GB2516818A - Antiviral drug derivatives - Google Patents

Abstract

A compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein R1 is (CR7R7)n­CO2R8 and an optionally substituted 5-6-membered heteroaryl, e.g. isoxazole; R2 and R3 are H, F or Cl; R4 is an optionally substituted triazole; R5 and R6 are azido, hydroxyl, cyano, alkoxy or (CR7R7)m­NR9R9; R7 is H or C1-4alkyl; R8 is H, C1-4alkyl, aryl, heteroaryl or C3-6cycloalkyl; R9 is H, C(O)R8, C1-4alkyl, aryl, benzyl or C3-6cycloalkyl; n is 0-4; and m is 0-2; may be useful as antiviral drug compounds with activity against both wild type and resistant strains of viruses, particularly influenza viruses. Pharmaceutical formulations of these antiviral compounds are also outlined. The compounds are based on the oseltamivir core structure, comprising a triazole substituent in place of the oseltamivir pent-3-oxy ether group.

Description

Antiviral Drug Derivatives [0001] This invention relates to antiviial drug compounds which have activity against both wild type and resistant strains of viruses, particularly influenza viruses. It also relates to pharmaceutical formulations of antiviral drug compounds. It also relates to uses of antiviral diug compounds in treating viral infections and in methods of tieating viial infections.

Background

[0002] In 1918-1 920, the Spanish flu' pandemic spread around the world, killing between and 100 million people. In 2009, the Swine flu pandemic killed an estimated 18,000 people worldwide.

[0003] Oseltamivir (see US 5,763,483) is an antiviral drug which is active against influenza (flu). It is a prodrug, with its ethyl ester being hydrolysed hepatically to form the free carboxylate. Oseltamivir acts as a neuraminidase inhibitor. In blocking the activity of the viral neuraminidase enzyme, oseltamivir prevents the virus from being released by infected cells and thus slows the spread of the virus. The activity as a neuraminidase inhibitor of oseltamivir arises from its ability to compete with sialic acid.

[0004] Oseltamivir exhibits a range of side effects. The most common of which include adverse gastrointestinal effects such as vomiting and diarrhea, hepatitis, headache, allergic reactions and Stevens-Johnson syndrome.

[0005] A number of strains of the influenza have developed resistance to oseltamivir, these include H1N1 (the cause of both the 1918 and 2009 pandemics), H3N2 and H5N1.

[0006] Zanamivir (US 5,648,379) is another neuraminidase inhibitoi which is used in the tieatment of influenza. Unlike oseltamivir there aie no known strains of influenza which are resistant to zanamivir, but there is a need for alternative treatments to oseltamivir and zanamivir, to be used in the event that strains are found in the future which are resistant to oseltamivir and/or zanamivir.

[0007] Zanamivir has poor oral availability. This means that it can only be taken by inhalation. This can cause additional respiratory pioblems in asthmatics oi patients with other respiratory diseases. Such patients are often those most in need of effective treatments against influenza.

[0008] It is an aim of certain embodiments of this invention to provide further compounds for the treatment of influenza. Ideally, the compounds can be administered orally in unit dosage form.

[0009] It is an aim of certain embodiments of this invention to provide compounds for the treatment of strains of influenza which are resistant to oseltamivir and/or zanarnivir.

[0010] It is an aim of certain embodiments of this invention to provide compounds for the treatment of influenza which exhibit higher oral bioavailablity than zanamivir.

[0011] It is an aim of certain embodiments of this invention to provide further compounds for the treatment of influenza, which do not exhibit any one or more than one of the adverse symptoms exhibited by oseltamivir.

[0012] It is an aim of certain embodiments of this invention to provide compounds which have an activity against strains of influenza which are resistant to oseltamivir which is lower than their activity against wild type strains by a factor of less than 100 (or in some embodiments by a factor of less than 10). In other words it is an aim to provide compounds for which the difference between the activity against resistant strains and the activity against susceptible strains is smaller than for oseltamivir.

[0013] Certain embodiments of the present invention satisfy one or more of the above aims.

BRIEF SUMMARY OF THE DISCLOSURE

[0014] In a first aspect of the invention, there is provided a compound according to formula (I), or a pharmaceutically acceptable salt thereof: wherein R1 is a group independently selected from the group comprising: -(CR7R')-CO2R8 and a 5-or 6-membered heteroaryl; wherein the heteroaryl group is optionally substituted with from 1 to 3 groups independently selected at each occurrence from the group comprising: halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, C02R8, C(O)NR9R9, C(O)R°, CHNOR10, NR9R9 and OR9; S2 and 3 are independently at each occurrence selected from the group comprising: H, F and Cl; R is a triazole, optionally substituted with 1 or 2 groups independently selected at each occurrence from the group comprising: halo, C1-06 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, nitro, C02R8, C(O)NR9R9, C(O)R8, CH=N0510, NR959 and os; R5 and P6 are independently selected from the group comprising: azido, hydroxyl, cyano, nitro, alkoxy or-(CR7R7)m-NR9R9; 5' is independently at each occurrence selected from the group comprising: H or C1-C4 alkyl; R8 and P1° are independently at each occurrence selected from the group comprising: H; C1-C4 alkyl; aryl; heteroaryl; C3-C6 cycloalkyl; R9 is independently at each occurrence selected from the group comprising: H, C(O)R8, C1-C4 alkyl, aryl, benzyl, and C3-C6 cycloalkyl; n is an integer selected from: 0, 1, 2, 3 and 4; m is an integer selected from 0, 1 and 2; wherein any alkyl, aryl, benzyl, cycloalkyl, or heteroaryl group present in any of the aforementioned P1 to 10 groups may be optionally substituted with from 1 to 3 groups independently selected at each occurrence from the group comprising: oxo, halo, hydroxy, Ci-C6 alkyl, C2-C6 alkenyl. C3-C6 cycloalkyl, C3-C6 halocycloalkyl, C3-C6-heterocycloalkyl.

Ci-C6 alkoxy, benzyl, Ci-C6 haloalkyl, aryl, heteroaryl, cyano, nitro, CO2RU, C(O)NRbRb, C(O)Ra, CH=NORC, =NORC, NRbRb and ORb; wherein R and Re are independently at each occurrence selected from the group comprising: H; C1-C4 alkyl; aryl; heteroaryl; C3-C6 cycloalkyl; and pb is independently at each occurrence selected from the group comprising: H, C(O)R8, C1-C4 alkyl, aryl, benzyl, and C3-C6 cycloalkyl.

[0015] Like oseltamivir, the compounds of the present invention are based on a cyclohexene ring; however the compounds differ in that the 3-position (a pentoxy group in oseltamivir) is substituted with a planar electron-rich substituent which necessarily changes the binding characteristics of these molecules.

[0016] In an embodiment, the compound of formula (I) is a compound of formula (II); (CF7)1CO2R8 wherein R2, R3, R4, R5, R6, R', R8 and n are as described for formula (I).

[0017] In an embodiment, the compound of formula (I) is a compound of formula (110; wherein R2, R3, R4, R5, R6, R', R8 and n are as described for formula (I) and wherein R1 is a 5-or 6-membered heteroaryl; wherein the heteroaryl group is optionally substituted with from 1 to 3 groups independently selected at each occurrence from the group comprising: halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C5 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, C02R8, C(O)NR°R9, C(O)R°, CH=N0R10, NR9R9 and OR9.

[0018] In an embodiment, the compound of formula (I) is a compound of formula (IV):

NN

R12t5RlV); wheiein R1, R2, R3, R5 and R6 are as described for formula (I) and wherein R11 and R12 are each independently selected at each occurrence from the group comprising: H, halo, 01-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, nitro, C02R8, C(O)NR9R°. C(O)R8, CHNOR10, NR9R9 and OR°.

[0019] In an embodiment, the compound of formula (I) is a compound of formula (V): AcHN NH2 wherein S1 and 4 are as described for formula (I).

[0020] In an embodiment, the compound of formula (I) is a compound of formula (VI):

N N R12\i

wherein l is as described for formula (I) and wherein 11 and 12 are as described for formula (IV) [0021] In an embodiment, the compound of formula (I) is a compound of formula (VII): 55j1'ç> R13 wherein 2, 3, 5 and 6 are as described for formula (I) and wherein R and S12 are as described for formula (IV) and wherein R13 and 14 are independently at each occurrence selected from the group comprising: H, halo, C1-06 alkyl, C2-06 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, C02R8, C(O)NR9R9, C(O)R°, CHNOR10, N59R9 and Q9* [0022] In an embodiment, the compound of formula (I) is a compound of formula (VIII):

NN

wherein R2, R3, R5, R6 and R° are as described for formula (I) and wherein R11 and P12 are as described for formula (IV).

[0023] In an embodiment, the compound of formula (I) is a compound of formula (IX): P12 _Kr P13 c (IX) NH2 wherein P11 and P12 are as described for formula (II) and wherein P13 and S14 are as described for formula (VII).

[0024] In an embodiment, the compound of formula (I) is a compound of formula (X):

N -

RI 2__4,\ CO2 P8 (X) NH2 wherein p8 is as described tor formula (I) and wherein p11 and P12 are as described for formula (IV).

[0025] The following embodiments apply to compounds of any of formulae (l)-(X) (where chemically allowable). These embodiments are independent and interchangeable. Any one embodiment may apply in combination with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically alllowable) be combined with the features described in one or more other embodiments.

[0026] In an embodiment, R1 is -(CR7R7)-OO2R8. In another embodiment, n is 0.

[0027] Alternatively, R1 may be a 5-or 6-membered heteroaryl group.

[0028] In an embodiment, R1 is a 5-membered heteroaryl group; in which the heteroaromatic ring is substituted with 1-3 heteroatoms selected from 0, S and N and wherein the heteroaryl group is optionally substituted with from ito 3 groups independently selected at each occurrence from the group comprising: H, halo, 01-C6 alkyl, C2-C alkenyl, C3-C cycloalkyl, benzyl, 01-06 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, C02R8, C(O)NR9R9, C(0)R8, CH=N0R10, NR9R9 and OR9.

[0029] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with 01-06 alkyl, optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, Ci-C6-alkoxy, C1-C6-fluoroalkyl, oxo, C02R8, aryl or heteroaryl. In an embodiment, it is substituted with an optionally substituted C1-03 alkyl group. In particular, it may be substituted with an optionally substituted methyl group. Alternatively, it may be substituted with an optionally substituted ethyl group. In a further alternative, it may be substituted with an optionally substituted propyl group. In a further alternative, it may be substituted with an optionally substituted butyl group (e.g. an n-butyl group or an isobutyl group).

[0030] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with an optionally substituted C3-06 cycloalkyl group (e.g. a cyclopropyl group).

[0031] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with a C1C6 alkyl group substituted with C02R8, e.g. CO2H (for example, R1 may be substituted with a CH2CH2002H group). Alternatively, it may be substituted with 01-06 alkyl substituted with hydroxyl (for example, Rl may be substituted with a CH2OH group or a (CH(OH)Me group). Alternatively, it may be substituted with C-C6alkyl substituted with an aryl or heteroaryl group. For instance, it may be substituted with a C1-C6 alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, it may be substituted with a 01-C6 alkyl group substituted with a heteroaryl group, e.g. a pyridyl group which may be a 3-pyridinyl or a 2-pyridinyl group. In a further alternative, it may be substituted with a ClC6 alkyl substituted with amino (for example, it may be [0032] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with an optionally substituted aryl group. In a preferred embodiment of this feature, it may be substituted with an optionally substituted phenyl group. Thus, it may be substituted with a phenyl group substituted with C02R8 (e.g. substituted with CO2H). Alternatively, it may be substituted with a phenyl group substituted with a halo group, e.g. a fluoro group (for example, R1 may be substituted with a 4-fluorophenyl). Alternatively, it may be substituted with a phenyl group substituted with two halo groups, which may be the same or different e.g. two chloro groups (for example, R1 may be substituted with a 3,4-dichlorophenyl). In a further alternative, it may be substituted with a phenyl group substituted with a C1-C5 alkoxy group, e.g. a methoxy group (for example, R9 may be 4-methoxyphenyl). Or it may be substituted with a phenyl group substituted with a Ci-C6-fluoroalkyl group, e.g. CF3 group (for example, R1 may be substituted with a 2-(trifluoromethyl)phenyl).

[0033] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with an optionally substituted heteroaryl group. For instance, it may be substituted with thiophenyl (e.g. thiophen-3-yl). Alternatively, it may be substituted with pyridinyl (e.g. 2-pyridinyl or3-pyridinyl).

[0034] In another embodiment, where S1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with C02R8 or C(O)R8. Thus, R1 may be substituted with C02R8, e.g. CO2H. Alternatively, 51 may be substituted with C(O)R8, e.g. C(O)H.

[0035] In an embodiment, where l is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with a group containing a nitrogen with a free lone pair of electrons.

Examples of such groups include pyridines, amines, imidazoles, pyrimidines and pyrazines. Thus, it may be substituted with a group comprising an optionally substituted pyridine ring, e.g. it may be substituted with an optionally substituted pyridine ring or a C-C5 alkyl group substituted with an optionally substituted pyridine ring.

[0036] In another embodiment, pi is a group selected from: N°

N

\ R13; \)Lo R13; \N R13;

NIIIC N

\R13 / R13)Rl3

N

N

N__N N°

N )-/

N N \ /

N -N

wherein R13 and R14 are independently at each occurrence selected from H, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, CrC6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano C02R8, C(O)NR9R9, C(O)R8, CHNOR10, NR9R9 and OR9 Preferably, R1

N is H4

[0037] In an embodiment, R1 is not tetrazole.

[0038] In an embodiment, R8 is C1-06 alkyl. In an embodiment, R8 is C1-C4 alkyl. Thus, S8 may be methyl, ethyl, isopropyl, n-propyl, tert-butyl. In an alternative embodiment, 8 is H. [0039] In an embodiment R14 is H. [0040] In an embodiment, 513 is H. [0041] In an embodiment, 513 is not H. Thus, 513 may be selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-Ce halocycloalkyl, aryl, heteroaryl, cyano, CO2R8, C(O)NR9R9, C(O)R8, CH=NOR10, NR9R9 and OR9 [0042] In an embodiment, I3 is C1-C6 alkyl, optionally substituted with ito 3 groups independently selected at each occurrence from halo, hydroxyl, Ci-C5-alkoxy, C1-C5-fluoroalkyl, oxo, CO2R8, aryl or heteroaryl. In an embodiment, 13 is an optionally substituted C1-C3 alkyl. In particular, R13 may be an optionally substituted methyl group.

Alternatively, R13 may be an optionally substituted ethyl group. In a further alternative, R13 may be an optionally substituted propyl group. In a further alternative, 513 may be an optionally substituted butyl group (e.g. an n-butyl group or an isobutyl group).

[0043] In an embodiment, l3 may be an optionally substituted C3-C6 cycloalkyl group (e.g. a cyclopropyl group).

[0044] In an embodiment, I3 is C1-C6 alkyl group substituted with C0258, e.g. CO2H (for example, I3 may be a CH2CH2CO2H group). Alternatively, I3 is C1-C6 alkyl substituted with hydroxyl (for example, P13 may a CH2OH group or a (CH(OH)Me group).

Alternatively, 13 may be C1-C6 alkyl substituted with an aryl or heteroaryl group. For instance, 13 may be a C1-C5 alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, R13 may be a C1-C6 alkyl group substituted with a heteroaryl group, e.g. a pyridyl group which may be a 3-pyridinyl or a 2-pyridinyl group. In a further alternative, R13 is Ci-C6 alkyl substituted with amino (for example, R13 may a CH2NH2 group).

[0045] In an embodiment, R13 is an optionally substituted aryl group. In a further embodiment, R13 may be an optionally substituted phenyl group. Thus, R13 may be a phenyl group substituted with C02R8, e.g. CO2H. Alternatively! R13 may be a phenyl group substituted with a halo group, e.g. a fluoro group (for example, R13 may be 4-fluorophenyl).

Alternatively, R13 may be a phenyl group substituted with two halo groups, which may be the same or different e.g. two chloro groups (for example, R13 may be 3,4-dichlorophenyl).

In a further alternative, S13 may be a phenyl group substituted with a C1-C6 alkoxy group, e.g. a methoxy group (for example, S13 may be 4-methoxyphenyl). Or I3 may be a phenyl group substituted with a Ci-C6-fluoroalkyl group, e.g. CF3 group (for example, R13 may be 2-(trifluoromethyl)phenyl).

[0046] In an embodiment, 13 is an optionally substituted heteroaryl group. For instance, S13 may be thiophenyl (e.g. thiophen-3-yl). Alternatively, I3 may be pyridinyl (e.g. 2-pyridinyl or 3-pyridinyl).

[0047] In an embodiment, R13 is C02R8 or C(O)58. Thus, R13 may be C0258, e.g. CO2H.

Alternatively, 13 may be C(O)R8, e.g. C(O)H.

[004.8] In an embodiment, R13 is a group containing a nitrogen with a free lone pair of electrons. Examples of such groups include pyridines, amines, imidazoles, pyrimidines and pyrazines. Thus, R13 may be a group comprising an optionally substituted pyridine ring, e.g. may be an optionally substituted pyridine ring or a C1-C6 alkyl group substituted with an optionally substituted pyridine ring.

[0049] In an embodiment, R13 is selected from the group comprising: OH OH)LH 0H &) CF3 HO 0 NH2 H [0050] In an alternative embodiment, R13 is an optionally substituted aryl or heteroaryl group, optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, hydroxyl, C1-C6-alkoxy, Ci-C6-fluoroalkyl, C02R8, awl or heteroaryl.

[0051] In an embodiment, R14 is C02R8 or C(O)R8.

[0052] In a further alternative embodiment, R14 is an optionally substituted alkyl group optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, oxo, hydroxyl, C1-C6-alkoxy, Ci-C6-fluoroalkyl, C02R8, aryl or heteroaryl.

[0053] In an embodiment, R2 is H. In an embodiment, R3 is H. Thus, in a preferred embodiment, R2 is H and S3 is H [0054] In an embodiment, m is 0.

[0055] In an embodiment, R5 and R6 are independently at each occurrence: NR9R9.

Thus, in an embodiment, 6 is NH-C(O)58 (e.g. NHAc). In a further embodiment, 6 is NH2. Preferably, 55 is NHAc and 6 is NH2.

[0056] In an embodiment, 7 is H. [0057] In an embodiment, R8 is independently at each occurrence selected from: H and unsubstituted 01-C4 alkyl. In an embodiment, 9 is independently at each occurrence selected from H, unsubstituted C(O)-C1-C4 alkyl and unsubstituted C1-C4 alkyl. In an embodiment, p1' is independently at each occurrence selected from: H and unsubstituted C1-C4 alkyl. Thus, it may be that 8 is independently at each occurrence selected from: H and unsubstituted C1-C4 alkyl; 9 is independently at each occurrence selected from H, unsubstituted C(O)-C1-C4 alkyl and unsubstituted C1-C4 alkyl; and l0 is independently at each occurrence selected from: H and unsubstituted CrC4 alkyl.

[0058] In an embodiment, R is independently at each occurrence selected from: H and unsubstituted 01-C4 alkyl. In an embodiment, Rb is independently at each occurrence selected from H, unsubstituted C(O)-C1-C4 alkyl and unsubstituted C1-C4 alkyl. In an embodiment, Re is independently at each occurrence selected from: H and unsubstituted cl-c4 alkyl. Thus, it may be that R is independently at each occurrence selected from: H and unsubstituted c1-c4 alkyl; R" is independently at each occurrence selected from H, unsubstituted C(O)-c1-C4 alkyl and unsubstituted C1-C4 alkyl; and Re is independently at each occurrence selected from: H and unsubstituted c1-c4 alkyl.

[0059] In an embodiment, R11 is H. [0060] In an embodiment, R4 is a triazole, optionally substituted with 1 or 2 groups independently selected at each occurrence from the group comprising: c1-c6 alkyl, c3-c6 cycloalkyl, benzyl, c1-c6 haloalkyl, c3-c6 halocycloalkyl, aryl. In another embodiment, R4 is a triazole, optionally substituted with 1 group independently selected at each occurrence from the group comprising: c1-c5 alkyl, c3-c6 cycloalkyl, benzyl, c1-c6 haloalkyl, c3-c6 halocycloalkyl, aryl. In another embodiment, R4 is a triazole, optionally substituted with 1 group independently selected at each occurrence from the group comprising: c1-c6 alkyl, aryl. In a preferred embodiment, R4 is a triazole substituted with an aryl group (e.g. a phenyl group), wherein the awl group (e.g. phenyl group) may be unsubstituted or substituted with from ito 3 groups selected from halo, NR°R9, c1-c4-haloalkyl, and OR9 Thus, R4 may be a triazole substituted with a phenyl group, wherein the phenyl group is substituted with from 1 to 3 groups selected from halo and C1-C4-haloalkyl. Alternatively, R4 may be a triazole substituted with a phenyl group, wherein the phenyl group is substituted with from 1 to 3 groups selected from NR9R9 and OR9 [0061] In an embodiment, R12 is selected from the group comprising: c1-c5 alkyl, c3-c6 cycloalkyl, benzyl, Cl-Cs haloalkyl, C3-C6 halocycloalkyl, awl. In another embodiment, R12 is selected from the group comprising: C1-C6 alkyl, aryl.

[0062] In an embodiment, R12 is C1-C6 alkyl. In an embodiment R12 is unsubstituted Cl-C6 alkyl. Alternatively, R12 may be a C1-C6 alkyl substituted with from 1 to 3 hydroxyl groups. Thus, R12 may be a hydroxymethyl group. R12 may be an ethyl group substituted with 1 or 2 hydroxy groups (e.g. a group selected from: a 1-hydroxyethyl group, a 2-hydroxyethyl group or a 1,2-dihydroxyethyl group).

[0063] In an embodiment, R12 is aryl. Thus, R12 may be phenyl (e.g. unsubstituted phenyl or substituted phenyl). R12 may be a substituted phenyl group. R12 may be phenyl group substituted with from ito 3 groups selected from halo, NR9R9, c1-C4-haloalkyl, and OR9. Thus, R12 may be a phenyl group selected from: fluorophenyl, difluorophenyl, aminophenyl, hydroxyphenyl. R12 may be a phenyl group substituted with 1 or 2 halo groups (e.g. 1 or 2 fluorogroups). Thus, R12 may be 4-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl or 3,5-difluorophenyl. R12 may also be a group selected from hydroxyl phenyl and aminophenyl, e.g. 4-amino phenyl or 3-hydroxyphenyl.

[0064] In yet another embodiment, S12 is pyridinyl. Thus, 512 may be a pyridine-2-yl group or a pyridine-3-yl group or a pyridine-4-yl group. Whatever its orientation, the [0065] Any alkyl, aryl (including phenyl), benzyl, cycloalkyl, or heteroaryl group present in any of the aforementioned R1 to P14 groups may, unless otherwise stated, be optionally substituted with from 1 to 3 groups independently selected at each occurrence from: oxo, halo, hydroxy, 01-C6 alkyl, 02-06 alkenyl, C3-06 cycloalkyl, 03-06 halocycloalkyl, 03-C6-heterocycloalkyl, C1-C6 alkoxy, benzyl, C1-C6 haloalkyl, aryl, heteroaryl, cyano, nitro, co2sa, C(O)NRbRb, C(O)Ra, CHNORC, NORC, NRbRb and ORb; wherein R and Re are independently at each occurrence selected from the group comprising: H; 01-04 alkyl; aryl; heteroaryl; C3-C6 cycloalkyl; and Rb is independently at each occurrence selected from the group comprising: H, C(O)R°, C1-C4 alkyl, aryl, benzyl, and 03-C6 cycloalkyl.

[0066] Due to valency restrictions, familiar to those skilled in the art, when P1 to p14 contain an aryl, benzyl or heteroaryl group, that aryl, benzyl or heteroaryl group cannot be substituted with a group selected from: oxo and =NORC.

[0067] In an embodiment, the compound of formula (I) is selected from:

F

N NN o F-[Nl AcHN'H AcHN'i NH2 NH2 0 N -J [OR8 H2N-:N rr0R8 AcHVY NH2 NH2

F HO

0 NN o F AcHNY AcHN( NH2 NH2; and CF3

I NH2

[0068] In an embodiment, the compound of foimula (I) is selected from: HQNN o HO\/ 0 \\N OR8 / OR8 AcHW( AcHN'( NH2 NH2 HO PLN 0 H2NNN o HO)J 0R8 AcHN AcHN NH2 NH2; and o 8 rT OR AcHN'Y NH2 [0069] In an embodiment, the compound of formula (I) is selected from: 0 NN a N:iOR8 NTOR8 AcHN AcHN NH2; and NH2 [0070] In an embodiment, the compound of formula (I) is: F. N.N

N AcHN NH2

DETAILED DESCRIPTION

[0071] The compounds of the invention are structurally related to oseltamivir. The synthetic routes to oseltamivir are available in the literature and accordingly are not reproduced here. These publicly available disclosures insofar as the synthetic procedures are concerned for preparing the oseltamivir ring system specifically form part of the disclosure of the present invention. In the interests of brevity, the details of these synthetic procedures are not reproduced here but it is intended that this subject matter is specifically incorporated into the disclosure of these documents by reference.

[0072] The skilled man will appreciate that adaptation of methods known in the art could be applied in the manufacture of the compounds of the present invention.

[0073] For example, the skilled person will be immediately familiar with standard textbooks such as "Comprehensive Organic Transformations -A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions), "March's Advanced Organic Chemistry -Reactions, Mechanisms and Structure", MB Smith, J. March, Wiley, (5th edition or later) "Advanced Organic Chemistry, Part B, Reactions and Synthesis", FA Carey, RJ Sundberg, Kluwer Academic/Plenum Publications, (2001 or later editions), "Organic Synthesis -The Disconnection Approach", S Warren (Wiley), (1982 or later editions), "Designing Organic Syntheses" S Warren (Wiley) (1983 or later editions), "Guidebook To Organic Synthesis" RK Mackie and DM Smith (Longman) (1982 or later editions), etc., and the references therein as a guide.

[0074] The skilled chemist will exercise his judgement and skill as to the most efficient sequence of reactions for synthesis of a given target compound and will employ protecting groups as necessary. This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the protection / deprotection steps. These and other reaction parameters will be evident to the skilled person by reference to standard textbooks and to the examples provided herein. 1*7

[0075] Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis" by TW Greene and PGM Wuts, John Wiley & Sons Inc (1999), and references therein.

[0076] Each of the compounds of the present invention may be used as a medicament.

Thus, in another aspect of the invention, there is provided compound as defined above for the treatment of viral infections. The compounds and formulations of the present invention may be used in the treatment of a wide range of viral infections.

[0077] In an embodiment, the viral infection is influenza. In an embodiment, the viral infection is caused by a viral strain which is resistant to currently known antiviral compounds (e.g. a strain which is resistant to oseltamivir and/or zanamivir). In a further embodiment, the viral infection is influenza, caused by a viral strain which is resistant to other antiviral compounds (e.g. a strain which is resistant to oseltamivir and/or zanamivir).

[0078] The viral infection may, for example, be a viral infection selected from: HIV, Hepatitis C, herpes; norovirus, Epstein-Barr, chicken pox, smallpox, dengue fever, viral meningitis, cytomegalovirus, monkeypox, vaccinia and rotavirus.

[0079] In another aspect the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient.

[0080] In another aspect of the invention is provided a method of treating a viral infection, the method comprising treating a subject in need thereof with a therapeutically effective amount of a compound of the invention.

[0081] In an aspect of the invention is provided a compound of the invention for medical use. The use may be in the treatment of any of the indications mentioned above.

[0082] In yet another aspect of the invention is provided a compound for use in the preparation of a medicament. The medicament may be for use in the treatment of any of the indications mentioned above.

[0083] The term resistant strains' is intended to mean viral strains which have shown resistance to one or more known antiviral drug. For example, it may refer to strains which are resistant to oseltamivir or strains that are resistant to other antivirals drugs (e.g. peramivir or zanamivir). A resistant strain is one in which the IC 50 of a given compound or class of compounds for that strain has shifted to a significantly higher number than for the parent (susceptible) strain.

[0084] The compounds of the present invention can be used in the treatment of the human body. They may be used in the treatment of the animal body. In particular, the compounds of the present invention can be used to treat commercial animals such as livestock. Alternatively, the compounds of the present invention can be used to treat companion animals such as cats, dogs, etc. [0085] The compounds of the invention (e.g. the compounds of any of formulae (I) to (X)) may be obtained, stored and/or administered in the form of a pharmaceutically acceptable salt. 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, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids.

[0086] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying.

Microwave or radio frequency drying may be used for this purpose.

[0087] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (pg/kg) to 100 milligrams per kilogram body weight (mg/kg).

[0088] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals -The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0089] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition.

[0090] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g.. of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[0091] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0092] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0093] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0094] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0095] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. The standard duration of treatment with compounds of the invention is expected to vary between one and seven days for most clinical indications. It may be necessary to extend the duration of treatment beyond seven days in instances of recurrent infections or infections associated with tissues or implanted materials to which there is poor blood supply including bones/joints, respiratory tract, endocardium, and dental tissues.

[0096] Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of the invention contains a double bond such as a C=C or C=N group, geometric cis/trans (or ZIE) isomers are possible. Specifically, any oxime group present in the compounds of the invention may be present as the E-oxime, as the Z-oxime or as a mixture of both in any proprotion. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism (tautomerism') can occur. This can take the form of proton tautomerism in compounds of the invention containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds which contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.

[0097] Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of the invention, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counter ion is optically active, for example, d-lactate or 1-lysine, or racemic, for example, dl-tartrate or dI-arginine.

[0098] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0099] Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[00100] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[00101] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

[00102] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) reterred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equirnolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiorner.

[00103] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racernate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art -see, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel and S. H. Wilen (Wiley, 1994).

[00104] Aryl groups have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements. Aryl groups satisfy the Huckel rule. Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups. Equally, aryl groups may include non-aromatic carbocyclic portions. Aryl group may be an optionally [00105] Heteroaryl groups may be 5-or6-membered heteroaryl groups. Heteroaryl groups may be selected from: 5-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-3 heteroatoms selected from 0, Sand N; and 6-membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-2 nitrogen atoms; 9-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 heteroatoms selected from 0, S and N; lO-membered bicyclic heteroaryl groups in which the heteroaromatic system is substituted with 1-4 nitrogen atoms. Specifically, heteroaryl groups may be selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine.

[00106] The aryl (including phenyl), benzyl and heteroaryl groups present in the compounds of the invention are optionally substituted with from 1 to 3 groups independently selected at each occurrence from: halo, hydroxy, CrC6 alkyl, C2-C6 alkenyl, 03-C6 cycloalkyl, 03-C6-heterocycloalkyl, 01-06 alkoxy, benzyl, 01-06 haloalkyl. aryl, heteroaryl, cyano, nitro, c02R', C(O)NRbRb, C(o)sa, CH=NOR°, NRbRb and OR5 [00107] The alkyl or cycloalkyl groups present in the compounds of the invention are optionally substituted with from 1 to 3 groups independently selected at each occurrence from: oxo, =NORC, halo, hydroxy, CrC6 alkyl, C2-C6 alkenyl, CrC6 cycloalkyl, C3-C6-heterocycloalkyl, 01-06 alkoxy, benzyl, 01-06 haloalkyl, aryl, heteroaryl, cyano. nitro, co2Ra, 0(O)NR5R', C(o)Ra, CHNORC, NRSRb and OR5 [00108] The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formulae (l)to (X) and their syntheses, wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[00109] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36C1, fluorine, such as 18F, iodine, such as 1231 and 1251 nitrogen, such as 13N and 15N, oxygen, such as 150 170 and IBQ phosphorus, such as 32P, and sulphur, such as 355 [00110] Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 140, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[00111] Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[00112] Substitution with positron emitting isotopes, such as 11C, 18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[00113] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.

[00114] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of them mean "including but not limited to", and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00115] Features, integers, characteristics! compounds! chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments.

The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00116] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

Example I -Synthesis of triazole compounds [00117] The compounds of the invention in which R1 is CO2R° can be synthesised according to Scheme 1.

o 0,NN o ____ R if AcNJOEt; OEt ____ 4 C AHN'( OAc C 0Ac 1 2 3 R12 __ R12 __ OLt >OEt 0 AcHN AcHNi AcHNti Et N3 OMs OH 6 5 4

N N

NN C R12* ij R NLOEt ____ DH AcHN

AGHN NH NH2 2

Scheme 1 [00118] Compounds 8a-d have been prepared in according to Scheme 1: F, NN 0 PJN

N OH N

AcHN a AcHN NH2 NH2 8a 8c p N' >....N/,.

AcHN " AcHN" NH2 NH2 8b Bd o AcHN"" ij H2 8e (IS, 5R, 65)-Ethyl 5-acetoxy-7-acetyl-7-azabicyclo[4. I.0]hept-2 -ene-3 -carboxylate I [00119] The compound was prepared according to the preparation by L.-D. N/c etaL; Tetrahedron: Asymmetry 22 (2011) 1692-1699 169.

Ethyl (3R,4S,5R)-4-acetamido-5-acetoxy-3-azido-cyclohexene-1 -carboxylate 2 [00120] To a solution of ethyl (IS,5R,6S)-5-acetoxy-7-acetyl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate 1(5.0 g, 18.71 mmol) in DMF (65 mL) was added NaN3 (5.59 g, 86.05 mmol) and NH4CI (2.9 g, 54.25 mmol). The mixture was stirred at room temperature for 20 hours. The reaction mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL), sat. aq. NaCI solution (10 mL) and extracted with dichloromethane. The organic layers were dried over MgSO4, filtered and the solvents were removed in vacuo to afford the product as a yellow oil. (4.92 g, 15.90 mmol, 85.0% yield).

[00121] 1H NMR (ODd3): 67.45 (m, 1 H), 6.65 (m, 1 H), 5.1 (s, 1 H), 4.05-4.2 (m, 2H), 3.95- 4.05 (m, 3H), 3.8-3.9 (m, 2H), 2.8 (s, 1H), 2.7 (s, 1H), 2.5 (m, 2H),1.7-2.0 (m, 8H), 1.0-1.2 (m. 6H); MS (mlz. rel. intensity) 311.3 (M-1-H. 100).

Ethyl (3R,4S,5R)-4-acetamido-5-acetoxy-3-[4-(3-fluorophenyl)triazol -1-yl]cyclohexene-1 -carboxylate 3a [00122] 1 -Ethynyl-3-fluorobenzene (0.35m1, 3.01 mmol) and ethyl (3R,4S,5R)-4-acetamido-5-acetoxy-3-azido-cyclohexene-1 -carboxylate 2 (0.93 g, 3.01 mmol) were dissolved in a 1:1 mixture of tert-butanol (1 mL) and water (1 mL). (+)-Sodium L-ascorbate (59 mg, 0.30 mmol) was added, followed by copper(ll) sulfate pentahydrate (7.5 mg, 0.03 mmol). The solution was stirred vigorously overnight. The reaction was concentrated to dryness and the residue was taken up in ethyl acetate and washed with water. The organics were then separated and dried (MgSO4) before concentration to dryness. The crude product was then purified by flash column chromatography. The desired fractions were concentrated to dryness in vacua to afford ethyl (3R,4S,5R)-4-acetamido-5-acetoxy- 3-[4-(3-fluorophenyl)triazol-1 -yl]cyclohexene-1 -carboxylate (618 mg, 1.43 mmol, 47.7% yield).

[00123] 1H NMR (CDCI3): 58.15 (s, 1H), 7.45 (m, 3H), 7.2 (m, 1W, 6.9 (m, 2W, 5.85 (m, 1H), 5.45 (s, 1 H), 4.9 (m, 1H), 4.2 (m, 2H), 4.0 (m, 1 H), 2.75-2.95 (m, 2H), 1.9-2.1 (m, 6H), 1.5(s, 3H), 1.1-1.3(m, 6H) MS (mtz, rel. intensity) 431.2 (M+H, 100).

Ethyl (3R,4S,5R)-4-acetamido-3-[4-(3-fluorophenyl)triazol-1 -yl]-5-hydroxy-cyclohexene-1 -carboxylate 4a [00124] To a solution of ethyl (3R,4S,5R)-4-acetamido-5-acetoxy-3-[4-(3-fluorophenyl)triazol-1-yl] cyclohexene-1-carboxylate 3a (618 mg, 1.44 mmol)in ethanol (7.5 mL) was added K2003 (218 mg, 1.58 mmol). The solution was left to stir for 90 minutes.

The solvent was then removed in vacua and flash column purified to provide ethyl (3R,4S, 5R)-4-acetamido-3-[4-(3-fluorophenyl)triazol-1 -yl]-5-hydroxy-cyclohexene-1 -carboxylate (320 mg, 0.83 mmol, 57.4% yield) [00125] 1H NMR([d4] MeOD): 68.45 (s, 1H), 7.45-7.6 (m, 2H), 7.3-7.4 (m, 1H), 7.0 (m, 1H), 6.8 (m, 1H), 5.5(m, 1H). 5.4(s, 1H), 4.4(m, 1H), 3.95-4.2(m, 3H), 3.7(m, 1H), 3.3 (m, 1 H), 2.6-2.8 (m, 2H), 1.9 (m, 1 H), 1.8 (m, 3H), 1.2 (m, 3H) MS (mlz, rel. intensity) 389 (M+ H, 100).

Ethyl (3R,4S,5R)-4-acetamido-3-[4-(34luorophenyl)triazol-1 -yl]-5-methylsulfonyloxy-cyclohexene-1 -carboxylate 5a [00126] To a solution of ethyl (3R,4S,5R)-4-acetamido-3-[4-(3-fluorophenyl)triazol-1 -yl]-5-hydroxy-cyclohexene-1-carboxylate 4a (320 mg, 0.82 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (0.13 mL, 1.65 mmol). The resulting solution was cooled to 0 °C in an ice bath and triethylamine (0.23 mL, 1.65 mmol) was then added dropwise over 15 mm. After the addition was finished the reaction mixture was allowed to stir for 1 hour to allow the reaction to complete. The reaction was quenched by adding water (10 mL). The organic phase was washed successively with an aqueous K2003 solution (10% w/v, 10 mL) and sat. aq. NaCI solution (10 mL). The organics were dried over MgSO4, filtered and solvents removed in vacua to provide ethyl (3R,4S,5R)-4- acetamido-3-[4-(3-fluorophenyl)triazol-1 -yl]-5-methylsulfonyloxy-cyclohexene-1 -carboxylate, which was used in the next step without further purification. (363 mg, 0.78 mmol, 95.0%) [00127] MS (mlz, rel. intensity) 467.2 (M+ H, 100).

Ethyl (3R,4S,5R)-4-acetamido-5-azido-3-[4-(3-fluorophenyl)triazol-1 -yl]cyclohexene-I -carboxylate 6a [00128] To a solution of ethyl (3R,4S,5R)-4-acetamido-3-[4-(3-fluorophenyl)triazol-1 -yl]-5-methylsulfonyloxy-cyclohexene-1-carboxylate 5a (384 mg, 0.82 mmol) in ethanol (5 mL) and water (1 mL) was added NaN3 (214 mg, 3.30 mmol). The solution was heated under reflux at 90°C overnight and monitored by thin layer chromatography (TLC). When the TLC indicated that the reaction was complete, the solvents were removed in vacuo, and the residue was re-dissolved in ethyl acetate (10 mL) and water (10 mL). The organic phase was extracted, dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue was purified by flash column chromatography to provide ethyl (3R,4S,5R)- 4-acetamido-5-azido-3-[4-(3-fluorophenyl)triazol-1 -yl]cyclohexene-1 -carboxylate (246 mg, 0.59 mmol, 72.2% yield).

[00129] MS (mlz, rel. intensity) 414.2 (M H, 100).

(3R,4R,SS)-ethyl 4-acetamido-5-amino-3-(4-(3-fluorophenyl)-1 H-i,2,3-triazol-i -yl)cyclohex-I -enecarboxylate 7a [00130] To a solution of ethyl (3R,4S,5R)-4-acetamido-5-azido-3-[4-(3-fluorophenyl)triazol-1 -yl]cyclohexene-1 -carboxylate 6a (246mg, 0.S9mmol) in tetrahydrofuran (9 mL) and water (0.90 mL)was added triphenylphosphine (172 mg, 0.65 mmol). The solution was allowed to stir at room temperature for five minutes, and then heated at reflux at 80°C for seven hours until TLC showed the reaction to be complete.

The solvents were removed in vacuo and purified by tlash column chromatography to provide ethyl (3R,4R,5S)-4-acetamido-5-amino-3-[4-(3-fluorophenyl)triazol-1 -yl]cyclohexene-1-carboxylate (50 mg, 0.13 mmol, 21.6% yield).

[00131] 1H NMR ([d4] MeOD): 68.45(s, 1H), 7.6-7.7 (m, 2H), 7.35-7.45(m, 1H), 7.0-7.1 (m, 1H), 6.8(m, 1H), 5.5(s, 1H), 4.1-4.3(m, 3H), 3.3(m, 2H), 3.2 (s, 1H), 2.9-3.0 (m, 1H), 2.4 (m, 1 H), 1.9 (s, 3H), 1.3 (m, 3H) MS (mlz. rel. intensity) 388.3 (M-'-H, 100).

(3R,4R,SS)-4-acetamido-5-amino-3-(4-(3-fluorophenyl)-1 H-I,2,3-triazol-1 -yl)cyclohex- 1-enecarboxylic acid Ba [00132] To a solution of ethyl (3R,4R,5S)-4-acetamido-5-amino-3-[4-(3-fluorophenyl)triazol-1-yl] cyclohexene-1-carboxylate 7a (50 mg, 0.13 mmol) in water (3 mL) was added triethylamine (0.75 mL, 5.38 mmol). The mixture was stirred overnight. TLC (20% MeOH, 80% ethyl acetate) showed that the reaction was complete and the solvents were removed in vacuo. The resulting solid was then purified by preparative HPLC to provide pure (3R,4R, 5S)-4-acetamido-5-amino-3-[4-(3-fluorophenytriazol-1 -yl]cyclohexene-1-carboxylate (22 mg, 0.048 mmol, 37.2% yield).

[00133] 1H NMR (D20): 58.2-8.5 (m, 3H), 7.4-7.6 (m, 3H), 7.0-7.1 (m, 1H), 6.6 (s, 1H), 5.5-5.6 (m, 1H),4.35-4.5 (m, 1 H), 3.8-3.9 (m, 1H), 3.0-3.2 (m, 1 H), 2.5-2.7 (m, 1 H), 1.8-1.9 (s, 3H) MS (mlz, rel. intensity) 360.41 (M+H, 100).

[00134] Compounds 8b-e were prepared using analogous methods to those described above to prepare compound Ba.

(3R,4R,5S)-4-acetamido-5-amino-3-(4-(4-fluorophenyl)-1 H-i,2,3-triazol-1 -yl)cyclohex- 1-enecarboxylic acid Sb [00135] 1H NMR (CDCI3): 58.3 (s, 1 H), 7.7 (m. 2H). 7.1 (m. 2H), 6.5 (s, 1 H), 5.5 (s, 1 H).

4.35(m, 1H), 3.8 (m, 1H), 3.35 (m, 1H), 3.1 (m, 9H), 2.2 (s, 1H), 1.85(m, 7H), 1.2 (m, 15H) ) MS (m/z, rel. intensity) 360.2 (M+H, 100).

(3R,4R,5S)-4-acetamido-5-amino-3-(4-phenyl-1 H-i,2,3-triazol-i -yl)cyclohex-i -enecarboxylic acid Sc [00136] 1H NMR(CDCI3): 58.32(s, 1H), 7.69 (m, 2H), 7.42(m, 2H), 7.32(m, 1H), 6.39 (m, 1H), 5.39 (m, 1H), 4.40 (m, 1H), 4.01 (m, 1H), 3.10 (m, 1H), 2.32 (m, 1H), 1.87 (s, 3H).

MS (mlz, rel. intensity) 342.2 (M+H, 100).

(3R,4R,SS)-4-acetamido-5-amino-3-(4-(pyridin-3-yl)-1 H-i,2,3-triazol-1 -yl)cyclohex-1 -enecarboxylic acid 8d [00137] 1H NMR(CDCI3): 58.81 (a, 1H), 8.43 (m, 2H), 8.17(m, 1H), 7.50(m, 1H), 6.50 (m, 1 H), 5.40 (m, 1 H), 4.22 (m, 2H), 2.75 (m, 1 H), 2.62 (m, 1 H), 1.80 (s, 3H). MS (mlz, rel.

intensity) 444.5 (M+H, 100).

(3R,4R,5S)-4-acetamido-5-amino-3-(4-propyl-i H-I,2,3-triazol-1 -yl)cyclohex-i -enecarboxylic acid 8e (formed as the triethylamine salt) [00138] 1H NMR(D20): 57.7 (s, 1H), 6.6 (m, 1H), 5.5 (m, 1H), 4.5 (m, 1H), 3.4-3.7 (m, 2H), 3.05-3.15(m, 1H), 2.45-2.65(m, 3H), 1.7-1.85(m, 4H), 1.5-1.6(m, 2H), 0.8(m, 3H)) MS (mlz, rel. intensity) 308 (M+ H+, 85).

Example 2 -Synthesis of triazole/isoxazole compounds Compounds of the present invention in which R1 is an isoxazole can be prepared according to the following scheme. The starting material 7 is prepared as shown in Scheme 1 above. Analogous methods can be used to prepare compounds in which R1 is other heteroaromatic groups.

NN 0 0 NJ-tJ R12-<. R12 a b AcHN"( AcHN NH2 NH(BOC) NH(BOC) 7 9 10 N-N N-° .NN N e N OH d R12 N

___ N JO

AcHNt AcHN AcHN NH(BOC) NH(BOC) NH(B0C) NQ. 12 11 R12 Ac H N1 cj H2 a) Di-t-butyl dicarbonate (1.leq), Dichloromethane; b) DIBAL (3eq), Dichloromethane, 0°C; c) Dess-Martin periodinane (1.Seq), Dichloromethane; d) Hydroxylamine (1.leq), Pyridine (1.5eq), Ethanol; e) Alkyne-R13 (1.1 eq), Trifluoroacetic Acid (1 eq); Diacetoxyiodobenzene (1.1 eq); f) Trifluoroacetic Acid:Dichloromethane (1:4).

Scheme 2 Example 3 -Evaluation of Compounds in Neuraminidase Assays

Summary of Protocol

[00139] The controls used in this study are: 1) a dose of oseltamivir neuraminidase (NA) inhibitor as control compound! 2) vehicle control (10% dH2O in NA-XTD assay buffer) and 3) Heat inactivated NA enzyme. The selected 9-point dose response is: 300pM, 100pM, 10pM, 1pM, 0.lpM, l0nM, mM, 0.lnM and 0.0mM Assay protocol [00140] 1. To each well add 25pL of either: a. Oseltamivir or test compound or, b. 10% dH2O in NA-XTD assay buffer as a vehicle control.

2. Add 25pL of one of the following: a. Diluted NA enzyme or, b. As a control, heat inactivated NA enzyme (15 minutes at 60°C).

3. Place lid on the plate, incubate for 20 minutes at 37°C 4. Add 25pL of diluted NA-XTD substrate (1:1000 in NA-XTD assay buffer) to each well 5. Place lid on the plate, then incubate for 30 minutes at room temperature 6. Add 6OpL of NA-XTD accelerator to each well 7. WaitS minutes to read plate 8. Read the plate using a 1 sec/well read time using the Envision multi-mode plate reader (Perkin Elmer) [00141] Table I -Viral enzymes used Enzyme Serotype Oseltamivir Dilution used ___________________ _____________ susceptability _________________ Influenza A Neuraminidase-wild H1N1 + 1:10 000 type _______________ ____________________ ___________________ Influenza A Neuraminidase-H1N1 -1:10 000 H274Y_mutation _____________ __________________ _________________ Results [00142] Table 2-lCSO (nM) for tested compounds Compound number lCso (nM) WT enzyme 1C50 (nM) H274Y enzyme 8b 38 242 Bc 342 4619 8d 14207 66069 Oseltamivir 0.5 121 Zanamivir 0.2 0.3 [00143] Thus, certain compounds of the invention have been shown to be active against viral enzymes, and, particularly, those from viral strains which cause influenza. The compounds of the invention have also been shown to be active against resistant viral enzymes (e.g. those from strains which are resistant to oseltamivir), and, particularly, those from resistant viral strains which cause influenza.

Example 4 -Illustrative examples Compounds A-H, which do not form part of the present invention, were tested for activity against viral neuraminidase:

HN

OH

HN

A B N°

HN

HN

C D N0 N°

HN

HN

E F 2HN

HN

) H3O2CCF3 0 0

G H

Summaay of Protocol [00144] The controls used in this study are: 1) a dose of oseltamivir neuraminidase inhibitor as control compound, 2) vehicle control (0.01% DMSO only), 3) infection media and 4) Heat inactivated virus. The selected 8-point dose response is: 10pM, 1pM, lOOnM, lOnM, 3nM, mM, 0.3nM and 0.inM. For the preliminary test only Oseltamivir and Vibrio cholera neuraminidase (reagent activity control) were tested.

1. To each well add 25pL of either: a. Oseltamivir or test compound or, b. 0.01% DM50 when applicable or, c. NA-XTD buffer to wells not containing oseltamivir or test compound or vehicle 2. Add 25pL of one of the following: a. diluted virus to all wells except those shown in red above b. to the remaining wells add either pre-heated virus or c. influenza media (marked in red above) 3. Place lid on the plate, incubate 20 minutes at 37°C 4. Add 25pL of diluted NA-XTD substrate to each well 5. Place lid on the plate, then incubate for 30 minutes at room temperature 6. Add 6OpL of NA-XTD accelerator to each well 7. Wait 5 minutes to read plate 8. Read the plate using a 1 sec/well read time using the Victor 2 Luminescence Reader Prepare -20% excess substrate dilution, for example for 28 wells (825pL NA-XTD Assay Buffer + 00.8pL NA-XTD Substrate) -add 25pL per well. Make sure the buffer is at RT.

Table 3: Viral stocks used Virus Strain Serotype Oseltamivir Mutation Dilution used susceptibility Washington/01/2007 H1N1 + WT 1:20 California/07/2009 Hi Ni + WT 1:20 A/Texas/12/2007 H3N2 -E119V 1:4 Table 5 -IC50 mM) for illustrative compounds at indicated strains Compound Number Strain source IC50 (nM) A Washington/01/2007 35.9 B Washington/01/2007 2.4 B Texas/i2/2007 31.5 C Washington/01/2007 4.0 C Texas/i2/2007 103 D Washington/O1/2007 22.6 D California/0712009 6.7 D Texas/i212007 66.6 E Washington/01/2007 31.1 F California/07/2009 17.7 G California/07/2009 32.0 H WashingtontOl/2007 22.7 [00145] Many of the compounds of the present invention posses a heteroaromatic group at the C-i position (i.e. R1 of formula (I) above). As shown in the table above, compounds with a heteroaryl group at this position are active against viral neuraminidase.

Thus, certain derivatives of oseltamivir which have been shown to have neurarninidase inhibitory activity contain heteroaryl groups in place of a carboxylic acid/ester. These groups are structurally and electronically quite different from and cannot be considered to be isosteric with carboxylic acid groups, such as that ordinarily present in vivo in oseltamivir. Hence any finding of good activity in a compound of this type is surprising.