylNH 2 , -C 1- 6 alkylSC 1-6 alkylOH, -C 1-6 alkylSC 1-6 alkylSH, -C 1-6 alkylSC 1-6 alkylCO 2 H, -C 1-6 alkylSC 1- 6 alkylCONH 2 , -C 1-6 alkylSC 1-6 alkylNH 2 , -C 1-6 alkylN(H)C 1-6 alkylOH, -C 1-6 alkylN(CH 3 )C 1- 6 alkylOH, -C 1-6 alkylN(H)C 1-6 alkylSH, -C 1-6 alkylN(CH 3 )C 1-6 alkylSH, -C 1-6 alkylN(H)C 1- 6 alkylCO 2 H, -C 1-6 alkylN(CH 3 )C 1-6 alkylCO 2 H, -C 1-6 alkylN(H)C 1-6 alkylCONH 2 , -C 1- 6 alkylN(CH 3 )C 1-6 alkylCONH 2 , -C 1-6 alkylN(H)C 1-6 alkylNH 2 , -C 1-6 alkylN(CH 3 )C 1- 6 alkylNH 2 , -C 1-6 alkylS(O)C 1-6 alkylOH, -C 1-6 alkylS(O)C 1-6 alkylSH, -C 1-6 alkylS(O)C 1- 6 alkylCO 2 H, -C 1-6 alkylS(O)C 1-6 alkylCONH 2 , -C 1-6 alkylS(O)C 1-6 alkylNH 2 , -C 1- 6 alkylS(O) 2 N(H)C 1-6 alkylOH, -C 1-6 alkylS(O) 2 N(CH 3 )C 1-6 alkylOH, -C 1- 6 alkylS(O) 2 N(H)C 1-6 alkylSH, -C 1-6 alkylS(O) 2 N(CH 3 )C 1-6 alkylSH, -C 1-6 alkylS(O) 2 N(H)C 1- 6 alkylCO 2 H, -C 1-6 alkylS(O) 2 N(CH 3 )C 1-6 alkylCO 2 H, -C 1-6 alkylS(O) 2 N(H)C 1- 6 alkylCONH 2 , -C 1-6 alkylS(O) 2 N(CH 3 )C 1-6 alkylCONH 2 , -C 1-6 alkylS(O) 2 N(H)C 1-6 alkylNH 2 , -C 1-6 alkylC(O)OC 1-6 alkylOH, -C 1-6 alkylC(O)OC 1-6 alkylSH, -C 1-6 alkylC(O)OC 1- 6 alkylCO 2 H, -C 1-6 alkylC(O)OC 1-6 alkylCONH 2 , -C 1-6 alkylC(O)OC 1-6 alkylNH 2 , -C 1- 6 alkylS(O) 2 N(CH 3 )C 1-6 alkylNH 2 , -C 1-6 alkylN(H)S(O) 2 C 1-6 alkylOH, -C 1- 6 alkylN(CH 3 )S(O) 2 C 1-6 alkylOH, -C 1-6 alkylN(H)S(O) 2 C 1-6 alkylSH, -C 1- 6 alkylN(CH 3 )S(O) 2 C 1-6 alkylSH, -C 1-6 alkylN(H)S(O) 2 C 1-6 alkylCO 2 H, -C 1- 6 alkylN(CH 3 )S(O) 2 C 1-6 alkylCO 2 H, -C 1-6 alkylN(H)S(O) 2 C 1-6 alkylCONH 2 H, -C 1- 6 alkylN(CH 3 )S(O) 2 C 1-6 alkylCONH 2 , -C 1-6 alkylN(H)S(O) 2 C 1-6 alkylNH 2 and -C 1- 6alkylN(CH 3 )S(O) 2 C 1-6 alkylNH 2 , more especially -C 1-6 alkylOH, -C 1-6 alkylSH, -C 1- 6 alkylCO 2 H, -C 1-6 alkylCONH 2 , -C 1-6 alkylNH 2 , -C(O)OC 1-6 alkyl, -C(O)OC 1-6 alkylOH, - C(O)OC 1-6 alkylSH, -C(O)OC 1-6 alkylCO 2 H, -C(O)OC 1-6 alkylCONH 2 , -C(O)OC 1- 6 alkylNH 2 , -C 1-6 alkylOC 1-6 alkylOH, -C 1-6 alkylOC 1-6 alkylSH, -C 1-6 alkylOC 1-6 alkylCO 2 H, - C 1-6 alkylOC 1-6 alkylCONH 2 , -C 1-6 alkylOC 1-6 alkylNH 2 , -C 1-6 alkylSC 1-6 alkylOH, -C 1- 6 alkylSC 1-6 alkylSH, -C 1-6 alkylSC 1-6 alkylCO 2 H, -C 1-6 alkylSC 1-6 alkylCONH 2 and -C 1- 6 alkylSC 1-6 alkylNH 2 , even more especially -C 1-3 alkylOH, -C 1-3 alkylSH, -C 1-3 alkylCO 2 H, -C 1-3 alkylCONH 2 , -C 1-3 alkylNH 2 , -C 1-3 alkylOC 1-3 alkylOH, -C 1-3 alkylOC 1-3 alkylSH, -C 1- 3 alkyl0C 1-3 alkylCO 2 H, -C 1-3 alkylOC 1-3 alkylCONH 2 , -C 1-3 alkylOC 1-3 alkylNH 2 , -C 1- 3 alkylSC 1-3 alkylOH, -C 1-3 alkylSC 1-3 alkylSH, -C 1-3 alkylSC 1-3 alkylCO 2 H, -C 1-3 alkylSC 1- 3 alkylCONH 2 , -C 1-3 alkylSC 1-3 alkylNH 2 , -C(O)OC 1-3 alkyl, -C(O)OC 1-6 alkylOH, - C(O)OC 1-6 alkylSH, -C(O)OC 1-6 alkylCO 2 H, -C(O)OC 1-6 alkylCONH 2 and -C(O)OC 1- 6 alkylNH 2 even more especially -CH 2 OH, -CH 2 SH, -CH 2 CO 2 H, -CH 2 CONH 2 , - CH 2 NH 2 , -CH 2 OC 1-3 alkylOH, -CH 2 OC 1-3 alkylSH, -CH 2 OC 1-3 alkylCO 2 H, -CH 2 OC 1 - 3alkylCONH 2 , -CH 2 OC 1-3 alkylNH 2 , -CH 2 SC 1-3 alkylOH, -CH 2 SC 1-3 alkylSH, -CH 2 SC 1 - 3alkylCO 2 H, -CH 2 SC 1-3 alkylCONH 2 , -CH 2 SC 1-3 alkylNH 2 , -C(O)OC 1-3 alkyl, -C(O)OC 1- 3 alkylOH, -C(O)OC 1-3 alkylSH, -C(O)OC 1-3 alkylCO 2 H , -C(O)OC 1-3 alkylCONH 2 and - C(O)OC 1-3 alkylNH 2 , and most especially -CH 2 OH, -CH 2 SH, -CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 NH 2 , -CH 2 OCH 2 CH 2 OH, -CH 2 OCH 2 CH 2 SH, -CH 2 OCH 2 CH 2 CO 2 H, -

CH 2 OCH 2 CH 2 CONH 2 , -CH 2 OCH 2 CH 2 NH 2 , -CH 2 SCH 2 CH 2 OH, -CH 2 SCH 2 CH 2 SH, - CH 2 SCH 2 CH 2 CO 2 H, -CH 2 SCH 2 CH 2 CONH 2 , -CH 2 SCH 2 CH 2 NH 2 , -CO 2 CH 3 , - CO 2 CH 2 OH, -CO 2 CH 2 CH 2 OH, -CO 2 CH 2 CH 2 CH 2 OH,-CO 2 CH 2 SH, -CO 2 CH 2 CH 2 SH, - CO 2 CH 2 CH 2 CH 2 SH, -CO 2 CH 2 CO 2 H, -CO 2 CH 2 CH 2 CO 2 H, -CO 2 CH 2 CH 2 CH 2 CO 2 H, - CO 2 CH 2 CONH 2 , -CO 2 CH 2 CH 2 CONH 2 , -CO 2 CH 2 CH 2 CH 2 CONH 2 , -CO 2 CH 2 NH 2 , CO 2 CH 2 CH 2 NH 2 and -CO 2 CH 2 CH 2 CH 2 NH 2 ; iv) R 4 is hydrogen, -OH, -SH, -CO 2 H, -N(R 8 ) 2 or -CONH 2 , especially hydrogen, -OH, - SH, -CO 2 H, -NH 2 or -CONH 2 , more especially hydrogen or OH, most especially hydrogen; v) R 5 is hydroxy or a cyclic monosaccharide selected from D-allose, D-altrose, D- glucose, D-mannose, D-gulose, D-idose, D-galactose, D-talose and D-fructose, especially hydroxy or D-glucose and where the monosaccharide is preferably attached through an ether bond; vi) R 6 is hydrogen, -OH, -SH, -CO 2 H, -N(R 8 ) 2 or -CONH 2 , especially hydrogen, -OH, - SH, -CO 2 H, -NH 2 or -CONH 2 , more especially hydrogen or OH; vii) B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, morpholino, thiomorpholinyl, 3-oxomorpholinyl, furanyl, thienyl, thiophenyl, benzothienyl, benzofuranyl, benzodioxane, benzodioxin, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, imidazolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolinyl, thiazolyl and isothiazolyl, especially cyclopropyl, cyclohexyl, phenyl, naphthyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, furanyl, thienyl, thiophenyl, pyridinyl, pyrimidinyl and pyrrolyl, more especially cyclopentyl, cyclohexyl and phenyl, most especially phenyl; viii) X is O; ix) R 9 is selected from -C 1-6 alkylR 7 , -OH, -OC 1-6 alkylR 7 , -SH, -SC 1- 6 alkylR 7 , -N(R 8 ) 2 , -N(R 8 )C 1-6 alkylR 7 , -C(O)OC 1-6 alkylR 7 , -C(O)C 1-6 alkylR 7 , -S(O)C 1- 6 alkylR 7 , -S(O) 2 C 1-6 alkylR 7 , -S(O) 2 N(R 8 ) 2 , -S(O) 2 N(R 8 )C 1-6 alkylR 7 and -N(R 8 )S(O) 2 C 1- 6 alkylR 7 , especially -C 1-8 alkylOH, -C 1-8 alkylSH, -C 1-6 alkylCO 2 H, -C 1-6 alkylCONH 2 , -C 1- 6 alkylNH 2 , -C 1-6 alkylN(CH 3 ) 2 , -C 1-6 alkylN + (CH 3 ) 3 , OH, -OC 1-6 alkylOH, -OC 1-6 alkylSH, - OC 1-6 alkylCO 2 H, -OC 1-6 alkylCONH 2 , -OC 1-6 alkylNH 2 , -OC 1-6 alkylN(CH 3 ) 2 , -OC 1- 6 alkylN + (CH 3 ) 3 , -SH, -SC 1-6 alkylOH, -SC 1-6 alkylSH, -SC 1-6 alkylCO 2 H, -SC 1- 6 alkylCONH 2 , -SC 1-6 alkylNH 2 , -SC 1-6 alkylN(CH 3 ) 2 , -SC 1- 6 alkylN + (CH 3 ) 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , N + (CH 3 ) 3 , -NHC 1-6 alkylOH, -NHC 1- 6 alkylSH, -NHC 1-6 alkylCO 2 H, -NHC 1-6 alkylCONH 2 , -NHC 1-6 alkylNH 2 , -NHC 1- 6 alkylN(CH 3 ) 2 , -NHC 1-6 alkylN + (CH 3 ) 3 , -N(CH 3 )C 1-6 alkylOH, -N(CH 3 )C 1 - 6alkylSH, -N(CH 3 )C 1-6 alkylCO 2 H, -N(CH 3 )C 1-6 alkylCONH 2 , -N(CH 3 )C 1-6 alkylNH 2 , - N(CH 3 )C 1-6 alkylN(CH 3 ) 2 , - N(CH 3 )C 1-6 alkylN + (CH 3 ) 3 , -C(O)OC 1-6 alkylOH, -C(O)OC 1- 6 alkylSH, -C(O)OC 1-6 alkylCO 2 H, -C(O)OC 1-6 alkylCONH 2 , -C(O)OC 1-6 alkylNH 2 , - C(O)OC 1-6 alkylN(CH 3 ) 2 , -C(O)OC 1-6 alkylN + (CH 3 ) 3 , -S(O)C 1-e alkylOH, -S(O)C 1- 6 alkylSH, -S(O)C 1-6 alkylCO 2 H, -S(O)C 1-6 alkylCONH 2 , -S(O)C 1-6 alkylNH 2 , -S(O)C 1- 6 alkylN(CH 3 ) 2 , -S(O)C 1-6 alkylN + (CH 3 ) 3 , -S(O) 2 C 1-6 alkylOH, -S(O) 2 C 1-6 alkylSH, - S(O) 2 C 1-6 alkylCO 2 H, -S(O) 2 C 1-6 alkylCONH 2 , -S(O) 2 C 1-6 alkylNH 2 , -S(O) 2 C 1- 6 alkylN(CH 3 ) 2 , -S(O) 2 C 1-6 alkylN + (CH 3 ) 3 , -S(O) 2 NH 2 , -S(O) 2 NH(CH 3 ), - S(O) 2 N(CH 3 ) 2 , -S(O) 2 NHC 1-6 alkylOH, -S(O) 2 NHC 1-6 alkylSH, -S(O) 2 NHC 1- 6 alkylCO 2 H, -S(O) 2 NHC 1-6 alkylCONH 2 , -S(O) 2 NHC 1-6 alkylNH 2 , -S(O) 2 NHC 1- 6 alkylN(CH 3 ) 2 , -S(O) 2 NHC 1-6 alkylN + (CH 3 ) 3 , -S(O) 2 N(CH 3 )C 1- 6 alkylOH, -S(O) 2 N(CH 3 )C 1-6 alkylSH, -S(O) 2 N(CH 3 )C 1-6 alkylCO 2 H, -S(O) 2 N(CH 3 )C 1- 6 alkylCONH 2 , -S(O) 2 N(CH 3 )C 1-6 alkylNH 2 , -S(O) 2 N(CH 3 )C 1-6 alkylN(CH 3 ) 2 , - S(O) 2 N(CH 3 )C 1-6 alkylN + (CH 3 ) 3 , -NHS(O) 2 C 1-6 alkylOH, -NHS(O) 2 C 1- 6 alkylSH, -NHS(O) 2 C 1-6 alkylCO 2 H, -NHS(O) 2 C 1-6 alkylCONH 2 , -NHS(O) 2 C 1-6 alkylNH 2 , -NHS(O) 2 C 1-6 alkylN(CH 3 ) 2 , -NHS(O) 2 C 1-6 alkylN + (CH 3 ) 3 , -N(CH 3 )S(O) 2 C 1- 6 alkylOH, -N(CH 3 )S(O) 2 C 1-6 alkylSH, -N(CH 3 )S(O) 2 C 1-6 alkylCO 2 H, -N(CH 3 )S(O) 2 C 1- 6 alkylCONH 2 , -N(CH 3 )S(O) 2 C 1-6 alkylNH 2 , -N(CH 3 )S(O) 2 C 1-6 alkylN(CH 3 ) 2 , - N(CH 3 )S(O) 2 C 1-6 alkylN + (CH 3 ) 3 , more especially -C 1-6 alkylOH, -C 1-6 alkylSH, -C 1- 6 alkylCO 2 H, -C 1-6 alkylCONH 2 , -C 1-6 alkylNH 2 , -C 1-6 alkylN(CH 3 ) 2 , -C 1-6 alkylN + (CH 3 ) 3 , OH, -OC 1-6 alkylOH, -OC 1-6 alkylSH, -OC 1-6 alkylCO 2 H, -OC 1-6 alkylCONH 2 , -OC 1- 6 alkylNH 2 , -OC 1-6 alkylN(CH 3 ) 2 , -OC 1-6 alkylN + (CH 3 ) 3 , -SH, -SC 1-6 alkylOH, -SC 1- 6 alkylSH, -SC 1-6 alkylCO 2 H, -SC 1-6 alkylCONH 2 , -SC 1-6 alkylNH 2 , -SC 1-6 alkylN(CH 3 ) 2 , - SC 1-6 alkylN + (CH 3 ) 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NHC 1-6 alkylOH, -NHC 1- 6 alkylSH, -NHC 1-6 alkylCO 2 H, -NHC 1-6 alkylCONH 2 , -NHC 1-6 alkylNH 2 , -NHC 1- 6 alkylN(CH 3 ) 2 , -NHC 1-6 alkylN + (CH 3 ) 3 , -N(CH 3 )C 1-6 alkylOH, -N(CH 3 )C 1- 6 alkylSH, -N(CH 3 )C 1-6 alkylCO 2 H, -N(CH 3 )C 1-6 alkylCONH 2 , -N(CH 3 )C 1-6 alkylNH 2 , - N(CH 3 )C 1-6 alkylN(CH 3 ) 2 and - N(CH 3 )C 1-6 alkylN + (CH 3 ) 3 , even more especially -C 1- 3 alkylOH, -C 1-3 alkylSH, -C 1-3 alkylCO 2 H, -C 1-3 alkylCONH 2 , -C 1-3 alkylNH 2 , -C 1- 3 alkylN(CH 3 ) 2 , -C 1-3 alkylN + (CH 3 ) 3 , OH, -OC 1-3 alkylOH, -OC 1-3 alkylSH, -OC 1- 3 alkylCO 2 H, -OC 1-3 alkylCONH 2 , -OC 1-3 alkylNH 2 , -OC 1-3 alkylN(CH 3 ) 2 , -OC 1- 3 alkylN + (CH 3 ) 3 , -SH, -SC 1-3 alkylOH, -SC 1-3 alkylSH, -SC 1-3 alkylCO 2 H, -SC 1- 3 alkylCONH 2 , -SC 1-3 alkylNH 2 , -SC 1-3 alkylN(CH 3 ) 2 , -SC 1-

3 alkylN + (CH 3 ) 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , -NHC 1-3 alkylOH, -NHC 1-3 alkylSH, -NHC 1- 3 alkylCO 2 H, -NHC 1-3 alkylCONH 2 , -NHC 1-3 alkylNH 2 , -NHC 1-3 alkylN(CH 3 ) 2 , -NHC 1- 3 alkylN + (CH 3 ) 3 ,-N(CH 3 )C 1-3 alkylOH, -N(CH 3 )C 1-3 alkylSH, -N(CH 3 )C 1 - 3 alkylCO 2 H, -N(CH 3 )C 1-3 alkylCONH 2 , -N(CH 3 )C 1-3 alkylNH 2 , -N(CH 3 )C 1-6 alkylN(CH 3 ) 2 , - N(CH 3 )C 1-6 alkylN + (CH 3 ) 3 , -C(O)OC 1-3 alkylOH, -C(O)OC 1-3 alkylSH, -C(O)OC 1- 3 alkylCO 2 H, -C(O)OC 1-3 alkylCONH 2 , -C(O)OC 1-3 alkylNH 2 , -C(O)OC 1-3 alkylN(CH 3 ) 2 , - C(O)OC 1-3 alkylN + (CH 3 ) 3 , most especially -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, - CH 2 SH, -CH 2 CH 2 SH, -CH 2 CH 2 CH 2 SH, -CH 2 CO 2 H, -CH 2 CH 2 CO 2 H, - CH 2 CH 2 CH 2 CO 2 H, -CH 2 CONH 2 , -CH 2 CH 2 CONH 2 , -CH 2 CH 2 CH 2 CONH 2 , -CH 2 NH 2 , -

CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , - CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 N + (CH 3 ) 3 , -CH 2 CH 2 N + (CH 3 ) 3 , -CH 2 CH 2 CH 2 N + (CH 3 ) 3 ,-

OCH 2 OH, -OCH 2 CH 2 OH, -OCH 2 CH 2 CH 2 OH, -OCH 2 SH, -OCH 2 CH 2 SH, - OCH 2 CH 2 CH 2 SH, -OCH 2 CO 2 H, -OCH 2 CH 2 CO 2 H, -OCH 2 CH 2 CH 2 CO 2 H, - OCH 2 CONH 2 , -OCH 2 CH 2 CONH 2 , -OCH 2 CH 2 CH 2 CONH 2 , -OCH 2 NH 2 , -OCH 2 CH 2 NH 2 ,

-OCH 2 CH 2 CH 2 NH 2 , -OCH 2 N(CH 3 ) 2 , -OCH 2 CH 2 N(CH 3 ) 2 , -OCH 2 CH 2 CH 2 N(CH 3 ) 2 , - OCH 2 N + (CH 3 ) 3 , -OCH 2 CH 2 N + (CH 3 ) 3 , -OCH 2 CH 2 CH 2 N + (CH 3 ) 3 , -SCH 2 OH, -

SCH 2 CH 2 OH, -SCH 2 CH 2 CH 2 OH, -SCH 2 SH, -SCH 2 CH 2 SH, -SCH 2 CH 2 CH 2 SH,- SCH 2 CO 2 H, -SCH 2 CH 2 CO 2 H, -SCH 2 CH 2 CH 2 CO 2 H,

-SCH 2 CONH 2 , -SCH 2 CH 2 CONH 2 , -SCH 2 CH 2 CH 2 CONH 2 , -SCH 2 NH 2 , -SCH 2 CH 2 NH 2 ,

-SCH 2 CH 2 CH 2 NH 2 , -SCH 2 N(CH 3 ) 2 , -SCH 2 CH 2 N(CH 3 ) 2 , -SCH 2 CH 2 CH 2 N(CH 3 ) 2 , - SCH 2 N + (CH 3 ) 3 , -SCH 2 CH 2 N + (CH 3 ) 3 , S-CH 2 CH 2 CH 2 N + (CH 3 ) 3 , -NHCH 2 OH, - NHCH 2 CH 2 OH, -NHCH 2 CH 2 CH 2 OH, -NHCH 2 SH, -NHCH 2 CH 2 SH, - NHCH 2 CH 2 CH 2 SH, -NHCH 2 CO 2 H, -NHCH 2 CH 2 CO 2 H, -NHCH 2 CH 2 CH 2 CO 2 H, -NHCH 2 CONH 2 , -NHCH 2 CH 2 CONH 2 , -NHCH 2 CH 2 CH 2 CONH 2 , -NHCH 2 NH 2 , -NHCH 2 CH 2 NH 2

, -NHCH 2 CH 2 CH 2 NH 2 , -NHCH 2 N(CH 3 ) 2 , -NHCH 2 CH 2 N(CH 3 ) 2 , - NHCH 2 CH 2 CH 2 N(CH 3 ) 2 , -NHCH 2 N + (CH 3 ) 3 , -NHCH 2 CH 2 N + (CH 3 ) 3 , - NHCH 2 CH 2 CH 2 N + (CH 3 ) 3 , -N(CH 3 )CH 2 OH, -N(CH 3 )CH 2 CH 2 OH, N(CH 3 )CH 2 CH 2 CH 2 OH, -N(CH 3 )CH 2 SH, -N(CH 3 )CH 2 CH 2 SH, -N(CH 3 )CH 2 CH 2 CH 2 SH, -N(CH 3 )CH 2 CO 2 H, -N(CH 3 )CH 2 CH 2 CO 2 H, -N(CH 3 )CH 2 CH 2 CH 2 CO 2 H, -N(CH 3 )CH 2 CO NH 2 , -N(CH 3 )CH 2 CH 2 CONH 2 , -N(CH 3 )CH 2 CH 2 CH 2 CONH 2 , -N(CH 3 )CH 2 NH 2 , - N(CH 3 )CH 2 CH 2 NH 2 , -N(CH 3 )CH 2 CH 2 CH 2 NH 2 , -N(CH 3 )CH 2 N(CH 3 ) 2 , - N(CH 3 )CH 2 CH 2 N(CH 3 ) 2 , -N(CH 3 )CH 2 CH 2 CH 2 N(CH 3 ) 2 , -N(CH 3 )CH 2 N + (CH 3 ) 3 , - N(CH 3 )CH 2 CH 2 N + (CH 3 ) 3 , -N(CH 3 )CH 2 CH 2 CH 2 N + (CH 3 ) 3 , -CO 2 CH 2 OH, -

CO 2 CH 2 CH 2 OH, -CO 2 CH 2 CH 2 CH 2 OH, -CO 2 CH 2 SH, -CO 2 CH 2 CH 2 SH, - CO 2 CH 2 CH 2 CH 2 SH, -CO 2 CH 2 CO 2 H, -CO 2 CH 2 CH 2 CO 2 H, -CO 2 CH 2 CH 2 CH 2 CO 2 H, - CO 2 CH 2 CONH 2 , -CO 2 CH 2 CH 2 CONH 2 , CO 2 CH 2 CH 2 CH 2 CONH 2 , -CO 2 CH 2 NH 2 , - CO 2 CH 2 CH 2 NH 2 , -CO 2 CH 2 CH 2 CH 2 NH 2 , - CO 2 CH 2 N(CH 3 ) 2 , - CO 2 CH 2 CH 2 N(CH 3 ) 2 , - CO 2 CH 2 CH 2 CH 2 N(CH 3 ) 2 , - CO 2 CH 2 N + (CH 3 ) 3 , - CO 2 CH 2 CH 2 N + (CH 3 ) 3 , - CO 2 CH 2 CH 2 CH 2 N + (CH 3 ) 3 ; x) n is 1 or 2, especially 1;

[0039] Particular compounds of formula (I) include are shown in Table 1:

Table 1

[0040] In particular embodiments, the compound of formula (I) is selected from compounds 352, 377, 380, 381, 485, 486, 487 and 488, especially compounds 352, 377 and 381.

[0041] The compounds of formula (I) may be prepared by methods known in the art. For example, a substituted chromone may be prepared from an appropriately substituted phenol, such as set out in Scheme 1 :

Scheme 1

[0042] A protected substituted phenol ring may be subject to Friedel Crafts acylation in the presence of a Lewis Acid such as AICl 3 or a strong Brønsted acid such as HF or Triflic acid to provide, after deprotection of the phenolic hydroxyls, an alpha acetyl phenol ring. Further reaction with an aldehyde provides an aryl, cycloalkyl, heterocyclyl or heteroaryl substituted chromone.

[0043] The 4-hydroxy substituted benzaldehyde used in step 3 of Scheme 1 may be prepared by reaction of 4-hydroxybenzaldehyde with an appropriately substituted alkyl halide, such as an alkyl bromide. Alternatively, the 4-hydroxybenzaldehyde may be used in step 3 of Scheme 1 and the hydroxy group subsequently derivatised. For example, the hydroxy or carboxy groups on the aryl substituted chromone ring may be further derivatised to ethers or esters by means known in the art, for example with an alkyl halide in the presence of a base, as shown in Scheme 2:

Scheme 2

[0044] Variation of the alkyl halide may also be used to provide different functional groups. Furthermore, the chromone carboxylic acid may be reduced to a primary alcohol by methods known in the art, before or after reaction with the alkyl halide.

[0045] The position of the further substitution may be defined by the use of a protection strategy for phenolic hydroxy groups or carboxylic acids to give single or multiple substitutions.

A person skilled in the art would be able to determine suitable protecting group strategies and suitable protecting groups may be found in, for example, Greene's Protective Groups in Organic Synthesis, Fourth Edition, Wuts & Greene, 2006, John Wiley & Sons.

[0046] The sugar group may be introduced by means known in the art, for example, by reaction of an acyl protected sugar group with the phenolic hydroxy group of the chromone group in the presence of base and a Lewis acid as shown in Scheme 3:

Scheme 3

[0047] Further deprotection provides the desired compounds.

Methods of Treatment

[0048] In one aspect of the present invention there is provided a method of treating or preventing a viral infection caused by a virus of the Family Flaviviridae comprising administering to a subject a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, the viral infection caused by a virus from the Family Flaviviridae is a virus selected from the genus Flavivirus, genus Pestivirus, genus Hepacivirus and genus Pegivirus.

[0050] In particular embodiments the virus is a virus of the genus Flavivirus including mosquito-borne, tick-borne, insect-specific Flaviviruses as well as those with an unknown vector. In some embodiments, the virus of the genus Flavivirus is selected from dengue virus (DENV) (including serotypes 1 to 4), Zika virus (ZIKV), Kunjin virus, West Nile virus (WNV), yellow fever virus, Japanese encephalitis virus, tick-borne encephalitis virus (Seabird and Mammalian), Paramatta river virus, Palm Creek virus, Entebbe bat virus, Gadgets Gully virus, Kadam virus, Kyasanur Forest disease virus, Langat virus, Louping-ill virus, Murray Valley encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus, Royal Farm virus (Karshi virus), Saint Louis encephalitis virus, Usutu virus, Modoc virus, Rio Bravo virus and Wesselsbron virus. In particular embodiments, the virus of the genus Flavivirus is selected from dengue virus, Zika virus, Kunjin virus, West Nile virus, yellow fever virus, Japanese encephalitis virus and tick-borne encephalitis virus, especially dengue virus, Zika virus and Kunjin virus.

[0051] In some embodiments, the virus is selected from the genus Pestivirus including Pestiviruses A to K.

[0052] In some embodiments, the virus is selected from the henus Hepacivirus including Hepatitis C virus. [0053] In some embodiments, the virus is selected from the genus Pegivirus including Hepatitis G (GBV-C).

[0054] The subjects, individuals or patients to be treated are mammalian subjects including but not limited to humans, primates, livestock animals such as sheep, cattle, pigs, horses, donkeys and goats; laboratory test animals such as mice, rats, rabbits and guinea pigs; companion animals such as cats and dogs or captive wild animals such as those kept in zoos.

In a particular embodiment, the subject is a human.

[0055] The compounds of formula (I) may be administered in an effective amount. An "effective amount" means an amount necessary at least partly to attain the desired response, or to delay the onset or inhibit progression or halt altogether, the onset or progression of a particular condition being treated. The amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individuals to be treated, the degree of protection desired, the formulation of the composition, the assessment of the medical situation, and other relevant factors. It is expected that the amount will fall in a relatively broad range that can be determined through routine trials. An effective amount in relation to a human patient, for example, may lie in the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage is preferably in the range of μg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1g per kg of body weight per dosage. In one embodiment, the dosage is in the range of 1 mg to 500 mg per kg of body weight per dosage.

In another embodiment, the dosage is in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per kg of body weight per dosage. In yet another embodiment, the dosage is in the range of 1 μg to 1 mg per kg of body weight per dosage. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals, or the dose may be proportionally reduced as indicated by the exigencies of the situation.

[0056] Reference herein to "treatment" and "prevention" is to be considered in its broadest context. The term "treatment" does not necessarily imply that a subject is treated until total recovery. "Treatment" may also reduce the severity of an existing condition. The term "prevention" does not necessarily mean that the subject will not eventually contract a disease condition. The term "prevention" may be considered to include delaying the onset of a particular condition. Accordingly, treatment and prevention include amelioration or alleviation of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.

[0057] In some embodiments, the compounds of formula (I) or their pharmaceutically acceptable salts thereof may be administered together with another therapy. For example, the compounds of formula (I) may be administered together with an antipyretic agent to reduce fever. Suitable antipyretic drugs include non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, ketoprofen and nimesulide; aspirin and related salicylates such as choline salicylate, magnesium salicylate and sodium salicylate; acetaminophen; metamizole; nabumetone and phenazone.

[0058] In another aspect of the invention there is provided a pharmaceutical composition for use in treating or preventing a viral infection; wherein the composition comprises a compound of formula (I) as described above.

[0059] In a further aspect of the invention there is provided a use of a compound of formula (I) as described above in the manufacture of a medicament for treating or preventing a viral infection.

Compositions of the invention

[0060] While it is possible that, for use in therapy, a compound of the invention may be administered as a neat chemical, it is preferable to present the active ingredient as a pharmaceutical composition. The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as described herein and a pharmaceutically acceptable carrier or excipient.

[0061] The carrier(s) and/or excipients must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0062] Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual) or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The compounds of the invention, together with a conventional adjuvant, carrier, excipient, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Formulations containing 10 milligrams of active ingredient or, more broadly, 0.1 to 1000 milligrams, per tablet, are accordingly suitable representative unit dosage forms. The compounds of the present invention can be administered in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt or derivative of the compound of the invention.

[0063] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

[0064] In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.

[0065] In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

[0066] The powders and tablets preferably contain from five or 10 to about 70 percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "composition" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, cachets, and lozenges can be used as solid forms suitable for oral administration.

[0067] For preparing suppositories, a low melting wax, such as admixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. [0068] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

[0069] The compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

[0070] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired.

[0071] Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

[0072] Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0073] Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins or formulated with their agents expected to enhance delivery and retention in the nasal mucosa. [0074] Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a hydrofluoroalkane (HFA) or chlorofluorocarbon (CFC) for example, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin.

The dose of drug may be controlled by provision of a metered valve.

[0075] Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).

[0076] Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.

[0077] In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 1 to 50 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.

[0078] When desired, formulations adapted to give sustained release of the active ingredient may be employed.

[0079] The pharmaceutical compositions are preferably in unit dosage forms. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged composition, the package containing discrete quantities of composition, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0080] The invention will now be described with reference to the following Examples which illustrate some preferred aspects of the present invention. However, it is to be understood that the particularity of the following description of the invention is not to supersede the generality of the preceding description of the invention.

Example(s)

Abbreviations

DCM: dichloromethane DENV: Dengue virus

DMAP: dimethylaminopyridine

DMSO: dimethylsulfoxide

EDC.HCL: 1 ,3-ethylcarbodiimide hydrochloride

Equiv: equivalent

Hr: hour

Min: minutes

Rt: room temperature

TBDMS: tertiary butyl dimethyl silyl

TLC: thin layer chromatography

WNV: West Nile virus

ZIKV: Zika virus

Example 1 : Synthesis of Chromone intermediate (J)

Methyl 3,5-dimethoxybenzoate (B)

[0081] 3,5-Dihydroxybenzoic acid (A) (10 gm, 1.0 equiv), potassium carbonate (40.3 gm, 4.5 equiv) and methyl iodide (30.4 gm, 3.3 equiv) were stirred in dimethylformamide (100 mL) overnight at Rt. The reaction was monitored by TLC. After completion of the reaction, water (600 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 × 350 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford methyl 3,5-dimethoxybenzoate (B) (86%). Methyl 3,5- dimethoxybenzoate (B) was used next step without any purification.

Methyl 2-acetyl-3,5-dimethoxybenzoate (C)

[0082] Methyl 3,5-dimethoxybenzoate (B) (5 gm, 1.0 equiv), acetyl chloride (10.9 mL, 5 equiv) were dissolved in dichloromethane (100 mL) under argon in ice bath. To this AlCl 3 (17.0 gm, 5 equiv) was added and reaction was stirred for 1.5 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI (500 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 × 250 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford methyl 2-acetyl-3,5-dimethoxybenzoate (C) which was purified by column chromatography using hexane:ethyl acetate as the solvent system (71%).

Methyl 2-acetyl-3,5-dihydroxybenzoate (D) [0083] Methyl 2-acetyl-3,5-dimethoxybenzoate (C) (3.0 gm, 1 equiv) was dissolved in dichloromethane and AICI 3 (16.8 gm, 10 mmol) was added slowly at rt. The reaction mixture was heated to reflux for 24 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI (500 mL) was added slowly, and the reaction mixture was extracted with ethyl acetate (3 × 250 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford methyl 2-acetyl-3,5-dihydroxybenzoate (D) which was further by column chromatography (68%).

Methyl 2-(4-(benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxylat e (F)

[0084] Methyl 2-acetyl-3,5-di hydroxy benzoate (D) (500 mg, 1 equiv), 4-(benzyloxy)benzaldehyde (1 equiv) and pyrrolidine (145 μL , 0.5 equiv) were dissolved in DMSO (8 mL) and the reaction mixture was allowed to reflux for 3.5 hr. The progress of the reaction was monitored by TLC.

After completion of the reaction, 1 N HCI (200 mL) was added slowly, and the reaction mixture was extracted with ethyl acetate (3 × 150 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford methyl 2-(4- (benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxylate (F) which was purified by column chromatography using hexane:ethyl acetate as the solvent system (30%).

2-(4-(Benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxy lic acid (G)

[0085] Methyl 2-(4-(benzyloxy)phenyl)-7-hydroxy-4- oxochromane-5-carboxylate (F) (150 mg, 1 equiv) was dissolved in methanol (10 mL) and stirred at Rt for 10 min. To the solution, 30% KOH solution (5 mL) was added and refluxed for 48 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI (50 mL) was added slowly, and the reaction mixture was extracted with ethyl acetate (3 × 50 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford 2- (4-(benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxylic acid (G) which was purified by column chromatography using hexane:ethyl acetate as the solvent system (65%).

Tert-butyldimethylsilyl 2-(4-(benzyloxy)phenyl)-7-((tert-butyldimethylsilyl)oxy)-4- oxochromane-5-carboxylate (H) [0086] 2-(4-(Benzyloxy)phenyl)-7-hydroxy-4- oxochromane-5-carboxylic acid (G) (90 mg, 1 equiv), DMAP (11 mg, 0.4 equiv), imidazole (50 mg, 3.2 equiv) was dissolved in DCM (5 mL) and stirred at Rt for 10 min. To the solution, TBDMS-CI (77 mg, 2.2 equiv) was added and stirred at RT for 18 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, water (50 mL) was added slowly, and the reaction mixture was extracted with DCM (3 × 25 mL). The combined DCM layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford tert-butyldimethylsilyl 2-(4-(benzyloxy)phenyl)-7-((tert- butyldimethylsilyl)oxy)-4-oxochromane-5-carboxylate (H) which was purified by column chromatography using hexane:ethyl acetate as the solvent system.

2-(4-(Benzyloxy)phenyl)-7-((tert-butyldimethylsilyl)oxy)- 4-oxochromane-5-carboxylic acid

(I)

[0087] Tert-butyldimethylsilyl 2-(4- (benzyloxy)phenyl)-7-((tert-butyldimethylsilyl)oxy)- 4-oxochromane-5-carboxylate (H) (1 equiv) was dissolved in THF: water: acetic acid (50:10:40) mixture and stirred at Rt for 24 min. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added slowly, and the reaction mixture extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent evaporated under reduced pressure to afford 2-(4-(benzyloxy)phenyl)-7-((tert- butyldimethylsilyl)oxy)-4-oxochromane-5-carboxylic acid (I) which was purified by column chromatography using hexane:ethyl acetate as the solvent system.

7-((Tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)-4-ox ochromane-5-carboxylic acid (J)

[0088] 2-(4-(Benzyloxy)phenyl)-7-((tert- butyldimethylsilyl)oxy)-4-oxochromane-5-carboxylic acid (I) (1 equiv) was dissolved in methanol and palladium on carbon (10 wt % dry basis) was added. The mixture was stirred vigorously at Rt under an atmosphere of H2 gas for 2 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite® and then the filtrate evaporated under reduced pressure. The product was purified by column chromatography using hexane:ethyl acetate as the solvent system to afford 7-((tert-butyldimethylsilyl)oxy)-2-(4-hydroxyphenyl)-4- oxochromane-5-carboxylic acid (J).

Example 2: Disubstituted chromone derivative (M)

3-((7-((Tert-butyldimethylsilyl)oxy)-2-(4-(2-carboxyethox y)phenyl)-4-oxochromane-5- carbonyl)- oxy)propanoic acid (K)

[0089] 7-((Tert-butyldimethylsilyl)oxy)-2-(4- hydroxyphenyl)-4-oxochromane-5-carboxylic acid (J) (1 equiv), triethylamine (3 equiv) and 3-bromo- propanoic acid (2.2 equiv) were dissolved in acetonitrile and refluxed for 24 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI was added slowly, and the reaction mixture extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent evaporated under reduced pressure to afford 3-((7-((tert-butyldimethylsilyl)oxy)-

2-(4-(2-carboxyethoxy)phenyl)-4-oxochromane-5-carbonyl)ox y)propanoic acid (K) which was purified by column chromatography using hexane:ethyl acetate as the solvent system.

3-(Benzyloxy)-3-oxopropyl 2-(4-(3-(benzyloxy)-3-oxopropoxy)phenyl)-7-((tert- butyldimethylsilyl)- oxy)-4-oxochromane-5-carboxylate (L)

[0090] 3-((7-((Tert-butyldimethylsilyl)oxy)-2- (4-(2-carboxyethoxy)phenyl)-4-oxochromane-5- carbonyl)oxy)propanoic acid (K) (1 equiv) was dissolved in DCM. To the solution, DMAP (0.4 equiv) and EDC.HCI (3 equiv) were added. After 10 min of stirring, benzyl alcohol (2.2 equiv) was added and the reaction mixture stirred for 24 hr at Rt. The progress of the reaction was monitored by TLC. After completion of the reaction, water was added slowly, and the reaction mixture extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent evaporated under reduced pressure to afford 3- (benzyloxy)-3-oxopropyl 2-(4-(3-(benzyloxy)-3-oxopropoxy)phenyl)-7-((tert- butyldimethylsilyl)oxy)-4-oxochromane-5-carboxylate (L) which was purified by column chromatography using hexane:ethyl acetate as the solvent system. 3-(Benzyloxy)-3-oxopropyl 2-(4-(3-(benzyloxy)-3-oxopropoxy)phenyl)-7-hydroxy-4- oxochromane-5-carboxylate (M)

[0091] 3-(Benzyloxy)-3-oxopropyl 2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-7-((tert- butyldimethylsilyl)oxy)-4-oxochromane-5- carboxylate (L) (1 equiv) was dissolved in methanol. To the solution, 32 wt % aq. HCI was added, and the solution was stirred for 18 hr. The solvent was evaporated under reduced pressure, and the residue triturated with dichloromethane to obtain 3-(benzyloxy)-3-oxopropyl 2-(4-(3-(benzyloxy)-3-oxopropoxy)phenyl)- 7-hydroxy-4-oxochromane-5-carboxylate (M) which was purified by column chromatography using hexane:ethyl acetate as the solvent system.

Example 3: Synthesis of Pyranose derivative (Q)

(2R ,3R ,4S,5R ,6S)-2-(Acetoxymethyl)-6-((5-((3-(benzyloxy)-3-oxopropoxy)ca rbonyl)-2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-4-oxochroman-7-yl)oxy)tetra hydro-2H-pyran-3,4,5-triyl triacetate (O)

[0092] 3-(Benzyloxy)-3-oxopropyl 2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-7- hydroxy-4-oxochromane-5-carboxylate (M) (1 equiv) and penta-O-acetyl-β-D- glucopyranose (1.5 equiv) were dissolved in DCM. To the solution, triethylamine (0.75 equiv) in DCM was added and the mixture stirred for 10 min. After 10 min of stirring, BF 3 etherate (3.75 equiv) in DCM was added in over a period of 30 mins. The reaction mixture was then stirred for 18 hr at Rt. The progress of the reaction was monitored by TLC. After completion of the reaction, sodium bicarbonate solution was added slowly, and the reaction mixture extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous MgSO 4 filtered, and the solvent evaporated under reduced pressure to afford

(2R ,3R ,4S,5R ,6S)-2-(Acetoxymethyl)-6-((5-((3-(benzyloxy)-3-oxopropoxy)ca rbonyl)-2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-4-oxochroman-7-yl)oxy)tetra hydro-2H-pyran-3,4,5-triyl triacetate (O) which was purified by column chromatography using hexane:ethyl acetate as the solvent system. 3-(Benzyloxy)-3-oxopropyl 2-(4-(3-(benzyloxy)-3-oxopropoxy)phenyl)-4-oxo-7-

(((2R,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetr ahydro-2H-pyran-2- yl)oxy)chromane-5-carboxylate (P)

[0093] (2R,3R,4S,5R,6S)-2- (Acetoxymethyl)-6-((5-((3-(benzyloxy)-3- oxopropoxy)carbonyl)-2-(4-(3-(benzyloxy)-3- oxopropoxy)phenyl)-4-oxochroman-7- yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (O) (1 equiv), triethylamine (8.0 equiv) and water (0.5 mL) were stirred for 18 hr at Rt in MeOH. The reaction was monitored by TLC. After completion of the reaction, water was added, and the reaction mixture extracted with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent evaporated under reduced pressure to afford 3-(benzyloxy)-3-oxopropyl 2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-4-oxo-7-(((2R,3R,4S,5R,6R)- 3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)chromane-5-carbo xylate (P) which was purified by column chromatography using hexane:ethyl acetate as the solvent system.

3-(4-(5-((2-Carboxyethoxy)carbonyl)-4-oxo-7-(((2R,3R,4S,5 R,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)chroman-2-yl)phe noxy)propanoic acid (Q)

[0094] 3-(Benzyloxy)-3-oxopropyl 2-(4-(3- (benzyloxy)-3-oxopropoxy)phenyl)-4-oxo-7- (((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2- yl)oxy)chromane-5-carboxylate (P) (1 equiv) was dissolved in methanol and palladium on carbon (10 wt % dry basis) was added. The mixture was stirred vigorously at Rt under an atmosphere of H2 gas for 3 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a pad of Celite® and then the filtrate was evaporated under reduced pressure. The product was purified by column chromatography using hexane:ethyl acetate as the solvent system to obtain 3-(4-(5-((2- carboxyethoxy)carbonyl)-4-oxo-7-(((2R,3R,4S,5R,6R)-3,4,5-tri hydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)chroman-2-yl)phe noxy)propanoic acid (Q). Example 4: Preparation of Compound 381 4-(3-Hydroxypropoxy)benzaldehyde

[0095] 4-hydroxybenzaldehyde (1 gm, 1.0 equiv), potassium carbonate (0.98 gm, 1.5 equiv) and 3-bromopropanol (0.83 gm, 1.25 equiv) were stirred in acetonitrile (50 mL) at Rt for 24 hr. The reaction was monitored by TLC. After completion of the reaction, water (6150 mL) was added, and the reaction mixture was extracted with ethyl acetate (3 × 75 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford 4-(3-hydroxypropoxy)benzaldehyde which was further purified using column chromatography (64%).

Methyl 2-(4-(benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxylat e (381)

[0096] Methyl 2-acetyl-3,5-dihydroxybenzoate (D) (500 mg, 1 equiv), 4-(3-hydroxypropoxy)benzaldehyde (428 mg, 1 equiv) and pyrrolidine (145 mL, 0.5 equiv) were dissolved in DMSO (8 mL) and the reaction mixture was allowed to reflux for 5 hr. The progress of the reaction was monitored by TLC. After completion of the reaction, 1 N HCI (200 mL) was added slowly, and the reaction mixture was extracted with ethyl acetate (3 × 150 mL). The combined ethyl acetate layers were dried over anhydrous MgSO 4 , filtered, and the solvent was evaporated under reduced pressure to afford methyl 2-(4- (benzyloxy)phenyl)-7-hydroxy-4-oxochromane-5-carboxylate (381) which was purified by column chromatography using hexane:ethyl acetate as the solvent system (30%). The two stereoisomers were separated using HPLC.

[0097] NMR data for 1 st isomer 1 H NMR (600 MHz, MeOD): 1 H NMR (400 MHz, DMSO-d6): 7.30 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 6.32-6.34 (m, 2H), 5.35 (dd, J= 2.8, 13.0 Hz,

1 H), 3.99 (t, J= 6.2 Hz, 2H), 3.76 (s, 3H), 3.64 (t, J= 6.2 Hz, 2H), 2.92 (m, 1 H), 2.62 (dd, J =

2.9, 17.0 Hz, 1H), 1.87 (m, 2H). MS: calculated for C 2 oH 2 o0 7 - [M-H]-: 372.12, found 371.50.

[0098] NMR data for 2 nd isomer 1 H NMR (600 MHz, MeOD): 1H NMR (400 MHz, DMSO- d6): 7.30 (d, J= 8.6 Hz, 2H), 6.85 (d, J= 8.7 Hz, 2H), 6.32-6.34 (m, 2H), 5.35 (dd, J= 2.8, 13.0 Hz, 1H), 3.99 (t, J= 6.2 Hz, 2H), 3.76 (s, 3H), 3.64 (t, J= 6.2 Hz, 2H), 2.92 (m, 1H), 2.62 (dd, J = 2.9, 17.0 Hz, 1 H), 1.87 (m, 2H). MS: calculated for C 20 H 20 O 7 - [M-H]-: 372.12, found 371.42. Example 5: Synthesis of compound 352

[0099] Compound 352 may be synthesised according to the following scheme. Example 6: In vitro assays for activity against the Flaviviruses

[0100] The compounds of the invention were tested for activity against flaviviruses selected from dengue virus, Kunjin virus and Zika virus using an in vitro assay.

[0101] Using the plaque assay method, 0.1 to 10 mg of compounds dissolved in methanol were added to wells containing Vero cell monolayers infected with virus and at specific time points after infection test compounds were added. The plates were incubated at 37 °C for the required time. The plates were then stained to determine the effectiveness of the compound. Positive (virus without compound) were run simultaneously.

[0102] Briefly, Vero cells were seeded at 1.25 x 10 5 cells/mL in 1 mL wells in 24 Well flat bottom plates in DMEM (Sigma Aldrich), 10% FBS (Invitrogen) and 1% SPG (Sigma). The cells were in monolayers and 80 - 100% confluent at the time of infection. Serial dilutions of Kunjin virus were prepared (10 -1 to 10 -6 ) in 2% v/v DMEM-HI-FBS + 1 x SPG. The media was removed from each well containing cell monolayers and 200 μL of the desired virus dilution was added to duplicate wells from highest to lowest dilution. The cells were incubated at 37 °C for 1 hr after which 2 mL per well of 50% w/v double strength media and sterile 8% w/v low viscosity carboxymethylcellulose sodium salt was added. The plates were then incubated for a further 3 days. Compound 381 was added to the wells at a concentration of 3.6 mM at 24 hours or at 72 hours post infection. The culture medium was removed at completion of incubation and the cells were rinsed with phosphate buffered saline. 1 mL of ice cold acetone and methanol solution 1 :1 was added to each well and the plates incubated for 30 minutes to inactivate the virus. The liquid was removed and the plates allowed to air dry. The cells were stained with 1 mL per well of 0.5 % w/v crystal violet in 5% v/v formalin: phosphate buffered saline. The plates were incubated for 60 minutes then the stain solution was removed and the cells rinsed with water and air dried.

[0103] The results are shown in Figure 1. At 24 hrs, plate a), the two treated columns of wells show no plaques (two left columns) whereas the untreated wells show significant plaques at the 10 -1 to 10 -4 virus concentration. Similarly, at 72 hrs, plate b), the two treated columns (two right columns) show no plaques, whereas the untreated wells show plaque formation at all viral concentrations.

Example 7: In vitro assays for activity against the Flaviviruses at varying concentrations [0104] The experiment in Example 5 was repeated using compound 381 at concentrations of 2700, 1350, 1000, 500, 250 and 125 mM. The Vero cells infected with Kunjin virus at a multiplicity of infection of 0.1 were treated with compound 381 one hour after virus absorption. Supernatants were collected at 24 hr and 48 hr post infection and viral titres determined using the plaque assay as described in Example 5. The results are shown in Tables 2 (24 hr) and 3 (48 Hr).

[0105] No infectious virus was detected in the supernatant, at both 24Hr and 48Hr, with the highest concentration of the compound (2.7mM). At 24Hr and lower compound concentrations (Table 2), infectious virus particles were detected in the supernatant with a reduction in virus yield of ~2 logs when compared to the positive control (i.e. virus without Compound 381).

[0106] However, at 48Hr post infection (Table 3), there was only I log reduction in virus yield at the second highest compound concentration (1.35mM). At all lower concentrations, there was no reduction in virus yield.

Table 2: Virus yield at 24Hr

Table 3: Virus yield at 48Hr Example 8: Computer modelling against NS5 RNA-dependent RNA polymerase (NS5- RdRp) and NS3 RNA helicase

[0107] NS3 RNA helicase and NS5 RNA-dependent RNA polymerase (RdRp) are two enzymes found in all members of the Family Flaviviridae that closely interact to affect the viral replication cycle. NS5 RdRp catalyses the synthesis of the RNA strand complementary to the RNA template. NS3 RNA helicase unwinds the double stranded RNA to create fully mature positive strand RNA virions.

[0108] To assess whether the compounds of formula (I) potentially bind the DENV NS3 RNA helicase and NS5 RdRp, known crystal structures of these enzymes were used in computer modelling exercises, along with compounds of formula (I) and vitexin, to ascertain docking scores. Example NS3 and NS5 crystal structures obtained from the RCSB Protein Data Base include, but are not limited, to: 2JLS (NS3; www.rcsb.ora/structure/2JLS) and (NS5; www.rcsb.ora/structure/2J7W), respectively. The modelling exercises used Maestro (version 12.0) implemented from the Schrodinger Molecular Modelling Suite - 2019-2. All molecules were sketched in in 3D format using the structure building panel of Maestro, and the LigPrep module was used to generate low energy conformers.

[0109] The docking scores for compounds of the invention with the NS5-RdRp and NS3 enzyme active sites are given in Table 4:

Table 4

[0110] Molecular docking studies revealed that the compounds of formula (I) bind in the nucleotide triphosphate (NTP) cofactor binding pockets of the DENV NS3 and NS5 proteins and interact with a number of amino acids including those known to bind the NTP cofactor suggesting that the compounds inhibit cofactor binding.

[0111] In particular, the amino acids interacting with the compounds of formula (I) tested can be indicated, using the numbering of particular DENV proteins that served as the basis for the molecular structure/docking studies, as:

• NS3 (numbering based on DENV serotype 4; NCBI RefSeq NP_740321; www.ncbi.nlm.nih.gov/protein/NP_740321): Gly 196, Lys199, Thr200, Lys201, Arg202, Glu230, Glu233, Asn329, Gly414, Asn416, Arg418, Gln456, Arg460, Arg463, Asn464 and Gln467;

• NS5 (numbering based on DENV serotype 3; NCBI RefSeq YP_001531176; www.ncbi.nlm.nih.gov/protein/YP_001531176): Asp663, Asp664, Ser710, His711 , Arg729, Ser796, His798, His800, His801 and Gln802.

[0112] Functional elements of the DENV NS3 and NS5 enzymes are also conserved, in molecular structure and conformation and in amino acid sequence, across members of the Family Flaviviridae and therefore are targets for therapeutic inhibition.

[0113] Analysis of sequence conservation across the member species of the Family Flaviviridae allows us to predict that the compounds of formula (I) will also bind to the NS3 and NS5 proteins of all species in genera Flavivirus, Pestivirus, Hepacivirus and Pegivirus.

[0114] In particular, the antiviral compounds of formula (I) may bind the conserved amino acids and others functionally equivalent to the DENV residues including, but not limited to (based on the DENV numbering):

NS3: Gly196, Lys199, Thr200, Asn329, Gly414, Asn416, Gln456, Arg460 and Arg463,

NS5: Asp663, Asp664, Ser710, Arg729, Ser796 and His798. [0115] By the term “functionally equivalent” is meant that the amino acid residue has some level of physicochemically conservative amino acid substitution in non-DENV species.

Example 7: Analysis of NS5 RNA-dependent RNA polymerase (NS5-RdRp) and NS3 RNA helicase interactions with compounds 393, 429, 431 and 463

[0116] Analysis of the individual amino acid interactions between the DENV NS3 and NS5 proteins and compounds 393, 429, 431 and 463 were undertaken. Tables 5 and 6 list individual amino acid interactions with the compounds for each protein.

Table 5: NS3 amino acid interactions with compounds of formula (I)

Table 6: NS5 amino acid interactions with compounds of formula (I) Example 8: Analysis of NS5 RNA-dependent RNA polymerase (NS5-RdRp) and NS3 RNA helicase sequences between species of Family Flaviviridae

[0117] The role and level of amino acid conservation for NS3 and NS5 proteins between genuses of the Family Flaviviridae was also analysed.

[0118] Tables 7 and 8 list the (reported) roles of the amino acids of NS3 protein and NS5 protein and their conservation across the various groups (clades) of the Family Flaviviridae. In these tables, the level of conservation is considered between:

• DENV serotypes 1 - 4

• A sub-group of the mosquito-borne species of Flavivirus - in this case DENV, ZIKV and WNV (Kunjin sub-type)

• Genus Flavivirus- some 50 individual species spanning mosquito-borne, tick-borne, insect-specific and those with an unknown vector.

• Genus Pestivirus

• Genus Hepacivirus

• Genus Pegivirus.

[0119] Table 5 indicates the (antiviral-interacting) amino acids are those involved in binding of the ATP cofactor (Gly196, Lys199, Thr200, Asn416, Gln456, Arg460 and Arg463) as well two residues of unknown function: Gly414 and Asn329. Both Gly414 and Asn429 line the binding pocket and are located quite close to the cofactor when bound. These nine amino acids are conserved, or substituted with a physicochemically similar amino acid, across the Family Flaviviridae.

[0120] Table 4 indicates the (A V- interacting) amino acids are those involved in binding of the GTP cofactor (Ser710, Arg729 and Ser796) or a metal ion cofactor (D663 and D664) as well as His798, which lines the GTP binding pocket. The metal ion cofactor (Mn 2+ ) also binds directly with the GTP cofactor. These six amino acids are mostly conserved, or substituted with a physicochemically similar amino acid, across the Family Flaviviridae. Alignment of the carboxy-terminus of the Flaviviridae NS5 proteins is problematic due to the extent of sequence diversity and the introduction of gaps to maximise alignment and thus it is difficult to demonstrate the conservation or physicochemically conservative substitution of Ser796 in Hepacivirus and Pestivirus and Arg729 in the latter genus.

[0121] The conclusion from Tables 7 and 8 are that the compounds of formula (I) will bind to the NS3 RNA helicase and/or NS5 RNA-dependent RNA polymerase across the Family Flaviviridae.

[0122] Tables 9 and 10 then look at which of the lead compounds binds to the most conserved amino acids for NS3 and NS5 proteins, respectively. The assumption is that more binding is better - leading to higher affinity and greater disruption to protein structure in competitive, reversible binding scenarios.

[0123] The Conclusion from Tables 9 and 10 is that Compound 431 binds the most number of conserved amino acids in NS3 and NS5 is thus likely to be the most effective of the four compounds studied, both across the Family Flaviviridae and in competitive binding scenarios with the various NTP and metal ion cofactors.

Table 7: NS3 - role & conservation of amino acids across the various clades of species from Family Flaviviridae

able 8: NS5 - role & conservation of amino acids across the various clades of species from Family Flaviviridae

Table 9: NS3 -compounds with most interactions with NS3 conserved amino acids

able 10: NS5 - lead compound with most interactions with NS5 conserved amino acids