This invention relates to derivatives of antiviral drug compounds. It also relates to pharmaceutical formulations of derivatives of antiviral drug compounds. It also relates to uses of the derivatives in treating viral infections and in methods of treating viral infections. In particular, the antiviral compounds of the invention are derivatives of oseltamivir.

Background

In 1918-1920, the 'Spanish flu' pandemic spread around the world, killing between 50 and 100 million people. In 2009, the Swine flu pandemic killed an estimated 18,000 people worldwide.

Oseltamivir (see US 5,763,483) is an antiviral drug with activity 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.

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.

A number of strains of the influenza have developed resistance to oseltamivir, these include H1 N1 (the cause of both the 1918 and 2009 pandemics), H3N2 and H5N1.

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.

Zanamivir has poor oral availability. 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.

It is an aim of this invention to provide further compounds for the treatment of influenza.

It is a further aim of this invention to provide compounds for the treatment of strains of influenza which are resistant to oseltamivir and/or zanamivir.

It is a further aim of this invention to provide compounds for the treatment of influenza which exhibit higher oral bioavailablity than zanamivir.

It is a further aim 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.

Summary of the Invention

In a first aspect, there is provided a compound according to formula (I):

; wherein

is independently selected from and ; and

Y is OR ⁵ or NR ⁵ R ⁶ ;

R ¹ is a group independently selected from -(CR ¹³ R ¹³ ) _n -C0 ₂ R ⁴ and a 5- or 6- membered heteroaryl; wherein the heteroaryl group is optionally substituted with from 1 to 3 R ² groups and wherein R ² is independently selected at each occurrence from H, halo, C C ₆ alkyl, C ₂ - C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyi, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ;

R ⁴ and R ⁵ are independently at each occurrence selected from H; C C ₆ alkyl; aryl; heteroaryl; C ₃ -C ₆ cycloalkyi;

R ⁶ is independently at each occurrence selected from H, C(0)R ⁴ , C(0)NR ⁶ R ⁶ , C C ₄ alkyl, aryl, benzyl, and C ₃ -C ₆ cycloalkyi;

R ¹⁰ is independently at each occurrence selected from H, F and CI;

R ⁹ is independently at each occurrence selected from H, F and CI;

R ¹¹ is independently selected from NR ⁶ R ⁶ and a heterocycle; or R ¹¹ together with X forms an aziridine ring in which the nitrogen is substituted with R ⁶ ; or R ¹¹ together with R ¹² forms an aziridine ring in which the nitrogen is substituted with R ⁶ ;

R ¹² is independently selected from azido, hydroxyl, cyano, nitro, alkoxy or -(CR ¹³ R ¹³ ) _n - NR ⁶ R ⁶ ;

R ¹³ is independently at each occurrence selected from H or C Ci ₂ alkyl;

R ¹⁴ is independently selected from H or -ZR ⁶ ;

Z is a bond, O, NR ⁶ , NOR ⁵ , NNR ⁶ R ⁵ , S, S(O), S(0) ₂ ;

wherein any alkyl, aryl, benzyl, cycloalkyi, or heteroaryl group present in any of the aforementioned R ¹ to R ¹⁴ groups may be optionally substituted with 1 to 3 groups independently selected at each occurrence from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, C ₃ -C ₆ -heterocycloalkyl, C C ₆ alkoxy, benzyl, C C ₆ haloalkyi, aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶

with the proviso that if R ¹ is -(CR ¹³ R ¹³ ) _n -C0 ₂ R ⁴ ,

In an embodiment, the compound of formula (I) is a compound according to formula (la):

; wherein is independently selected from and and

Y is OR ⁵ or NR ⁵ R ⁶ ;

R ¹ is a group independently selected from -(CR ¹³ R ¹³ ) _n -C0 ₂ R ⁴ and a 5- or 6- membered heteroaryl

R ⁴ and R ⁵ are independently at each occurrence selected from H; C C ₆ alkyl; aryl; heteroaryl; C ₃ -C ₆ cycloalkyl;

R ⁶ is independently at each occurrence selected from H, C(0)R ⁴ , C(0)NR ⁶ R ⁶ , C C ₄ alkyl, aryl, benzyl, and C ₃ -C ₆ cycloalkyl;

R ⁹ is independently at each occurrence selected from H, F and CI

R ¹⁰ is independently at each occurrence selected from H, F and CI;

R ¹¹ is independently selected from NR ⁶ R ⁶ and a heterocycle; or R ¹¹ together with X forms an aziridine ring in which the nitrogen is substituted with R ⁶ ; or R ¹¹ together with R ¹² forms an aziridine ring in which the nitrogen is substituted with R ⁶ ;

R ¹² is independently selected from azido, hydroxyl, cyano, nitro, alkoxy or -(CR ¹³ R ¹³ ) _n - NR ⁶ R ⁶ ;

R ¹³ is independently at each occurrence selected from H or C Ci ₂ alkyl;

R ¹⁴ is independently selected from H or -ZR ⁶ ;

Z is a bond, O, NR ⁶ , NOR ⁵ , NNR ⁶ R ⁵ , S, S(O), S(0) ₂ ;

wherein any alkyl, aryl, benzyl, cycloalkyl, or heteroaryl group present in the aforementioned R ¹ to R ⁶ groups may be optionally substituted with 1 to 3 groups independently selected at each occurrence from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ;

with the proviso that if R ¹ is -(CR ¹³ R ¹³ ) _n -C0 ₂ R ⁴ , is not

In an embodiment of the present invention, the compound of formula (I) is a compound according to formula (lb):

NH ₂

wherein

R is a group selected from C0 ₂ R ⁴ ;

R ³ is independently at each occurrence a group selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyi, aryl, heteroaryl, C0 ₂ R ⁴ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ;

R ³ is independently at each occurrence a group selected from H, halo, substituted or unsubstituted C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyi, aryl, heteroaryl, C0 ₂ R ⁴ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ;

R ⁴ and R ⁵ are independently at each occurrence selected from H; C C ₆ alkyl; aryl;

heteroaryl; C ₃ -C ₆ cycloalkyi;

R ⁶ is independently at each occurrence selected from H, C(0)R ⁴ , C C ₄ alkyl, aryl, benzyl, and C ₃ -C ₆ cycloalkyi;

wherein any alkyl, aryl, benzyl, cycloalkyi, or heteroaryl group present in the

aforementioned groups R ¹ to R ⁶ may be optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, oxo, C0 ₂ R ⁴ and aryl.

is independently selected fro

and

Y is OR ⁵ or NR ⁵ R ⁶ ; provided that if R ¹ is C0 ₂ R ⁴ , is not

I nd of formula (I) is a compound according to formula (II):

NH ₂

wherein

R ¹ is a group selected from 5- or 6- membered heteroaryl and C0 ₂ R ⁴ ;

R ⁴ and R ⁵ are independently at each occurrence selected from H; C C ₆ alkyl; aryl; heteroaryl; C ₃ -C ₆ cycloalkyl;

R ⁶ is independently at each occurrence selected from H, C(0)R ⁴ , C(0)NR ⁶ R ⁶ , C1-C ₄ alkyl, aryl, benzyl, and C ₃ -C ₆ cycloalkyl;

wherein any alkyl, aryl, benzyl, cycloalkyl, or heteroaryl group present in the aforementioned groups R ¹ to R ⁶ may be optionally substituted with 1 to 3 groups independently selected at each occurrence from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ;

is independently selected from

and

Y is OR ⁵ or NR ⁵ R ⁶ ;

In an embodiment, the compound of formula (I) is a compound according to formula (III):

NH,

In an alternative embodiment, R ¹ is a 5- or 6- membered heteroaryl. In a rmula (I) is a compound according to formula (IV):

(IV)

NH _?

wherein R ¹ is a 5- or 6- membered heteroaryl. is a compound according to formula (V):

wherein R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ; and

R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ .

In an alternative embodiment, the compound of formula (I) is a compound according to

NH ₂

wherein R ^2a is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ; and

R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ . is a compound according to formula (VII):

NH,

wherein R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ ,

NR R and OR ^b .

In an embodiment, the compound of formula (I) is a compound according to formula (VIII):

In an embodiment, the compound of formula (I) is a compound according to formula (IX):

is a compound according to formula (X):

a compound according to formula (XI):

wherein R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ; and

R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ .

The following embodiments are applicable to any of formulae (l)-(IX), as appropriate: In an embodiment, R ¹¹ is NHAc. In an embodiment, R ¹² is NH ₂ . In an embodiment, R ¹⁰ is H. In an embodiment, R ⁹ is H.

In an embodiment, R ¹ is a 5-membered heteroaryl; wherein the 5-membered heteroaryl group is optionally substituted with from 1 to 3 R ² groups and wherein R ² is independently selected at each occurrence from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ .

In an embodiment, R ¹ is a heteroaryl group (e.g. a 5-membered heteroaryl group) which is substituted with from 1 to 3 R ² groups. Many of the compounds which have been shown to have neuraminidase inhibitory activity in the present disclosure contain substituted heteroaryl groups. These groups are quite different from the carboxylic acid groups which are otherwise present in oseltamivir and zanamivir.

In an embodiment, R ² is C C ₆ alkyl, optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, CrC ₆ -alkoxy, CrC ₆ -fluoroalkyl, oxo, C0 ₂ R ⁴ , aryl or heteroaryl. In an embodiment, R ² is an optionally substituted C C ₃ alkyl group. In particular, R ² may be an optionally substituted methyl group. Alternatively, R ² may be an optionally substituted ethyl group. In a further alternative, R ² may be an optionally substituted propyl group. In a further alternative, R ² may be aan optionally substituted butyl group (e.g. an n-butyl group or an isobutyl group).

In an embodiment, R ² may be an optionally substituted C C ₆ cycloalkyl group (e.g. a cyclopropyl group).

In an embodiment, R ² is C C ₆ alkyl group substituted with C0 ₂ R ⁴ , e.g. C0 ₂ H (for example, a CH ₂ CH ₂ C0 ₂ H group). Alternatively, R ² is C C ₆ alkyl substituted with hydroxyl (for example, a CH ₂ OH group or a (CH(OH)Me group). Alternatively, R ² may be C C ₆ alkyl substituted with an aryl or heteroaryl group. For instance, R ² may be a C C ₆ alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, R ² may be a C C ₆ 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, R ² is C C ₆ alkyl substituted with amino (for example, a CH ₂ NH ₂ group

In an embodiment, R ² is an optionally substituted aryl group. In a preferrred embodiment of this feature, R ² may be an optionally substituted phenyl group. Thus, R ² may be a phenyl group substituted with C0 ₂ R ⁴ , e.g. C0 ₂ H. Alternatively, R ² may be a phenyl group substituted with a halo group, e.g. a fluoro group (for example, 4-fluorophenyl). Alternatively, R ² may be a phenyl group substituted with two halo groups, which may be the same or different e.g. two chloro groups (for example, 3,4,dichlorophenyl). In a further alternative, R ² may be a phenyl group substituted with a C C ₆ alkoxy group, e.g. a methoxy group (for example, 4-methoxyphenyl). Or R ² may be a phenyl group substituted with a C C ₆ -fluoroalkyl group, e.g. CF ₃ group (for example, 2-(trifluoromethyl)phenyl).

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

In another embodiment, R ² is C0 ₂ R ⁴ or C(0)R ⁴ . Thus, R ² may be C0 ₂ R ⁴ , e.g. C0 ₂ H. Alternatively, R ² may be C(0)R ⁴ , e.g. C(0)H.

In an embodiment, R ² is a basic group (e.g. a group comprising an optionally substituted pyridine ring).

In another embodiment, R ¹ is a group selected from:

wherein R is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, d- C ₆ haloalkyi, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ ; and R ³ is selected from H, halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyi, benzyl, C C ₆ haloalkyi, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ .

In another embodiment, R ¹ is selected from:

In an embodiment, R ⁴ is C C ₆ alkyl. In an embodiment, R ⁴ is C C ₄ alkyl. Thus, R ⁴ may be methyl, ethyl, isopropyl, n-propyl, tert-butyl. In an alternative embodiment, R ⁴ is H.

In another embodiment, Y is OR ⁵ . In an alternative embodiment, Y is NR ⁵ R ⁶ .

In an embodiment R ^2a is H. In another embodiment, R ³ is H.

In an embodiment, R ³ is not H. Thus, R ³ may be selected from halo, C C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl, benzyl, C C ₆ haloalkyl, optionally substituted aryl, heteroaryl, C0 ₂ R ⁴ , C(0)NR ⁶ R ⁶ , C(0)R ⁴ , CH=NOR ⁵ , NR ⁶ R ⁶ and OR ⁶ In an embodiment, R ³ is C C ₆ alkyl, optionally substituted with 1 to 3 groups independently selected at each occurrence from halo, hydroxyl, CrC ₆ -alkoxy, CrC ₆ -fluoroalkyl, oxo, C0 ₂ R ⁴ , aryl or heteroaryl. In an embodiment, R ₃ is an optionally substituted C C ₃ alkyl. In particular, R ³ may be an optionally substituted methyl group. Alternatively, R ³ may be an optionally substituted ethyl group. In a further alternative, R ³ may be an optionally substituted propyl group. In a further alternative, R ³ may be an optionally substituted butyl group (e.g. an n-butyl group or an isobutyl group).

In an embodiment, R ³ may be an optionally substituted C C ₆ cycloalkyl group (e.g. a cyclopropyl group).

In an embodiment, R ³ is C C ₆ alkyl group substituted with C0 ₂ R ⁴ , e.g. C0 ₂ H (for example, a CH ₂ CH ₂ CO ₂ H group). Alternatively, R ³ is C C ₆ alkyl substituted with hydroxyl (for example, a CH ₂ OH group or a (CH(OH)Me group). Alternatively, R ₃ may be C C ₆ alkyl substituted with an aryl or heteroaryl group. For instance, R ₃ may be a C C ₆ alkyl group substituted with an aryl group, e.g. a phenyl group. Alternatively, R ₃ may be a C C ₆ 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, R ³ is C C ₆ alkyl substituted with amino (for example, a CH ₂ NH ₂ group

In an embodiment, R ₃ is an optionally substituted aryl group. In a further embodiment, R ³ may be an optionally substituted phenyl group. Thus, R ³ may be a phenyl group substituted with C0 ₂ R ⁴ , e.g. C0 ₂ H. Alternatively, R ³ may be a phenyl group substituted with a halo group, e.g. a fluoro group (for example, 4-fluorophenyl). Alternatively, R ³ may be a phenyl group substituted with two halo groups, which may be the same or different e.g. two chloro groups (for example, 3,4,dichlorophenyl). In a further alternative, R ³ may be a phenyl group substituted with a C C ₆ alkoxy group, e.g. a methoxy group (for example, 4-methoxyphenyl). Or R ³ may be a phenyl group substituted with a CrC ₆ -fluoroalkyl group, e.g. CF ₃ group (for example, 2-(trifluoromethyl)phenyl).

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

In an embodiment, R ³ is C0 ₂ R ⁴ or C(0)R ⁴ . Thus, R ³ may be C0 ₂ R ⁴ , e.g. C0 ₂ H. Alternatively, R ³ may be C(0)R ⁴ , e.g. C(0)H. In an embodiment, R ³ is a basic group (e.g. a group comprising an optionally substituted pyridine ring).

In an embodiment, R ³ is selected from the group comprising:

In an embodiment, R ^2a is C0 ₂ R ⁴ or C(0)R ⁴ .

In an alternative embodiment, R ³ is an optionally substituted aryl or heteroaryl group, optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, hydroxyl, d-C ₆ -alkoxy, CrC ₆ -fluoroalkyl, C0 ₂ R ⁴ , aryl or heteroaryl.

In a further alternative embodiment, R ^2a is an optionally substituted alkyl group optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, oxo, hydroxyl, CrC ₆ -alkoxy, CrC ₆ -fluoroalkyl, C0 ₂ R ⁴ , aryl or heteroaryl.

In an embodiment R ⁵ is H.

Alternatively, R ⁵ may be an aryl or heteroaryl group optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, hydroxyl, CrC ₆ -alkoxy, C C ₆ - fluoroalkyl, C0 ₂ R ⁴ , aryl or heteroaryl. In a further embodiment, R ⁵ may be an aryl group (e.g. a phenyl group) optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, hydroxyl, CrC ₆ -alkoxy, CrC ₆ -fluoroalkyl, C0 ₂ R ⁴ , aryl or heteroaryl. In an alternative embodiment, R ⁵ may be a C C ₆ alkyl group, optionally substituted with 1 to 3 groups independently at each occurrence selected from halo, hydroxyl, d-C ₆ -alkoxy, CrC ₆ -fluoroalkyl, oxo, C0 ₂ R ⁴ , aryl or heteroaryl. Thus, R ⁵ may be a methyl group, an ethyl group, a propyl group (e.g. isopropyl or n-propyl group) or a butyl group (e.g. iso-butyl, tert- butyl or n-butyl group). In an embodiment, R ⁵ may be an alkyl group substituted with a C0 ₂ R ⁴ group, e.g. C0 ₂ H.

In an embodiment R ⁶ is H.

The compounds of the invention are structurally related to oseltamivir. The synthetic routes to oseltamivir are available in the literature and in the relevant EMA and FDA regulatory files 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.

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.

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.

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.

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.

Each of the compounds of the present invention may be used as a medicament. Thus, in another aspect of the invention, there is provided compounds for use in the treatment of a viral infection. 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).

In another aspect the present invention provides a pharmaceutical formulation (for example: capsules, tablets, caplets and lozenges) comprising a compound of the invention and a pharmaceutically acceptable excipient.

The compounds and formulations of the present invention may be used in the treatment of a wide range of viral infections.

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.

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. 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. 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.

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 l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

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

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).

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.

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. 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.

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. Eliel and S. H. Wilen (Wiley, 1994).

Aryl groups may be phenyl groups, biphenyl groups, naphthalenyl groups or anthracenyl groups. In some embodiments optionally substituted aryl groups are optionally substituted phenyl groups.

Heterocycloalkyl groups are 3-7 membered rings, in which the ring contains from 1-3 atoms selected from N, O and S.

Alkyl groups, cycloalkyl group and heterocycloalkyl groups are optionally substituted with with from 1 to 4 groups independently selected at each occurrence from: oxo, halo, nitro, cyano, hydroxyl, C0 ₂ H, C0 ₂ -(CrC ₄ alkyl), C(0)H, C C ₄ -alkyl, C C ₄ haloalkyl, C C ₄ alkoxy, and Ci-C ₄ haloalkoxy.

Heteroaryl groups may be independently selected from: 5 membered heteroaryl groups in which the heteroaromatic ring is substituted with 1-4 heteroatoms independently selected from O, 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 independently selected from O, 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 independently selected from: pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, triazole, oxadiazole, thiodiazole, tetrazole; pyridine, pyridazine, pyrimidine, pyrazine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, indazole, benzimidazole, benzoxazole, benzthiazole, benzisoxazole, purine, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, pteridine, phthalazine, naphthyridine. In certain cases, however, heteroaryl is not tetrazole.

The heteroaryl groups are optionally substituted with from 1 to 4 groups independently selected at each occurrence from: halo, nitro, cyano, hydroxyl, C0 ₂ H, C0 ₂ -(CrC ₄ alkyl), C(0)H, C C ₄ -alkyl, C C ₄ haloalkyl, C C ₄ alkoxy, and C C ₄ haloalkoxy.

A basic group is a group that comprises a nitrogen with a free lone pair of electrons. A basic group may be one which when protonated has a pKa of between 2 and 12 (e.g. between 4 and 8). An example of a basic group is an alkyl or cycloalkyl group substituted with an amino group (e.g. an NR ⁶ R ⁶ group wherein R ⁶ is independently at each occurrence selected from H, C C ₄ alkyl, benzyl, and C ₃ -C ₆ cycloalkyl). A specific example of a basic group is an alkyl or cycloalkyl group substituted with a tertiary amino group (e.g. an NR ⁶ R ⁶ group wherein R ⁶ is independently at each occurrence selected from C C ₄ alkyl, benzyl, and C ₃ -C ₆ cycloalkyl). Another example of a basic group is a group that comprises a nitrogen heterocycle, (i.e. a heterocycle in which the ring comprises at least one NR ⁶ group wherein R ⁶ is independently at each occurrence selected from H, C C ₄ alkyl, benzyl, and C ₃ -C ₆ cycloalkyl. A specific example of a basic group is a heterocycle in which the ring comprises at least one NR ⁶ group wherein R ⁶ is independently at each occurrence selected from Ci-C ₄ alkyl, benzyl, and C ₃ -C ₆ cycloalkyl.). Yet another example of a basic group is group comprising a heteroaryl group in which the ring comprises nitrogen (e.g. an optionally substituted imidazole group or an optionally substituted pyridine group).

One surprising feature of the present invention is that the ester position in oseltamivir (which is converted to a carboxylic acid in vivo) can be replaced by a heterocycle substituted with a basic group (such as one comprising a pyridine) whilst retaining the neuraminidase inhibitory activity. It should be noted, however, that the presence of a basic group is not necessary for neuraminidase inhibitory activity.

The present invention also includes the synthesis of all pharmaceutically acceptable isotopically-labelled compounds of the invention 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.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ² H and ³ H, carbon, such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine, such as ³⁶ CI, fluorine, such as ¹⁸ F, iodine, such as ¹²³ l and ¹²⁵ l, nitrogen, such as ¹³ N and ¹⁵ N, oxygen, such as ¹⁵ 0, ¹⁷ 0 and ¹⁸ 0, phosphorus, such as ³² P, and sulphur, such as ³⁵ S.

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. ³ H, and carbon-14, i.e. ¹⁴ C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ² H, 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.

Substitution with positron emitting isotopes, such as ¹¹ C, ¹⁸ F, ¹⁵ 0 and ¹³ N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

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.

Throughout the description and claims of this specification, the words "comprise" and "contain" and variations of the words, for example "comprising" and "comprises", means "including but not limited to", and is not intended to (and does 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.

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. In addition to a total synthesis approach any of the derivatives of Formula (I) can conveniently be prepared from oseltamivir itself.

Example 1 Synthetic routes

Method

General procedure A: Synthesis of Oseltamivir Oxime (2) from Oseltamivir Aldehyde (1 )

To a solution of Aldehyde (1) (1 eq) in Ethanol was added Hydroxylamine.HCI (1.5 eq) followed by pyridine (3 eq). The protected aldehyde (1) can conveniently be obtained from oseltamivir itself. The reaction was stirred overnight, TLC (100%; Ethyl Acetate).

The solvents were removed in vacuo. The reaction mixture was partitioned between Sodium Carbonate solution and Dichloromethane. The organics were extracted with Dichloromethane (3 x 50ml). The organics were dried over MgS0 ₄ , filtered and solvents removed to give solid product. 50% - 60% Yield.

1 : ¹ H NMR (CDCI ₃ ): δ 9.7 (s, 1 H), 6.3 (s, 1 H), 4.1 (m, 1 H), 4 (m, 1 H), 3.8 (m, 1 H), 3.4 (m, 2H), 2.6 (m, 1 H), 2.8 (s, 1 H), 1.85 (s, 3H), 1.55 (m, 4H) 0.85 (m, 6H). MS (m/z, rel. intensity) 269.2 (M ⁺ H ⁺ , 100).

2: ¹ H NMR (CDCI ₃ ): δ 7.7 (s, 1 H), 5.8 (s, 1 H), 4.15 (m, 1 H), 4.1 (m, 1 H), 3.8 (m, 1 H), 3.45 (m, 2H), 2.7 (m, 1 H), 2.8 (s, 1 H), 2.05 (s, 3H), 1.5 (m, 4H) 0.9 (m, 6H). MS (m/z, rel. intensity) 284.2 (M ⁺ H ⁺ , 100).

General procedure B: Synthesis of Oseltamivir Isoxazole (3) from Oseltamivir Oxime (2)

To a stirred solution of (Diacetoxyiodo)benzene (1.1 eq) in Methanol was added the Alkyne (1.1 eq) with Trifluoroacetic Acid (cat.) and stirred over 5 mins. A solution of Oxime (2) (1 eq) in Methanol was added over 15 mins. The reaction was stirred overnight, TLC showed product formation (80% Ethyl Acetate: 20% Hexane). The solvents were removed in vacuo and solids dissolved in 80% Ethyl Acetate: 20% Hexane. The solids were purified using automated grace flash chromatography. Solvent gradient 80% Hexane: 20% Ethyl Acetate to 80% Ethyl Acetate: 20% Hexane over 7 mins followed by 3 mins at 100% Ethyl Acetate. 20% - 50% Yield.

General procedure C: Synthesis of Oseltamivir 1 ,3-Oxazole (5) from Oseltamivir Aldehyde (1)

To a mixture of Aldehyde (1) (1 eq) and Tosylmethyl Isocyanide (1 eq) in Methanol was added K ₂ C0 ₃ (1 eq). The solution was refluxed at 50°C for 2 hours. TLC (100%) Ethyl Acetate showed product formation. The solvents were removed in vacuo and the residue re-dissolved in Dichloromethane and partitioned with water. The organics were extracted with Dichloromethane (3 x 50ml). The combined organics were then washed with 2% Hydrochloric Acid (10ml, dried over MgS0 ₄ and concentrated in vacuo. The compound was purified using automated grace flash chromatography.75% Yield.

General procedure D: BOC de-protection of Oseltamivir Isoxazoles (3) and Oxazole (5)

A solution of Isoxazole (3) and Oxazole (5) in Dichloromethane was stirred at room temperature and TFA (3 drops) was added. Further drops were added until the starting material had been consumed. TLC (90% Ethyl Acetate: 10% Methanol) was used to follow the reaction progress. The solvents were removed in vacuo to give compound (4). 95% - 100% Yield.

4a: ¹ H NMR (CDCI ₃ ): δ 8.63 (s, 2H), 7.94 (m, 2H), 7.35 (s, 1H), 6.5 (s, 1H), 6.25 (s, 1H), 4.2 (m, 1H), 3.8 (m, 1H), 3.65 (s, 1H), 3.3 (m, 2H), 2.8 (s, 1H), 1.97 (s, 3H), 1.4- 1.3 (m, 4H) 0.9 - 0.6 (m, 6H). MS (m/z, rel. intensity) 384.2 (M ⁺ H ⁺ , 100).

4b: ¹ H NMR ([d ₄ ] MeOD): δ 6.2 (s, 1H), 6.1 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.97 (s, 1H), 3.4 (m, 2H), 2.9 (m, 1H), 2.7 (m, 2H), 2.0 (s, 3H), 1.5 (m, 4H), 1.25 (m, 2H), 1.0 (m, 3H), 0.9 (m, 6H). MS (m/z, rel. intensity) 350.2 (M ⁺ H ⁺ , 100).

4c: ¹ H NMR ([d ₄ ] MeOD): δ 7.26 (s, 1H), 6.46 (s, 1H), 4.2 (m, 1H), 4.0 (m, 1H), 3.55 (m, 1H), 3.4 (m, 1H), 2.8 (m, 2H), 1.96 (s, 3H), 1.46 (m, 4H), 0.85 (m, 6H). MS (m/z, rel. intensity) 351.2 (M ⁺ H ⁺ , 100).

4d: ¹ H NMR (CDCI ₃ ): δ 6.36 (s, 1H), 6.2 (s, 1H) 4.25 (d, 2H), 3.85 (s, 1H), 3.4 (s, 1H), 3.15 (m, 1H), 2.9, (m, 2H), 2.6 (s, 1H), 2.1 (s, 3H), 1.5 (m, 4H), 0.9 (m, 6H). MS (m/z, rel. intensity) 337.2 (M ⁺ H ⁺ , 100).

4e: ¹ H NMR (CDCI ₃ ): δ 9.93 (s, 1H), 7.1 (s, 1H) 6.3 (s, 1H), 3.85 (s, 1H), 3.45 (m, 1H), 3.35 (s, 1H), 2.9 (s, 1H), 2.8 (m, 2H), 2.05 (s, 3H), 1.53 (m, 4H), 0.9 - 0.8 (m, 6H). MS (m/z, rel. intensity) 368.2 (M ⁺ CH ₃ OH), 100).

4f: ¹ H NMR ([d ₄ ] MeOD): δ 7.3 (m, 5H), 6.87 (s, 1H), 6.4 (s, 1H), 4.26 (t, 1H), 4.13 (m, 1H), 3.8 (s, 2H), 3.5 (m, 1H), 3.1 (d, 1H), 3.0 (d, 1H), 2.7 (m, 1H), 2.05 (m, 3H), 1.55 (m, 4H), 0.93 (m, 6H). MS (m/z, rel. intensity) 398.2 (M ⁺ H ⁺ , 100). 4g: ¹ H NMR ([d ₄ ] MeOD): δ 6.48 (s, 1H), 6.42 (s, 1H), 4.2 (m, 1H), 4.05 (m, 1H), 3.7 (m, 1H), 3.5 (m, 2H), 3.08 (m, 2H), 2.8 (m, 1H), 2.75 (m, 2H), 2.05 (s, 3H), 1.56 (m, 4H), 0.96 (m, 6H). MS (m/z, rel. intensity) 380.2 (M ⁺ H ⁺ , 100).

4h: ¹ H NMR ([d ₄ ] MeOD): δ 6.9 (s, 1H), 6.44 (s, 1H), 4.25 (m, 1H), 4.05 (m, 1H), 3.8 (m, 1H), 3.5 (m, 1H), 3.1 (m, 1H), 3.0 (m, 1H), 2.8 (m, 2H), 2.05 (s, 3H), 1.7 (m, 2H) 1.56 (m, 4H), 1.4 (m, 2H) 0.95 (m, 9H). MS (m/z, rel. intensity) 385.2 (M ⁺ H ⁺ , 100).

4i: ¹ H NMR ([d ₄ ] MeOD): δ 9.1 (s, 1H), 8.7 (s, 1H), 8.4 (s, 1H), 7.7 (s, 1H), 7.4 (s, 1H), 6.6 (s, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 4.05 (m, 1H), 3.5 (m, 2H), 2.85 (m, 1H), 2.05 (s, 3H), 1.56 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 385.2 (M ⁺ H ⁺ , 100).

4j: ¹ H NMR ([d ₄ ] MeOD): δ 8.5 (s, 1H), 8.1 (m, 2H), 7.7 (m, 1H), 7.25 (s, 1H), 6.6 (s, 1H), 4.25 (m, 1H), 4.05 (m, 1H), 3.6 - 3.7 (m, 2H), 3.5 (m, 1H), 2.8 (m, 1H), 2.05 (s, 3H), 1.56 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 427.2 (M ⁺ H ⁺ , 100).

4k: ¹ H NMR ([d ₄ ] MeOD): δ 7.9 (m, 2H), 7.3 (m, 2H), 7.1 (s, 1H), 6.55 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.7 - 3.5 (m, 2H), 2.9 (m, 1H), 2.75 (m, 1H), 2.05 (s, 3H), 1.56 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 402.2 (M ⁺ H ⁺ , 100).

4I: ¹ H NMR ([d ₄ ] MeOD): δ 7.8 (s, 1H), 7.4 (s, 1H), 7.3 (s, 1H), 6.75 (s, 1H), 6.3 (s, 1H), 4.2 (m, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 3.0 (m, 1H), 2.55 (m, 2H), 2.05 (s, 3H), 1.56 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 390.2 (M ⁺ H ⁺ , 100).

4m: ¹ H NMR ([d ₆ ] DMSO): δ 8.0 (m, 4H), 7.8 (s, 1H) 7.1 (s, 1H), 4.2 (s, 1H), 3.8 (s, 3H), 3.7 (m, 1H), 3.5 (m, 1H), 3.3 (m, 2H), 2.8 (m, 1H), 1.89 (s, 3H), 1.45 (m, 4H), 0.85 (m, 6H). MS (m/z, rel. intensity) 414.2 (M ⁺ H ⁺ , 100).

4n: ¹ H NMR ([d ₄ ] MeOD): δ 7.9 (m, 1H), 7.7 (m, 3H), 6.97 (s, 1H), 6.55 (s, 1H), 4.3 (s, 1H), 4.1 (s, 1H), 3.8 (s, 1H), 3.5 (m, 2H), 2.75 (m, 1H), 2.05 (s, 3H), 1.55 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 452.2 (M ⁺ H ⁺ , 100). 4o: ¹ H NMR (CDCI ₃ ): δ 8.7 (m, 1H), 8.1-8 (m, 2H), 7.6 (m, 1H), 7.3 (s, 1H), 6.6 (s, 1H), 4.3 (m, 1H), 4.1 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8-2.7 (m, 2H), 2.1-2 (m, 3H), 1.7-1.4 (m, 4H), 1-0.8 (m, 6H). MS (m/z, rel. intensity) 385.2 (M ⁺ H ⁺ , 100).

4p: ¹ H NMR (CDCI ₃ ): δ 6.9 (s, 1H), 6.3 (s, 1H) 4.2 (m, 1H), 4 (m, 1H), 3.5 (m, 1H) 3.1 (m, 1H), 2.7-2.5 (m, 1H), 2.2-2 (m, 3H), 1.7-1.4 (m, 4H), 1.3 (m, 1H), 1.1 (m, 2H), 1-0.8 (m, 6H), 1-0.8 (m, 2H). MS (m/z, rel. intensity) 348.2 (M ⁺ H ⁺ , 100).

4q: MS (m/z, rel. intensity) 452.2 (M ⁺ H ⁺ , 100).

4r: ¹ H NMR ([d ₄ ] MeOD): δ 6.56 (s, 1H), 6.43 (s, 1H), 4.89 (m, 1H), 4.26 (m, 1H), 4.06 (m, 1H), 3.64 (m, 1H), 3.53 (m, 1H), 3.14 (m, 1H), 2.53 (m, 1H), 2.00 (s, 3H), 1.53 (m, 4H), 1.49 (m, 3H), 0.93 (m, 6H). MS (m/z, rel. intensity) 352.2 (M ⁺ H ⁺ , 100).

4s: ¹ H NMR ([d ₄ ] MeOD): δ 6.45 (s, 1H), 6.43 (s, 1H), 4.26 (m, 1H), 4.03 (m, 1H), 3.64 (m, 1H), 3.53 (m, 1H), 3.15 (m, 1H), 2.67 (d, 2H), 1.92 (s, 3H), 1.84 (m, 1H), 1.56 (m, 4H), 0.92 (m, 12H). MS (m/z, rel. intensity) 364.2 (M ⁺ H ⁺ , 100).

4u: ¹ H NMR ([d ₄ ] MeOD): δ 6.44 (s, 1H), 6.43 (s, 1H), 4.25 (m, 1H), 4.03 (m, 1H), 3.64 (m, 1H), 3.52 (m, 1H), 3.14 (m, 1H), 2.76 (t, 2H), 2.67 (m, 1H), 2.01 (s, 3H), 1.75 (m, 2H), 1.54 (m, 4H), 1.36 (m, 6H), 0.93 (m, 9H). MS (m/z, rel. intensity) 392.3 (M ⁺ H ⁺ , 100).

4t: ¹ H NMR ([d ₄ ] MeOD): δ 6.44 (s, 1H), 6.42 (s, 1H), 4.25 (m, 1H), 4.07 (m, 1H), 3.62 (m, 1H), 3.52 (m, 1H), 3.14 (m, 1H), 2.76 (t, 2H), 2.65 (m, 1H), 2.02 (s, 3H), 1.73 (m, 2H), 1.58 (m, 6H), 1.37 (m, 2H), 0.91 (m, 9H). MS (m/z, rel. intensity) 378.2 (M ⁺ H ⁺ , 100).

4v: MS (m/z, rel. intensity) 336.2 (M ⁺ H ⁺ , 10%), 359.26 (M ⁺ Na ⁺ , 100%)

4w: MS (m/z, rel. intensity) 391.28 (M ⁺ H ⁺ , 20%), 413.26 (M ⁺ Na ⁺ , 100%)

6: ¹ H NMR ([d ₄ ] MeOD): δ 8.2 (s, 1H), 7.2 (s, 1H) 6.35 (s, 1H), 4.3 (s, 1H), 4.1 (s, 1H), 3.65 (s, 1H), 3.5 (m, 1H), 2.9 (d, 1H), 2.7 (t, 1H) 2.05 (s, 3H), 1.56 (m, 4H), 0.95 (m, 6H). MS (m/z, rel. intensity) 330.2 (M ⁺ Na ⁺ , 100).

General procedure H: Synthesis of Oseltamivir 1 ,3,5-Oxadiazole (8) from Oseltamivir Acid (7)

To a stirred solution of Oseltamivir Acid (13) in DCM was added 3-Pyridinecarboxaldehyde (4 eq) and (Isocyanoimino)triphenylphosphorane (1 eq) and stirred at room temperature for 24h. The solvents were removed in vacuo and the residue purified using automated grace flash chromatography. Solvent gradient 90% EtOAc: 10% Heptane to 80% EtOAc:20% MeOH. 70% Yield.

8: ¹ H NMR ([d ₄ ] MeOD): δ 9.07 (m, 1 H), 8.81 (m, 2H), 8.14 (m, 1 H), 6.78 (s, 1 H), 6.42 (s, 1 H), 5.56 (s, 1 H), 4.20 (m, 1 H), 4.08 (m, 1 H), 3.38 (m, 1 H), 3.51 (m, 1 H), 3.47 (m, 2H), 3.32 (m, 1 H), 2.81 (m, 1 H), 2.51 (m, 1 H), 2.03 (s, 3H), 1.53 (m, 4H), 0.93 (m, 6H). MS (m/z, rel. intensity) 416.2 (M ⁺ H ⁺ , 100).

General procedure I: Synthesis of Oseltamivir 1 ,3-Pyrazole (9) from Oseltamivir Aldehyde (1) To a stirred solution of Oseltamivir Aldehyde (1) in MeOH was added Ammonium Acetate (5 eq). Over 10 mins was added Phenylglyoxal monohydrate (1 eq) in MeOH.

The reaction was stirred overnight and reactants were shown to be consumed by TLC (100% EtOAc). The solvents were removed in vacuo and the residue was partitioned between aqueous NaHC0 ₃ solution and DCM. The organic phase was extracted then dried over MgS0 ₄ , filtered and solvents removed in vacuo. 55% Yield.

9: ¹ H NMR (CDCI ₃ ): δ 7.9 (m, 1 H), 7.8 (m,2H), 7.55 (m, 2H), 7.5 (m, 1 H), 4.1 (m, 1 H), 3.8 (m, 1 H), 3.5 (m, 1 H), 3.2 (m, 1 H) 3.1 (m, 1 H), 2.9-2.8 (m, 1 H), 2.1 (s, 3H), 1.7-1.4 (m, 4H), 1 -0.8 (m, 6H). MS (m/z, rel. intensity) 383.2 (M ⁺ H ⁺ , 100).

Example 3 - Evaluation of Compound(s) in Neuraminidase Assays

Summary of Protocol

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: 10μΜ, 1 μΜ, Ι ΟΟηΜ, 10nM, 3nM, 1 nM, 0.3nM and 0.1 nM. For the preliminary test only Oseltamivir and Vibrio cholera neuraminidase (reagent activity control) were tested.

1. To each well add 25μΙ_ 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 25μΙ_ 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 25μΙ_ of diluted NA-XTD substrate to each well

5. Place lid on the plate, then incubate for 30 minutes at room temperature

6. Add 60μΙ_ 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 (825μΙ_ NA-XTD Assay Buffer + 00.8μΙ_ NA-XTD Substrate) - add 25μΙ_ per well. Make sure the buffer is at RT.

Table 1 : Viral stocks used

Table 2: Flu Infection Media (used to grow the viral stocks

• Optimem (500ml) - 50ml

• Pen/Strep (1x) - 5.2ml of stock 100X (0.52μΙ_)

• GLN (1x) - 5.2ml of stock 100X

• 0.3% BSA (Add 5.2ml of stock 30% BSA in PBS, will require lengthy agitation to resuspend)

• TPCK-Trypsin ^g/ml) (Add before use, 50μΙ_ of stock 2mg/ml to each 50ml media) NOT added

Table 3: Preparation of FLU media

To prepare 50ml flu infection media

• Optimem - 50ml

• Pen/Strep (1x) - 0.52ml of stock 100X

• GLN (1x) - 0.52ml of stock 100X

• 0.3% BSA (Add 0.52ml of stock 30% BSA in PBS, will require lengthy agitation to resuspend)

Note: All sample dilutions were prepared on round-bottom plate for easy transfer to assay plate Table 4: Dilutions prepared for Neuraminidase from Vibrio cholera

Preparation of Oseltamivir Dilution (based on NA-XTD Influenza Neuraminidase Assay Kit Protocol). Prepare a working dilution of 500μΜ to start dilutions. To do this add 3μΙ_ 10mM oseltamivir to 57μΙ_ H ₂ 0.

The Assay buffer (AB) contains 0.01 % vehicle DMSO plate 1-10ml of AB buffer + 1.μΙ_ of DMSO/plate 2-3 20ml of AB buffer + 2μΙ of DMSO.

Results

Table 5 - IC ₅₀ (nM) for compounds of the invention at indicated strains

4h Texas/12/2007 103

4i Washington/01/2007 22.6

4i California/07/2009 6.7

4i Texas/12/2007 66.6

4j Washington/01/2007 12

4j Texas/12/2007 366

4k Washington/01/2007 47.9

41 Washington/01/2007 31.1

4m Washington/01/2007 46.2

4n Washington/01/2007 405

4o California/07/2009 17.7

4p California/07/2009 32.0

4q Washington/01/2007 109

4r Washington/01/2007 93.1

4s Washington/01/2007 354

4t Washington/01/2007 224

4u Washington/01/2007 164

6 Washington/01/2007 22.7

8 California/07/2009 463

9 California/07/2009 644

Thus, the compounds of the invention have been shown to be active against viral strains, and, particularly, those viral strains which cause influenza.

The compounds of the invention have also been shown to be active against resistant viral strains (e.g. strains which are resistant to oseltamivir), and, particularly, those resistant viral strains which cause influenza.

Many of the compounds which have been shown to have neuraminidase inhibitory activity in the present disclosure contain substituted heteroaryl groups. These groups are structurally and electronically quite different from and cannot be considered to be isosteric with carboxylic acid groups, such as those present in vivo in oseltamivir and zanamivir, and hence the finding of good activity is quite surprising. It should be noted, however, that the presence of a substituent group on the heteroaryl group is not necessary for neuraminidase inhibitory activity.

Another surprising feature of the present invention is that the heteroaryl group in place of the carboxylic acid group which is present in vivo oseltamivir and zanamivir, may be substituted with a basic group (such as one comprising a pyridine) whilst still retaining the neuraminidase inhibitory activity. It should be noted, however, that the presence of a basic group is also not necessary for neuraminidase inhibitory activity.