GB2532178A - Antiviral compounds - Google Patents

Abstract

 Cyclohexenyl compounds of formula (I): wherein R1 is (CR7R7)n-CO2R8 or a 5- or 6-membered heteroaryl; R2 and R3 are H, F or Cl; X is CR7R7, O, S or NR9; R4 is a saturated 4-6-membered cycloalkyl group or a saturated 4-6-membered heterocycloalkyl group having a ring system with 1-2 heteroatoms selected from O, N and S; R5 is azido, hydroxyl, cyano, nitro, alkoxy, -(CR7R7)mNR9R9 or NR6aC(=NR6a)NR6aR6a; R6a is H, C1-4alkyl, aryl, benzyl or C3-6cycloalkyl; 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 anti-viral compounds with activity against both wild type and resistant strains of viruses, particularly influenza viruses. Preferred compounds possess a guanidine group at the 5-position.

Description

Antiviral Compounds [0001] This invention relates to antiviral 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 drug compounds in treating viral infections and in methods of treating viral infections.

Background

[0002] In 1918-1920, 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 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 inhibitor which is used in the treatment of influenza Unlike oseltamivir there are 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 bioavailability. This means that it can only be taken by inhalation. This can cause additional respiratory problems in asthmatics or 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 zanamivir.

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

[0011] It is an aim of certain embodiments of this invention to provide 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] 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: R2 (I); wherein R1 is a group independently selected from: -(CR7R7)n-CO2R8 and a 5-or 6-membered heteroaryl; R2 and R3 are independently at each occurrence selected from: H, F and CI; X is independently selected from: CIR7R7, 0, S and NR9; R4 is independently selected from a saturated 4-, 5-or 6-membered cycloalkyl group and a saturated 4-, 5-or 6-membered heterocycloalkyl group having a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N and S; wherein, if the heterocycloalkyl ring system contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group; R5 is independently selected from: azido, hydroxyl, cyano, nitro, alkoxy and -(CWIR7)mNR9R9; R6 is independently selected from: azido, hydroxyl, cyano, nitro, alkoxy, -(CIR7R7),,-NR9R9 and N R69C(=NR69)N R691R69; R6a is independently at each occurrence selected from: H, C1-04 alkyl, aryl, benzyl, and 03- 06 cycloalkyl R7 is independently at each occurrence selected from: H or 01-04 alkyl; R6 and IR151 are independently at each occurrence selected from: H; C1-C4 alkyl; aryl; heteroaryl; 03-06 cycloalkyl; R9 is independently at each occurrence selected from: H, C(0)R8, 01-04 alkyl, aryl, benzyl, and C3-06 cycloalkyl; n is an integer selected from: 0, 1, 2, 3 and 4; m is an integer selected from 0, 1 and 2; each of the aforementioned alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heterocycloalkyl, aryl (e.g. phenyl) and heteroaryl groups, are optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NRa, =NORa, halo, nitro, cyano, NRaRa, NRaS(0)2Ra, NRaCONRaRa, NRaCO2Ra, ORa; SRa, SORE, SO3Ra, SO2Ra, SO2NRaRa,CO2Ra C(0)Ra, CONRaRa, C2-C4-alkenyl, C2-C4-alkenyl, 01-04 haloalkyl, CIRbRbrs1R9R9, and =CRbCRbRbNRaRa; wherein Ra is independently at each occurrence selected from H, Cr C4 alkyl and C1-04 haloalkyl; and RI' is independently at each occurrence selected from H, halogen, C1-04 alkyl and 01-04 haloalkyl.

[0015] Like oseltamivir, the compounds of the present invention are based on a cyclohexene ring; however the compounds differ in that the 3-position is substituted with a cyclic substituent. Many of the compounds also possess a guanidine group at the 5-position. Either of these structural differences may change the binding characteristics and/or properties of these molecules relative to oseltamivir.

[0016] It may be that any alkyl, aryl, benzyl, cycloalkyl, or heteroaryl group, the optional substituents of which have not already been specified, present in any of the aforementioned R1 to R1° groups, may be optionally substituted with from 1 to 3 groups independently selected at each occurrence from the group comprising: oxo, halo, hydroxy, 01-06 alkyl, 02-C6 alkenyl, Ca-C6 cycloalkyl, Ca-C6 halocycloalkyl, C3-C6-heterocycloalkyl, 01-06 alkoxy, benzyl, C1-06 haloalkyl, aryl, heteroaryl, cyano, nitro, CO2R9, C(0)NRblRb, C(0)Ra, CH=NOIRc, =NOR°, NRbRb and ORb; wherein Ra and Rc are independently at each occurrence selected from the group comprising: H; C1-04 alkyl; aryl; heteroaryl; C3-06 cycloalkyl; and Rh is independently at each occurrence selected from the group comprising: H, C(0)-C1-C4 alkyl, C1-C4 alkyl, aryl, benzyl, and 03-C6 cycloalkyl.

[0017] Preferably, R1 is a group independently selected from the group comprising: - (CR71R7)6-0O2R8 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, Ci-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, Ci-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, CO2R8, C(0)NR9R9, C(0)R8, CH=NOR15, NR9R9 and OR9.

[0018] Preferably, R4 is independently selected from a saturated 4-, 5-or 6-membered cycloalkyl group and a saturated 4-, 5-or 6-membered heterocycloalkyl group with a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N, S; the cycloalkyl group or heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C14 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group.

[0019] In an embodiment, the compound of formula (I) is a compound of formula (II): R2 (CR7R7)n-CO2R8 N Rea Rea NR62 (II) wherein R2, R3, R4, R5, R68, R7, R8, X and n are as described for formula (I).

[0020] In an embodiment, the compound of formula (I) is a compound of formula (III): N Rea N R6a R6a NR6a (III) R4 IR3 R2 wherein R2, R3, R4, R5, IR' and X 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, Ci-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, CO2R8, C(0)NR9R9, C(0)R8, CH=NORla, NR9R9 and OR9.

[0021] In an embodiment, the compound of formula (I) is a compound of formula (IV): R2 R\ R3

N

H R5

NR6a NR6a1R6a NR6a (1V); wherein R1, R2, R3, R4, R5 and IR' are as described for formula (I).

[0022] In an embodiment, the compound of formula (I) is a compound of formula (V): R4-X"". AcHN

NH (V) wherein R1, R4 and X are as described for formula (I).

[0023] In an embodiment, the compound of formula (I) is a compound of formula (VI): NH (VI); wherein R1 and R4 are as described for formula (I).

[0024] In an embodiment, the compound of formula (I) is a compound of formula (VII): N R68 (VII); wherein R2, R3, R4, R5 and Rea are as described for formula (I) and wherein R11 and R12 are independently at each occurrence selected from the group comprising: H, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, Ca-C6 halocycloalkyl, aryl, heteroaryl, cyano, CO258, C(0)NR9R9, C(0)R8, CH=NOR13, NR9R9 and OR9.

[0025] In an embodiment, the compound of formula (I) is a compound of formula (VIII): R2 H R3 R4-N R11 R12 NIR63 NR88R88 H R3 CO2 R6 NR6aN R68 R88 NR68 (VIII); wherein R2, R3, R4, R5, Rea and R8 are as described for formula (I).

[0026] In an embodiment, the compound of formula (I) is a compound of formula (IX): R11 NH (IX); wherein R4 is as described for formula (I) and wherein R11 and R12 are as described above for formula (VII).

[0027] In an embodiment, the compound of formula (I) is a compound of formula (X): CO2Ra 7 NH2 NH (X); wherein R4 and R8 are as described for formula (I).

[0028] In an embodiment, the compound of formula (I) is a compound of formula (XI): NR6a (XI); wherein R1, R2, R3, R5 and Rea are as described above for formula (I) and wherein Y is 0, S or NR9; R13 is independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1-3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with 1, 2 or 3 groups independently selected from halo and OH; and p is an integer selected from 0, 1, 2, and 3. In some compounds of formula (XI), Y is 0.

[0029] In an embodiment, the compound of formula (I) is a compound of formula (XII): R2 H R3 N R1 (R13)p NReaNR6aR6a R11 NR6a,...NR6aR6a Rea (XII); wherein R2, R3, R5 and Rea are as described above for formula (I), wherein R11 and R12 are as described for formula (VII) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XII), Y is O. [0030] In an embodiment, the compound of formula (I) is a compound of formula (XIII): NR6 (XIII); wherein R2, R3, R5, R5, R', R5 and n are as described above for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XIII), Y is O. [0031] In an embodiment, the compound of formula (I) is a compound of formula (XIV): NH (XI V); wherein R1 is as described for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XIV), Y is 0 [0032] In an embodiment, the compound of formula (I) is a compound of formula (XV): NH (XV); wherein R11 and R12 are as described for formula (VII) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XV), Y is 0.

[0033] In an embodiment, the compound of formula (I) is a compound of formula (XVI):

HN NH2

CO2 R8 9 HN NH2 NH (XVI) wherein R4 and R8 is as described for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XVI), Y is 0.

[0034] In an embodiment, the compound of formula (I) is a compound of formula (XVII):

X R2

NR88 NR6aR6a NR88 (XVII) wherein R1, R2, R3, R4, R5, Rea and X are as described above for formula (I).

[0035] In an embodiment, the compound of formula (I) is a compound of formula (XVIII).

(CIR7R7)n-CO2R8 Re (XVIII) wherein 52, R3, R4, R5, R8, 57, R8, X and n are as described for formula (I).

[0036] In an embodiment, the compound of formula (I) is a compound of formula (XIX): R8 (XIX) wherein 52, 52, 54, Rs, R8 and X are as described for formula (I) and wherein IR1 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, Cl-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, CO2R8, C(0)NR8R8, C(0)R8, CH=NOR10, NIR8R8 and OR9.

[0037] In an embodiment, the compound of formula (I) is a compound of formula (XX): R2 R6 (XX); wherein R1, R2, R3, R4, R5 and R6 are as described for formula (I).

[0038] In an embodiment, the compound of formula (I) is a compound of formula (XXI): R4-X"",, AcH N NH2 (XXI) wherein R1, R4 and X are as described for formula (I).

[0039] In an embodiment, the compound of formula (I) is a compound of formula (XXII): NH2 (XXII); wherein R1 and R4 are as described for formula (I).

[0040] In an embodiment, the compound of formula (I) is a compound of formula (XXIII). R11

R6 (XXIII); wherein R2, R3, R4, R5 and R6 are as described for formula (I) and wherein R11 and R12 are as described above for formula (VII).

[0041] In an embodiment, the compound of formula (I) is a compound of formula (XXIV): CO2R8 11 Re (XXIV); wherein R2, R3, R4, R5, R6 and R8 are as described for formula (I).

[0042] In an embodiment, the compound of formula (I) is a compound of formula (XXV): R11 NH2 (XXV); wherein R4 is as described for formula (I) and wherein R11 and R12 are as described for formula (VII).

[0043] In an embodiment, the compound of formula (I) is a compound of formula (XXVI): CO2Re NH2 (XXVI); wherein R4 and R8 are as described for formula (I).

[0044] In an embodiment, the compound of formula (I) is a compound of formula (XXVII): Re (XXVII); wherein R1, R2, R3, R5 and R6 are as described above for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XXVII), Y 0.

[0045] In an embodiment, the compound of formula (I) is a compound of formula (XXVI I I): R11 12 R6 (XXVIII); wherein R2, R3, R5 and R6 are as described above for formula (I), wherein R11 and R12 are as described for formula (VII) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XXVIII), Y is 0 [0046] In an embodiment, the compound of formula (I) is a compound of formula (XXIX): (CIR7R7)nCO2R6 R6 (XXIX), wherein R2, R3, R6, R6, R', R8 and n are as described above for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XXIX), Y is O. [0047] In an embodiment, the compound of formula (I) is a compound of formula (XXX): NH2 (XXX); wherein R1 is as described for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XXX), Y is 0.

[0048] In an embodiment, the compound of formula (I) is a compound of formula (XXXI):

RII

NH2 (XXXI), wherein R11 and R12 are as described for formula (VII) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XV), Y is 0.

[0049] In an embodiment, the compound of formula (I) is a compound of formula (XXXII): CO2R8 13 NH2 (XXXII) wherein R4 and R8 is as described for formula (I) and wherein Y, R13 and p are as described above for formula (XI). In some compounds of formula (XVI), Y is 0.

[0050] The following statements apply to compounds of any of formulae (I) to (XXXII).

These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described in one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this invention in this specification.

[0051] In some embodiments, R1 is -(CR'R7)n-CO2R8. Preferably, n is 0. Thus, in some embodiments R1 is -CO2R8.

[0052] Alternatively, R1 may be a 5-or 6-membered heteroaryl group.

[0053] 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 1 to 3 groups independently selected at each occurrence from the group comprising: H, halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, benzyl, Cr-C6 haloalkyl, C3-C6 halocycloalkyl, aryl, heteroaryl, cyano, CO2R8, C(0)NR9R9, C(0)R8, CH=NOR10, NR9R9 and OR9.

[0054] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with C1-05 alkyl, optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, C1-C6-alkoxy, C1-C6-fluoroalkyl, oxo, CO2R8, aryl or heteroaryl. In an embodiment, it is substituted with an optionally substituted C1-C3 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).

[0055] 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).

[0056] In an embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with a C1-C6 alkyl group substituted with CO2R8, e.g. CO2H (for example, R1 may be substituted with a CH2CH2CO2H group). Alternatively, it may be substituted with C1-06 alkyl substituted with hydroxyl (for example, R1 may be substituted with a CH2OH group or a (CH(OH)Me group). Alternatively, it may be substituted with CiC6alkyl substituted with an aryl or heteroaryl group. For instance, it may be substituted with a C1-06 alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, it may be substituted with a C1-06 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 C1-06 alkyl substituted with amino (for example, R1 may be substituted with a CH2NH2 group).

[0057] 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 CO2R8 (e.g. substituted with 002H). 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, R' may be substituted with a 3,4-dichlorophenyl). In a further alternative, it may be substituted with a phenyl group substituted with a Ci-C6 alkoxy group, e.g. a methoxy group (for example, R1 may be substituted with a 4-methoxyphenyl). Or it may be substituted with a phenyl group substituted with a C1-C6-fluoroalkyl group, e.g. CF3 group (for example, R1 may be substituted with a 2-(trifluoromethyl)phenyl).

[0058] 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 or 3-pyridinyl).

[0059] In another embodiment, where R1 is a 5-membered heteroaryl group (e.g. isoxazole group), it is substituted with CO2R8 or C(0)R8. Thus, R1 may be substituted with CO2R8, e.g. CO2H. Alternatively, 51 may be substituted with C(0)R8, e.g. C(0)H.

[0060] In an embodiment, where 51 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 GCs alkyl group substituted with an optionally substituted pyridine ring.

[0061] In another embodiment, R1 has a structure selected from: R11

NON

>---R11 N 0 R11 R11 R11 R11 R12 R11

N R9 R9 N R9 Nr R11

NCO

II >--R11 N N R12; and R12

N

wherein R11 and R12 are independently at each occurrence selected from H, halo, Ci-C6 alkyl, C2-06 alkenyl, 03-06 cycloalkyl, benzyl, C1-C6 haloalkyl, 03-06 halocycloalkyl, aryl, heteroaryl, cyano CO2R8, C(0)NR9R9, C(0)R8, CH=NOR19, NR9R9 and OR9. R8, R9 and Rl° are as defined herein. Where R11 and R12 are alkyl, heteroaryl, benzyl, cycloalkyl they may be substituted or unsubstituted. Preferably, R1 has the structure: R11 [0062] In an embodiment, Ri is not tetrazole.

[0063] In an embodiment, R8 is C1-C6 alkyl. In an embodiment, R8 is 01-04 alkyl. Thus, R8 may be methyl, ethyl, isopropyl, n-propyl, tert-butyl. In an embodiment, R8 is H. [0064] By analogy with oseltamivir, it may be that when R8 is an alkyl group, the compound will be hydrolysed hepatically to the carboxylic acid. Thus, it might be expected that compounds which have R8 as an alkyl group are prodrugs for an active compound. Although these prodrugs may have activity in their own right, it may be reduced relative to the free carboxylic acid when tested in in vitro conditions.

[0065] In an embodiment R12 is H. [0066] In an embodiment, R11 is H. [0067] In an embodiment, R11 is not H. Thus, R11 may be selected from halo, Cl-Ca alkyl, C2-C6 alkenyl, C3-Cs cycloalkyl, benzyl, C1-C6 haloalkyl, C3-Cs halocycloalkyl, aryl, heteroaryl, cyano CO2R8, C(0)NR9R9, C(0)R8, CH=NOR10, NR9R9 and OR9.

[0068] In an embodiment, R11 is Ci-05 alkyl, optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, C1-Csalkoxy, C1-Csfluoroalkyl, oxo, CO2R8, aryl or heteroaryl. In an embodiment, R11 is an optionally substituted Ci-C3 alkyl. In particular, R11 may be an optionally substituted methyl group.

Alternatively, R11 may be an optionally substituted ethyl group. In a further alternative, R11 may be an optionally substituted propyl group. In a further alternative, R11 may be an optionally substituted butyl group (e.g. an n-butyl group or an isobutyl group).

[0069] In an embodiment, R11 may be an optionally substituted C3-05 cycloalkyl group (e.g. a cyclopropyl group).

[0070] In an embodiment, R11 is C1-C6 alkyl group substituted with CO2R8, e.g. CO2H (for example, R11 may be a CH2CH2CO2H group). Alternatively, R11 is C1-C6 alkyl substituted with hydroxyl (for example, R11 may a CH2OH group or a (CH(OH)Me group).

Alternatively, R11 may be C1-Cs alkyl substituted with an aryl or heteroaryl group. For instance, R11 may be a C1-Ca alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, R11 may be a Ci-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, R11 is C1-C6 alkyl substituted with amino (for example, R11 may a CH2NH2 group).

[0071] In an embodiment, R11 is an optionally substituted aryl group. In a further embodiment, R11 may be an optionally substituted phenyl group. Thus, R11 may be a phenyl group substituted with CO2R8, e.g. CO2H. Alternatively, IR11 may be a phenyl group substituted with a halo group, e.g. a fluoro group (for example, R11 may be 4-fluorophenyl). Alternatively, R11 may be a phenyl group substituted with two halo groups, which may be the same or different e.g. two chloro groups (for example, R11 may be 3,4-dichlorophenyl).

In a further alternative, R11 may be a phenyl group substituted with a C1-C6 alkoxy group, e.g. a methoxy group (for example, RTh may be 4-methoxyphenyl). Or R11 may be a phenyl group substituted with a Ci-C6-fluoroalkyl group, e.g. CF3 group (for example, R11 may be 2-(trifluoromethyl)phenyl).

[0072] In an embodiment, R11 is an optionally substituted heteroaryl group. For instance, R11 may be thiophenyl (e.g. thiophen-3-yl). Alternatively, R11 may be pyridinyl (e.g. 2-pyridinyl or 3-pyridinyl).

[0073] In an embodiment, R11 is CO2R8 or C(0)R8. Thus, R" may be CO2R8, e.g. CO2H. Alternatively, R11 may be C(0)R8, e.g. C(0)H.

[0074] In an embodiment, R11 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, R1' may be a group comprising an optionally substituted pyridine ring, e.g. R11 may be an optionally substituted pyridine ring or a C1-C6 alkyl group substituted with an optionally substituted pyridine ring.

[0075] In an embodiment, R11 is selected from the group comprising: ?7-) OH 22,0H 22,)L° H ZarjL OH [0076] In an alternative embodiment, R11 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, C1-05-fluoroalkyl, CO2R8, aryl or heteroaryl.

[0077] In an embodiment, R12 is CO2R8 or C(0)R8.

[0078] In a further alternative embodiment, R12 is an optionally substituted alkyl group optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, oxo, hydroxyl, C1-05-alkoxy, C1-C6-fluoroalkyl, CO2R8, aryl or heteroaryl.

22W NH2 2Z-1No 2.4W /1'111

CI CI

[0079] Where R11 and R12 are alkyl, heteroaryl (e.g. pyridiyl), benzyl, aryl (e.g. phenyl), or cycloalkyl they may be substituted or unsubstituted as described herein.

[0080] In an embodiment, R2 is H. In an embodiment, R3 is H. In a preferred embodiment, R2 is H and IR8 is H. [0081] In an embodiment, m is 0.

[0082] In an embodiment, R5 is NR9R9. Thus, in an embodiment, R5 is NH-C(0)R8 (e.g. NHAc).

[0083] In an embodiment, R6 is NH2. Preferably, however R6 is NR6aC(=NR6a)NR6aR6a. Preferably, R6' is at each occurrence H. Thus, R6 may be NHC(=NH)N H2.

[0084] In an embodiment, R7 is H. [0085] In an embodiment, R8 is independently at each occurrence selected from: H and unsubstituted 01-04 alkyl. In an embodiment, R9 is independently at each occurrence selected from H, unsubstituted C(0)-C1-C4 alkyl and unsubstituted C1-C4 alkyl. In an embodiment, R1° is independently at each occurrence selected from: H and unsubstituted C1-04 alkyl. Thus, it may be that R8 is independently at each occurrence selected from: H and unsubstituted C1-04 alkyl; R9 is independently at each occurrence selected from H, unsubstituted C(0)-C1-a4 alkyl and unsubstituted 01-04 alkyl; and R19 is independently at each occurrence selected from: H and unsubstituted C1-04 alkyl.

[0086] In an embodiment, Xis independently selected from NH, 0 and S. In a preferred embodiment, Xis NR9. Alternatively, X may be 0 or X may be S. X will typically be NH but may also be NMe.

[0087] R4 may be an independently selected from a saturated 4-, 5-or 6-membered cycloalkyl group. Preferably, however, 54 is a saturated 4-, 5-or 6-membered heterocycloalkyl group with a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 01.3 alkyl and Ci_3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group.

[0088] Preferably, where 54 is a heterocycloalkyl group, the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between a carbon atom in the ring system and the group labelled X. [0089] In an embodiment, R4 is a saturated 5-membered heterocycloalkyl group with a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C1-3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group.

[0090] In an embodiment, R4 is a saturated 4-membered heterocycloalkyl group with a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1-3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group.

[0091] Possibly, R4 is a azetidine ring which is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1-3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein either the nitrogen atom of the azetidine ring is attached to the rest of the molecule via a covalent bond with the group labelled X or is a NR9 group.

[0092] In a further possibility, R4 is an oxetane ring which is optionally substituted with up to 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C _3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[0093] R4 may also be a thietane ring which is optionally substituted with up to 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[0094] In an embodiment, R4 is a saturated 5-membered heterocycloalkyl group with a ring system which contains 1 heteroatom independently selected from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 01-3 alkyl and C1_3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between the nitrogen atom and the group labelled X or the N is an NR9 group.

[0095] Thus, R4 may be a thiophane ring which is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 01-3 alkyl and C1-3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[0096] Possibly, R4 is a pyrrolidine ring which is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 01-3 alkyl and C1-3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein the nitrogen atom of the pyrrolidine ring is either attached to the rest of the molecule via a covalent bond with the group labelled X or is a NR9 group.

[0097] In a further possibility, R4 is be a tetrahydrofuran ring which is optionally substituted with up to 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, Ci_3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[0098] In an embodiment, 54 is (R13) wherein Y is independently selected from 0, S and NR9; 513 is independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 01_3 alkyl and C1_3 alkoxy, wherein each alkyl or alkoxy group may be substituted with 1, 2 or 3 groups independently selected from halo and OH; and p is an integer independently selected from 0, 1, 2, and 3. In a particular embodiment, 54

Y 1-/

is (R13) [0099] In an embodiment, at least one occurrence of R13 is a C1-Ca alkyl group which may be unsubstituted (e.g. a methyl group) or substituted with 1, 2 or 3 OH groups, e.g. a hydroxymethyl group. Alternatively, at least one occurrence of R13 is a hydroxyl group. In a further alternative, at least one occurrence of R13 is a Ci_3 alkoxy group (e.g. a methoxy group).

[00100] In an embodiment, p is 0. In another embodiment, p is independently selected from: 1, 2 and 3. Thus, p may be 1.

[00101] In an embodiment, R4 is independently selected from: and [00102] In an embodiment, Y is S. Alternatively or additionally, Y may be 0. Y may also be NR9 (e.g. NH).

[00103] In an embodiment, X is NH and Y is independently selected from S and 0.

[00104] In an embodiment, R4 is a saturated 6-membered heterocycloalkyl group with a ring system which contains 1 or 2 heteroatoms independently selected at each occurrence from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one or more nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between one or the nitrogen atom and the group labelled X or the or each N is an NR9 group.

[00105] In an embodiment, R4 is a saturated 6-membered heterocycloalkyl group with a ring system which contains 1 heteroatom independently selected from 0, N, S; the heterocycloalkyl group being unsubstituted or being substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, Ci_s alkyl and C1_3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein, if the heterocycloalkyl ring contains one nitrogen atom, either the heterocycloalkyl group is attached to the rest of the molecule via a covalent bond between the nitrogen atom and the group labelled X or the N is an NR9 group.

[00106] Thus, R4 may be a tetrahydrothiopyran ring which is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1-3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[00107] Possibly, R4 is a piperidine ring which is optionally substituted with 1, 2 or 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH; wherein the nitrogen atom of the pyrrolidine ring is either attached to the rest of the molecule via a covalent bond with the group labelled X or is a NR9 group.

[00108] In a further possibility, IR4 is be a tetrahydropyran ring which is optionally substituted with up to 3 substituents independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, 014 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with up to 3 groups independently selected from halo and OH.

[00109] In an embodiment, R4 is (R14.)q wherein Z is independently selected from 0, S and NR9; R14 is independently selected at each occurrence from the group comprising: halo, NO2, OH, oxo, C1.3 alkyl and C1.3 alkoxy, wherein each alkyl or alkoxy group may be substituted with 1, 2 or 3 groups independently selected from halo and OH; and q is an integer independently selected from 0, 1, 2, and 3. In a particular embodiment, 54 is (R14 )q [00110] In an embodiment, q is 0. In another embodiment, q is independently selected from: 1, 2 or 3. Thus, q may be 1.

[00111] In an embodiment, at least one occurrence of 514 is a C1-03 alkyl group which may be unsubstituted (e.g. a methyl group) or substituted with 1, 2 or 3 OH groups, e.g a hydroxymethyl group. Alternatively or additionally, at least one occurrence of R14 is a hydroxyl group. It may that at least one occurrence of R14 is an oxo group. In a further embodiment, at least one occurrence of R14 is a C1.3 alkoxy group (e.g. a methoxy group). [00112] In an embodiment, 54 is independently selected from: and [00113] In an embodiment, Z is S. Alternatively or additionally, Z may be 0. Z may also be NR9 (e.g. NH).

[00114] In an embodiment, Xis NH and Z is S or O. [00115] In an embodiment, the compound of formula (I) has the structure: N,"" CO2R8 In a further embodiment, R8 is H. [00116] In another embodiment, the compound of formula (I) has a structure selected Me [11)_H CO2Rs N,", CO2R8 AcHN NH2

NH AcHN

NH AcHN

NH NH2 CO2R8

HN

NH NH

H

Nb,", CO2R8 AcHN /NH2 NH

H

Nk, CO2R8 AcHN NH2 CO2R8 NH2

NH CO2R8 NH2

NH

H CO2R8 AcHN NH2 NH and NH. In a further embodiment, R8 is H. [00117] In an embodiment, the compound of formula (I) has a structure selected from: CO2R8 CO2R8 and NH2 embodiment, R8 is H [00118] In another embodiment, the compound of formula (I) has a structure selected from: In a further OMe H CO2R8 CO2R8

O

NH2 NH2

H CO2R8 AcHN

H

O Me NH2 CO2R8

NH2; and CO2R8 In a further embodiment, R8 is H [00119] In yet another embodiment, the compound of formula (I) has the structure: H CO2R8

S 4cHN

[00120] NH2. In a further embodiment, R8 is H [00121] Any alkyl, aryl (including phenyl), benzyl, cycloalkyl, or heterocycloalkyl, heteroaryl group present in any of the aforementioned R1 to R14 groups may, unless otherwise stated, be optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NRa, =NORa, halo, nitro, cyano, NRaRa, NRaS(0)2Ra, NRaCONRaRa, NR2CO2Ra, ORa; SRa, SORa, SO3R2, SO2Ra, SO2NRaRa.0O2Ra C(0)Ra, CONRaRa, C1-C4alkyl, C2-C4-alkenyl, C2-C4-alkenyl, Cr-C4 haloalkyl, CRbRbNRaRa, and =CRbCRbRbNRaRa; wherein Ra is independently at each occurrence selected from H, C1-C4 alkyl and C1-a4 haloalkyl; and Rb is independently at each occurrence selected from H, halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[00122] Due to valency restrictions, familiar to those skilled in the art, when R1 to R14 contain an aryl, benzyl or heteroaryl group, that aryl, benzyl or heteroaryl group cannot be substituted with a group selected from: oxo, =NRa, =NORa and =CRbCRbRbNRaRa.

DETAILED DESCRIPTION

[00123] 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.

[00124] 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.

[00125] 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.

[00126] 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.

[00127] 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.

[00128] 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.

[00129] 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).

[00130] 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.

[00131] In another aspect the present invention provides a pharmaceutical formulation comprising a compound of the invention and a pharmaceutically acceptable excipient.

[00132] 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.

[00133] 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.

[00134] 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.

[00135] 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.

[00136] 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. [00137] The compounds of the invention (e.g. the compounds of formulae (1)4=01) 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.

[00138] 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.

[00139] 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).

[00140] 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.

[00141] 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.

[00142] 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.

[00143] 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.

[00144] 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.

[00145] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00146] 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.

[00147] 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.

[00148] 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 Z/E) 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.

[00149] 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 dl-arginine.

[00150] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[00151] 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).

[00152] 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.

[00153] 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.

[00154] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[00155] 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 racemate. 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. Elie! and S. H. Wilen (Wiley, 1994).

[00156] The term thiophane is used throughout this specification. Thiophanes are often known as tetrahydrothiophenes. There is no difference between the heterocyclic groups represented by these terms.

[00157] 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 [00158] Heteroaryl groups may be 5-or 6-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, S and 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; 10-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.

[00159] The aryl (including phenyl), benzyl and heteroaryl groups present in the compounds of the invention are optionally substituted with from 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: oxo, =NRa, =NOW, halo, nitro, cyano, NRalRa, NRaS(0)2Ra, NRaCONRaRa, NRa002Ra, ORa; SR', SORa, SO3Ra, SO2Ra, SO2N1RaRa.0O21Ra 0(0)Ra, CONRaRa, Ci-C4-alkyl, 02-C4-alkenyl, C2-C4-alkenyl, Ci-C4 haloalkyl, CRbRbNR3R3, and =CIR'CR'RbNRaRs; wherein R3 is independently at each occurrence selected from H, Ci-C4 alkyl and Ci-C4 haloalkyl; and Rb is independently at each occurrence selected from H, halogen, 01-04 alkyl and 01-04 haloalkyl.

[00160] The present invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formulae (I) to (XXXII), 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.

[00161] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 110, 130 and 140, chlorine, such as 3601, fluorine, such as 18F, iodine, such as 1231 and 1251, nitrogen, such as 13N and 15N, oxygen, such as 150, 170 and 180, phosphorus, such as 32P, and sulphur, such as 35S.

[00162] 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.

[00163] 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.

[00164] Substitution with positron emitting isotopes, such as 11 C,18F, 150 and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[00165] 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.

[00166] 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.

[00167] 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.

[00168] 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.

[00169] Throughout the specification, the following abbreviations have the listed meanings: DCM -dichloromethane; DMF -N,N-dimethylformamide; DIBAL -diisobutylaluminium hydride; DMSO -dimethylsulfoxide; THE -tetrahydrofuran.

Example 1 -Synthesis of heterocyclic compounds The compounds of the present invention in which R1 is CO2R5 and R6 is NH2 can be synthesised according to Scheme 1 below. Similar routes can be used to synthesise compounds of the invention in which X is 0 or S. a) NaN3, DMF; b) PPh3, THF, H2O; c) di-t-butyl dicarbonate, DCM; d) K2003, Et0H; e) methanesulfonyl chloride, NEt3, DCM; f) NaN3, EtOH, H2O; g) Me0H, HCI; h) NaBH(OAc)3, R4=0, NEt3; i) PPh3, THF, H2O. OEt b OEt OEt d OAc AcN OEt OEt OEt a OEt OEt h

OH

Scheme 1 [00170] Compounds 10a, 10c, 10d, 11a and 11c have been prepared according to Scheme 1.

(1S,5R,6S)-Ethyl 5-acetoxy-7-acetyl-7-azabicyclo[4.1.0]hept-2-ene-3-carboxylate 1 [00171] The compound was prepared according to the preparation by L.-D. Nie et aL; Tetrahedron: Asymmetry 22 (2011) 1692-1699 169.

Ethyl (3R,45,5R)-4-acetamido-5-acetoxy-3-azido-cyclohexene-1-carboxylate 2 [00172] To a solution of ethyl (1S,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 10a 10b 10c 10d

OH

OH NH2 NH2 OEt OEt

H

HN

H

HN

1;1 H2 OEt OEt

H

HN NH2

O 11b

OH 11a

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 2 as a yellow oil. (4.92 g, 15.90 mmol, 85.0% yield).

[00173] 1H NMR (CDC13): 6 7.45 (m, 1H), 6.65 (m, 1H), 5.1 (s, 1H), 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 (m/z, rel. intensity) 311.3 (V' hi', 100).

(3R,4S,5R)-Ethyl 4-acetamido-5-acetoxy-3-aminocyclohex-1-enecarboxylate 3 [00174] Ethyl (3R,4S,5R)-4-acetamido-5-acetoxy-3-azido-cyclohexene-1-carboxylate 2 (2.0 g, 6.45 mmol) and triphenylphosphine (1.68 g, 6.40 mmol) were added to a mixture of water (15 mL) and tetrahydrofuran (15 mL) and the reaction heated to reflux for 8 hours.

The solvents were then removed in vacuo and the residue purified by flash column chromatography to afford (3R,4S,5R)-ethyl 4-acetamido-5-acetoxy-3-aminocyclohex-1-enecarboxylate 3 as a colourless foam (800 mg, 2.81 mmol, 44.0%).

(3R,4S,5R)-ethyl 4-acetamido-3-((tert-butoxycarbonyl)amino)-5-hydroxycyclohex-1-15 enecarboxylate 5 [00175] (3R,4S,5R)-Ethyl 4-acetamido-5-acetoxy-3-aminocyclohex-1-enecarboxylate 3 (670 mg, 2.35 mmol) was dissolved in dichloromethane (20 mL) and di-tert-butyl dicarbonate (522 mg, 2.39 mmol) was added. The reaction was then stirred at room temperature for 2 hours and the solvents removed in vacuo to afford (3R,4S,5R)-ethyl 4-acetamido-5-acetoxy-3-((tert-butoxycarbonyl)amino) cyclohex-1-enecarboxylate 4 in the crude reaction mixture. The residue was dissolved in ethanol (10 mL), finely ground K2CO3 was added and the reaction mixture stirred at room temperature for 16 hours. The reaction was gently warmed, filtered through a pad of Celite® and concentrated in vacuo to afford (3R,4S,5R)-ethyl 4-acetamido-3-((tert-butoxycarbonyl)amino) -5-hydroxycyclohex-1-enecarboxylate 5 as a colourless solid (800 mg, 2.33 mmol, 99.0%).

(3R,4S,5R)-Ethyl 4-acetamido-3-((tert-butoxycarbonyl)amino)-5-((methylsulfonyl)oxy) cyclohex-1-enecarboxylate 6 [00176] (3R,4S,5R)-Ethyl 4-acetamido-3-((tert-butoxycarbonyl)amino) -5-hydroxycyclohex1-enecarboxylate 5 (800 mg, 2.33 mmol) was dissolved in dichloromethane (60 mL) and triethylamine (884 pL). Methanesulfonyl chloride (294 pL) was added and the mixture stirred at room temperature for 30 minutes. The solvents were removed in vacuo and the residue purified by flash column chromatography to afford (3R,4S,5R)-ethyl 4-acetamido3-((tert-butoxycarbonyl)amino)-5-((methylsulfonyl)oxy) cyclohex-1-enecarboxylate 6 as a colourless solid (800 mg, 1.90 mmol, 82.0%).

(3R,4S,5S)-Ethyl 4-acetamido-5-azido-3-((tert-butoxycarbonyflamino) cyclohex-1-enecarboxylate 7 [00177] (3R,4S,5R)-Ethyl 4-acetamido-3-((tert-butoxycarbonyl)amino)-5-((methylsulfonyl)oxy) cyclohex-1-enecarboxylate 6 (800 mg, 1.90 mmol) was dissolved in ethanol (20 mL) and water (2 mL) was added NaN3 (440 mg, 6.77 mmol). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was evaporated and the residue purified by flash column chromatography eluting with neat ethyl acetate to afford (3R,4S, 5S)-ethyl 4-acetamido-5-azido-3-((tert-butoxycarbonyl)amino) cyclohex-1-enecarboxylate 7 as a colourless solid (520 mg, 1.42 mmol, 75.0%).

(3R,4S,5S)-ethyl 4-acetamido-3-amino-5-azidocyclohex-1-enecarboxylate hydrochloride 8 [00178] (3R,4S,5S)-ethyl 4-acetamido-5-azido-3-((tert-butoxycarbonyl)amino) cyclohex-1-enecarboxylate 7 (50 mg, 0.13 mmol) was dissolved in methanol (3 mL) and hydrogen chloride in dioxane (4 M) was added slowly until it was observed by thin layer chromatography (TLC) that reaction was taking place. The solution was stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo and co-evaporated from methanol to be used directly in the next step.

(3R,4S,5S)-Ethyl 4-acetamido-5-azido-3-((tetrahydro-2H-pyran-4-yl)amino) cyclohex1-enecarboxylate 9a [00179] (3R,4S,5S)-Ethyl 4-acetamido-3-amino-5-azidocyclohex-1-enecarboxylate hydrochloride 8 (38 mg, 0.14 mmol) in ethanol (1 mL) was treated with triethylamine (24 pL) followed by 4-pyranone (16 pL). The mixture was stirred at room temperature for 10 minutes then sodium triacetoxyborohydride (52 mg, 0.25 mmol) was added followed by acetic acid (3 drops). The mixture was stirred at room temperature for 2 hours then concentrated in vacuo to a minimum volume and purified by flash column chromatography (0-10% Me0H / DCM). The product fractions were concentrated in vacuo to give (3R,4S,5R)-ethyl 4-acetamido-5-azido-3-((tetrahydro-2H-pyran-4-yl)amino) cyclohex-1-enecarboxylate 9a as a yellow oil (34 mg, 0.10 mmol, 72.0%).

Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-pyran-4-ylamino) cyclohex-1-ene-1-carboxylate 10a [00180] Ethyl (3R, 4S, 5S)-4-(acetyl am i no)-5-azi do-3-(tetrahyd ro-2 H-pyran-4-ylamino)cyclohex-1-ene-1-carboxylate 9a (34 mg, 0.10 mmol) and triphenylphosphine (27 mg, 0.10 mmol) in THE/water (10:1; 1.1 mL) were heated under reflux for 90 minutes. The mixture was then allowed to cool, loaded onto silica and purified by silica! gel column chromatography (eluting 0-50% Me0H / EtOAc). The product fractions were concentrated in vacuo evaporated to give the desired intermediate ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-pyran-4-ylamino) cyclohex-1-ene-1-carboxylate as a pale brown solid (14 mg, 0.04 mmol, 43.0%).

[00181] Ester 10a can be characterised as the corresponding carboxylic acid 11a.

(3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-pyran-4-ylamino) cyclohex-1-ene-1-carboxylic acid 11a [00182] Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-pyran-4-ylamino) cyclohex-1-ene-1-carboxylate 10a (0.014 g) was dissolved in a mixture of water:triethylamine (2 mL, 5:1) and vigorously stirred at room temperature. The reaction mixture was evaporated (co-evaporated from Me0H) then triturated with diethyl ether (2 x 2 mL) the co-evaporated from DCM (x2) to give acid 11a as a pale powder (0.009g). 1H NMR (DMS0): 6 7.80 (m, 1H), 6.55 (s, 1H), 3.82 (m, 2H), 3.58-2.87 (broad, m, 3H plus HOD), 2.79-2.10 (m, 4H, plus DMSO), 2.05 (m, 2H), 1.89 (s, 3H), 1.70 (m, 2H), 1.28 (m, 4H). LCMS rt 3.57min MH+ 298 (W Ht, 100).

Ethyl (3R,4S,5S)-4-(acetylamino)-5-azido-3-(tetrahydrothien-3-ylamino) cyclohex-1-ene-1-carboxylate 9c [00183] (3R,4S,5R)-4-(acetylamino)-3-amino-5-azidocyclohex-1-ene-1-carboxylic acid (0.0375 g) in ethanol (1 mL) was treated with triethylamine (24 pL) followed by dihydrothiophen-3(2H)-one (17.9 pL). The mixture was stirred at room temperature for 10min then sodium triacetoxyborohydride (0.052 g) followed by acetic acid (3 drops). The mixture was stirred at room temperaturefor 2 hrs then evaporated to a minimum and purified by silica gel column chromatography (0-10% Me0H / DCM). Product fractions evaporated to give compound 9c as an orange oil (0.0338g).

Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydrothien-3-ylamino) cyclohex-1-ene-1-carboxylate 10c Ethyl (3R,4S,5S)-4-(acetylamino)-5-azido-3-(tetrahydro-2H-pyran-4-ylamino) cyclohex-1-ene-1-carboxylate (0.035 g) and triphenylphosphine (0.0269 g) in THE / H2O (10:1) (1.1 ml) were heated under reflux for 1.5 hrs. The mixture was then allowed to cool, loaded onto silica and purified by silica gel column chromatography (eluting 0-50% Me0H / EtOAc).

Product fractions evaporated to give the desired intermediate as a pale brown glass/foam which was scratched to a powder (0.017 g).

[00184] Ester 10c can be characterised as the corresponding carboxylic acid triethylamine salt 11c (3R,4R,5S)-4-(Acetylamino)-5-amino-3-(tetrahydrothien-3-ylamino) cyclohex-1-ene-1-carboxylic acid triethylamine salt 11c [00185] Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydrothien-3-ylamino) cyclohex1-ene-1-carboxylate (0.017g) 10c was dissolved in a mixture of water:triethylamine (2 mL, 5:1) and vigorously stirred at rt overnight. The reaction mixture was evaporated (co-evaporated from Me0H x 4) to give a title compound as a tan glass which was scratched to a tan powder (mixture of diastereoisomers) (0.013g).

[00186] 1H NMR (DMS0): 6 7.90-7.70 (m, 1H), 6.60 (s, 1H), 4.16-2.95 (broad, m, 10H plus HOD), 2.95-2.25 (broad, m, 5H plus DMSO), 2.15-1.65 (m, 7H), 1.42-1.05 (m, 2H), 0.95 (t, 9H). LCMS rt 3.24 and 3.37min MH+ 300.

Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 10d [00187] To a solution of ethyl (3R,4S,5S)-4-acetamido-5-azido-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 9d (prepared analogously to compound 9a; 200 mg, 0.59 mmol) in THE (10 mL) and water (1 mL) was added triphenylphosphine (186 mg, 0.71 mmol) and stirred under at reflux for 10 hours. TLC (10% Me0H / EtOAc) showed complete product formation -no starting material remained. The solvent was removed and the resultant mixture was dry loaded onto silica. The product was purified and isolated on automated column chromatography eluting 100% EtOAc to 70% Me0H / EtOAc.

Compound 10d was isolated as a clear gum (170 mg, 0.546 mmol, 92% yield); MS (m/z rel. intensity 312.4 (M+ H+, 84).

[00188] An alternative method for accessing compounds of formula 10 is shown in Scheme 2 below. OEt a b OEt OEt OEt OEt

a) NaBH(OAc)3, R4=0, NEt3; b) K2CO3, Et0H; c) methanesulfonyl chloride, NEt3, DCM; d) NaN3, Et0H, H2O; e) PPh3, THF, H2O.

Scheme 2 [00189] Compounds 10b and 11b have been prepared according to Scheme 2.

(3R,48,5R)-Ethyl 4-acetamido-5-acetoxy-3-((tetrahydro-2H-thiopyran-4-yl)amino) cyclohex-1-enecarboxylate 12b [00190] (3R,4S,5R)-Ethyl 4-acetamido-5-acetoxy-3-aminocyclohex-1-enecarboxylate 3 (300 mg) and 4-thiopyranone (0.159 g) were stirred in ethanol (5 mL) at room temperature for 15 min. Sodium triacetoxyborohydride (0.407 g) was added followed by acetic acid (6 drops). The mixture was stirred for 2 hrs then evaporated to a minimum and purified by silica gel chromatography (eluting with 0-6% Me0H / DCM). Product fractions were evaporated to the subtitle compound as a white foam (0.37g).

Ethyl (3R,4S,5R)-4-(acetylamino)-5-hydroxy-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1 -carboxylate I 3b [00191] (3R,4S,5R)-Ethyl 4-acetamido-5-acetoxy-3-((tetrahydro-2H-thiopyran-4-yl)amino) cyclohex-1-enecarboxylate 12b (0.329 g) in ethanol (5 mL) was treated with powdered potassium carbonate (0.13 g) and stirred for 3 hrs. The mixture was evaporated and purified by silica gel chromatography (eluted with 0-10% Me0H / DCM).

Product fractions were evaporated to give the subtitle compound as a pale yellow foam (0.210 g).

Ethyl (3R,4S,5R)-4-(acetylamino)-5-[(methylsulfonyl)oxy]-3- (tetrahydro-2H-thiopyran4-ylamino)cyclohex-1-ene-1-carboxylate 14b [00192] Ethyl (3R,4S,5R)-4-(acetylamino)-5-hydroxy-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1-carboxylate 13b (0.1 g) in DCM (5 mL) was treated with triethylamine (81 pL) then mesyl chloride (21.7 pL) and monitored by TLC immediately.

Further mesyl chloride (5 pL) added and the mixture loaded onto silica! gel column and chromatographed (eluted 0-5% Me0H / DCM). Product fractions evaporated to give the subtitle compound as a yellow oil (0.11 g).

Ethyl (3R,4S,5S)-4-(acetylamino)-5-azido-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1-carboxylate 9b [00193] Ethyl (3R,4S,5R)-4-(acetylamino)-5-[(methylsulfonyl)oxy]-3- (tetrahydro-2Hthiopyran-4-ylamino)cyclohex-1-ene-1-carboxylate 14b (0.11 g) and sodium azide (0.085 g) in ethanol/water (4:1) (2.5 mL) were heated under reflux for overnight. The mixture was then allowed to cool, loaded onto silica and purified by silica gel column chromatography (eluting 0-5%MeOH / DCM). Product fractions evaporated to give the desired subtitle compound as a pale foam after co-evaporation from DCM (0.05 g).

Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1-carboxylate 10b [00194] Ethyl (3R,4S,5S)-4-(acetylamino)-5-azido-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1-carboxylate 9b (0.05 g) and triphenylphosphine (0.042 g) in THE / H2O (10:1) (1.5 mL) were heated under reflux for 2 hrs. The mixture was then allowed to cool, loaded onto silica and purified by silica gel column chromatography (eluting 0-50% Me0H / EtOAc). Product fractions evaporated to give the desired intermediate as a clear oil which was scratched to a white powder (0.022g).

[00195] Ester 10b can be characterised as the corresponding carboxylic acid triethylamine salt 11 b.

(3R,4R,5S)-4-(acetylamino)-5-amino-3- (tetrahydro-2H-thiopyran-4-ylamino)cyclohex1-ene-l-carboxylic acid triethylamine salt 11 b [00196] Ethyl (3R,4R,5S)-4-(acetylamino)-5-amino-3-(tetrahydro-2H-thiopyran-4-ylamino) cyclohex-1-ene-1-carboxylate 10b (0.02 g) was dissolved in a mixture of water:triethylamine (3 mL, 5:1) and vigorously stirred at room temperatureovernight. The reaction mixture was evaporated (co-evaporated from Me0H) at 60°C to give the title product as a white solid (0.02g). 1H NMR (DMSO): 5 7.78 (m, 1 H), 6.50 (s, 1 H), 4.00-2.71 (broad, m, 10H plus HOD), 2.70-2.30 (m, 5H, plus DMSO), 2.08-1.65 (m, 7H), 1.30 (m, 4H), 0.95 (t, 9H). LCMS rt 3.52min MH+ 314 (M+ H+, 100).

[00197] Compounds of formula 10 can be converted to the compounds of the invention in which R6 is NHC(=NH)NH2(e.g. compounds of formulae 16 or 17) according to Scheme 3.

H N,, RI" OEt H OEt b R(Nk' OEt a

HN HN T HN

oi."--,, NH2 0,..",. HIFI NHBOC 0..,HFI NH2

NBOC 15

OH H R Ri

HN T HN

ce" yNH2 ce,, HNyNH2 17d

NH NH

a) 1,3-Di-Boc-2-(trifluoromethylsulfonyl)guanidine, DCM, NEt3; b) trifluoroacetic acid, DCM; c) NEt3, H2O.

Scheme 3 [00198] Compound 17d has been synthesised according to Scheme 3.

(3R,4R,5S)-Ethyl 4-acetamido-54(E)-2,3-bis(tert-butoxycarbonyflguanidino)-3-( (tetrahydrofuran-3-yl)amino)cyclohex-1-enecarboxylate 15d [00199] To a solution of ethyl (3R,4R,53)-4-acetamido-5-amino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 10d (170mg, 0.55mmol) in DCM (10mL) was added triethylamine (0.11mL, 0.82mmol) followed by 1,3-Di-Boc-2-(trifluoromethylsulfonyl)guanidine (235mg, 0.60mmol) and stirred at room temperature overnight. Water was added, followed by brine to aid separation. The organics were extracted twice with DCM and dried over MgSO4 and solvent concentrated. TLC 3% Me0H / EtOAc showed product formation. Column purified on automated column chromatography -eluting 100% EtOAc to 3% Me0H / EtOAc. Fractions combined and solvents removed in vacuo to afford the desired compound (280mg, 0.51mmol, 93% yield). 1H NMR (COOL): 6 11.38 (s, 1H), 8.64 (t, 1H), 7.51 (dd, 1H), 6.83 (dd, 1H), 4.38 (m, 1H), 4.24 (q, 2H), 3.80 (m, 3H), 3.53 (m, 2H), 3.36 (m, 1H), 2.81 (m, 1H), 2.32 (m, 3H), 2.10 (m,

NH c

OH

1H), 1.92 (s, 3H), 1.73 (m, 1H), 1.54 (s, 9H), 1.51 (s, 9H), 1.26 (t, 3H). MS (m/z rel. intensity 554.6 (M* H', 80).

Ethyl (3R,4R,5S)-4-acetamido-5-guanidino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 16d [00200] To a solution of ethyl (3R,4R,5S)-4-acetamido-5-[[(E)-N,N1-bis(tert- butoxycarbonyl)carbamimidoyl]amino]-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 15d (38mg, 0.07mmol) in DCM (2mL) was added Trifluoroacetic acid (0.4mL, 2.55mmol) (30% approx. of total solution) and stirred overnight. The remaining solvents were removed and put under vacuum at ambient temperature for 1 hour. TLC 10 % Me0H in EtOAc showed product formation -no starting material remained (27mg, 0.07 mmol, 100% yield). 1H NMR (MeOD): 6 6.89 (s, 1H), 4.46 (m, 1H), 4.28 (q, 2H), 4.21 (m, 1H), 4.05-3.78 (m, 5H), 3.31 (m, 1H), 3.00 (dd, 1H), 2.46 (m, 2H), 2.05 (s, 3H), 1.35 (t, 3H). MS (m/z rel. intensity 354.5 (Mt H", 100).

(3R,4R,5S)-4-acetamido-5-guanidino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylic acid 17d [00201] To a solution of ethyl (3R,4R,53)-4-acetamido-5-guanidino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylate 16d (68mg, 0.190 mmol) in water (4mL) was added Triethylamine (1.34mL, 9.64mmol). This was allowed to stir at room temperature for 4 hours. After which time the solvent was removed in vacuo to yield (3R,4R,5S)-4-acetamido-5-guanidino-3-(tetrahydrofuran-3-ylamino) cyclohexene-1-carboxylic acid (30mg, 0.09mmol, 48% yield). 1H NMR (CDCI3): 6 6.62 (s, 1H), 4.79. solvent, 4.43 (m, 1H), 4.30 (m, 2H), 4.17 (m, 1H), 4.06-3.99 (m, 3H), 3.89 (m, 1H), 3.30 (q, 1H), 3.04 (m, 1H), 2.57 (m, 2H) 2.17 (m, 3H), 1.38 (t, 1H). MS (m/z, rel. intensity 326.47 (Mt lit, 97).

Example 2 -Synthesis of heterocyclic/oxazolidinone compounds [00202] Compounds of the present invention in which R1 is an isoxazole (e.g. compounds of formulae (XXIII) and (XXV)) can be prepared according to Scheme 4. Analogous methods can be used to prepare compounds in which R1 is other heteroaromatic groups.

[00203] The starting material 10 can be made according to Scheme 1 above. NH2 OEt

NH(BOC) 18 NH(BOC) 19 b d e N.0H NH(BOC) 21 NH(BOC) f AcHN T AcHN NH2 HN NHBOC

NBOC R11 Rt. AcHN

HN NH2 NH N-0 N-0 R11 Rii h NH(BOC) 20 a) di-t-butyl dicarbonate (1.1 eq), DCM; b) DIBAL (3 eq), DCM, 0°C; c) Dess-Martin periodinane (1.5 eq), DCM; d) hydroxylamine (1.1 eq), pyridine (1.5 eq), EtOH; e) alkyneR13 (1.1 eq), trifluoroacetic acid (1 eq); diacetoxyiodobenzene (1.1 eq); f) trifluoroacetic acid:DCM (1:4); g) 1,3-di-Boc-2-(trifluoromethylsulfonyl)guanidine, NEt3; h) trifluoroacetic acid; DCM.

Scheme 4 Example 3 -Evaluation of Compounds in Neuraminidase Assays Summary of Protocol [00204] Purified neuraminidase enzymes were used to evaluate compounds in the NA-XTD assay from Life Technologies. 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, 0.1pM, 10nM, 1nM, 0.1nM and 0.01nM Assay protocol [00205] 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 60pL 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 BMG Omega multi-mode plate reader [00206] Table 1: Viral enzymes used Enzyme Serotype Oseltamivir susceptibility Supplied conc. U/mL Dilution used in assay Influenza A Neuraminidase-wild type H1N1 + 200 1:10 000 Influenza A Neuraminidase- H1N1 - 200 1:10 000 H274Y mutation Influenza A Neuraminidase-wild type H7N9 + 100 1:5 000 Influenza A Neuraminidase- H7N9 - 20 1:1000 R292K mutation Results Table 2-IC50 (nM) for compounds of the invention at indicated strains Compound number ICso (nM) ICso (nM) NI, I-1274Y enzyme ICso (nM) N9, WT enzyme ICso (nM) N9, R292K enzyme NI, WT enzyme Oseltamivir 0.4 180 0.8 13 000 Zanamivir 0.4 0.4 0.3 12 16d 252 615 900 27 000 17d 2.4 3.5 3.7 127 11a 80 1830 11b 144 3365 11c 2.9 68 [00207] 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. Compounds 17d and 11c in particular has been shown to be more active than oseltamivir against enzymes from resistant viral strains which cause influenza.

Example 4 -Reference examples [00208] Compounds A-H, which do not form part of the present invention, were tested for activity against viral neuraminidase:

Summary of Protocol

[00209] 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, 100nM, 10nM, 3nM, 1nM, 0.3nM and 0.1nM.

1. To each well add 25pL of either: a. Oseltamivir or test compound or, b. 0.01% DMSO 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 b. to the remaining wells add either pre-heated virus or c. influenza media 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 60pL 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 Table 3: Viral stocks used Virus Strain Serotype Oseltamivir susceptibility Mutation Dilution used Washington/01/2007 H1N1 + WT 1:20 California/07/2009 H1N1 + WT 1:20 A/Texas/12/2007 H3N2 E119V 1:4 Table 4 -IC50 (nM) 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/12/2007 31.5 C Washington/01/2007 4.0 C Texas/12/2007 103 D Washington/01/2007 22.6 D California/07/2009 6.7 D Texas/12/2007 66.6 E Washington/01/2007 31.1 F California/07/2009 17.7 G California/07/2009 32.0 H Washington/01/2007 22.7

N

HN

N F13+02CCF3-

A

[00210] Many of the compounds of the present invention posses a heteroaromatic group at the C-1 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 neuraminidase 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.