ANTIVIRAL COMPOUNDS AND USES THEREOF

FIELD

[0001] The present disclosure relates to the field of medical treatment. More particularly, this disclosure relates to novel antiviral agents and their use in treating a disease or condition caused by a viral infection.

BACKGROUND

[0002] Any reference to background art herein is not to be construed as an admission that such art constitutes common general knowledge in Australia or elsewhere.

[0003] Viruses are responsible for a wide range of mammalian disease which represents a great cost to society. The effects of viral infection can range from common flu symptoms to serious respiratory problems and can result in death, particularly amongst the young, elderly and immunocompromised members of the community.

[0004] Viruses of the family Orthomyxoviridae, including influenza virus types A, B and C, and the family Paramyxoviridae are the pathogenic organisms responsible for a significant number of human infections annually.

[0005] Taking the family Paramyxoviridae as one example, human parainfluenza viruses types 1 and 3 (hPIV-1 and 3) are a leading cause of upper and lower respiratory tract disease in infants and young children and impact the elderly and immunocompromised. Significantly, it is estimated that in the United States alone up to five million lower respiratory tract infections occur each year in children under 5 years old, and hPIV has been isolated in approximately one third of these cases. hPIV infections are frequently reported in transplant patients, with the mortality rate as high as 30% in hematopoietic stem cell transplant patients. There are currently neither vaccines nor specific antiviral therapy to prevent or treat hPIV infections respectively, despite continuing efforts. Some of the more recent approaches have focussed on an entry blockade and the triggering of premature virus fusion by a small molecule. [0006] An initial interaction of the parainfluenza virus with the host cell is through its surface glycoprotein, haemagglutinin-neuraminidase (HN) and involves recognition of N-acetylneuraminic acid-containing glycoconjugates. The parainfluenza virus HN is a multifunctional protein that encompasses the functions of receptor binding (for cell adhesion) and receptor destruction (facilitating virus release), not only within the one protein, but apparently in a single binding site. In addition, the HN is involved in activation of the viral surface fusion (F) protein necessary to initiate infection of the target host cell. Inhibition of haemagglutinin-neuraminidase may therefore provide a target for antivirals.

[0007] While certain antiviral compounds have been disclosed in the present Applicant's earlier fded International Applications, published as WO 2016/033660 (US publication equivalent US20170290809A) and WO 2021/016670 (US publication equivalent US20220274965), as modulators of viral haemagglutinin-neuraminidase functions there remains a need for further compounds showing desirable efficacy and/or physicochemical profiles.

BRIEF SUMMARY

[0008] Embodiments of the present disclosure provide for antiviral compounds presenting an N-linked pyrazole attached to the C-4 position of the dehydroneuraminic acid-like core ring. The pyrazole ring presents a cyano group and is itself fused with at least one further ring system. The compounds have been found by the present inventors to provide useful efficacy as is described herein.

[0009] Accordingly, in a first aspect, the present disclosure provides for a compound of Formula I, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:

wherein,

R1 is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11, wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

R3 is wherein ring A, together with the carbons to which it is attached, forms an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7- membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring; and ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring;

R4 is selected from the group consisting of sulfonamide; urea; -NHC(O)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkylamino, C1-C6 alkyl-NHC(O)R17’, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and carbon of the C(O) group, which ring may be optionally fused with a further ring, each of which foregoing groups and rings may be optionally substituted;

R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, - NH(C=O)R18, -C(=O)NR18R18’, and S(O)nR18, wherein n = 0 to 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein each R19 group is optionally substituted.

[0010] According to a second aspect of the present disclosure there is provided a pharmaceutical composition comprising an effective amount of a compound of the first aspect, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

[0011] Suitably, the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0012] A third aspect of the present disclosure resides in a method of treating or preventing a disease, disorder or condition caused by a viral infection in a subject including the step of administering an effective amount of a compound of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect to the subject.

[0013] A fourth aspect of the present disclosure provides for a compound of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect for use in the treatment or prophylaxis of a disease, disorder or condition caused by viral infection in a subject.

[0014] A fifth aspect of the present disclosure provides for a pharmaceutical composition comprising a compound of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, for use in the treatment or prophylaxis of a disease, disorder or condition caused by viral infection in a subject.

[0015] A sixth aspect of the present disclosure provides for use of a compound of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect, for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0016] A seventh aspect of the present disclosure provides for use of a compound of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect, in the manufacture of a medicament for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0017] In embodiments of the third, fourth, fifth, sixth or seventh aspects, the disease, disorder or condition is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia. In one embodiment of the third, fourth, fifth, sixth or seventh aspects, the disease, disorder or condition is parainfluenza and/or influenza.

[0018] An eighth aspect of the present disclosure provides for a method of modulating a viral haemagglutinin and/or neuraminidase function including the step of contacting the viral haemagglutinin-neuraminidase with a compound of the first aspect or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect. [0019] A ninth aspect of the present disclosure provides for a compound of the first aspect or an N-oxide. pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect, for use in modulating viral haemagglutinin and/or neuraminidase function.

[0020] A tenth aspect of the present disclosure provides for use of a compound of any embodiment or formulae of the first aspect or an N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect, for modulating viral haemagglutinin and/or neuraminidase function.

[0021] The various features and embodiments of the present disclosure, referred to in individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently, features specified in one section may be combined with features specified in other sections as appropriate.

[0022] Further features and advantages of the present disclosure will become apparent from the following detailed description.

DETAILED DESCRIPTION

General

[0023] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e. one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter.

[0024] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. [0025] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the present disclosure.

[0026] Any embodiment of the present disclosure herein shall be taken to apply mutatis mutandis to any other embodiment of the disclosure unless specifically stated otherwise.

[0027] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for embodiments, in organic synthetic chemistry, cell culture, molecular genetics, immunology, immunohistochemistry, medicinal chemistry, and biochemistry).

[0028] The term “and/or”, e.g., “X and/or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0029] The terms “from” and “to”, when indicating a range, shall be understood to mean the range is inclusive of the recited lower and upper values. For example, “x is an integer from 0 to 6” shall be understood as including the situation in which x is not present (x is 0), that in which x is 6, as well as each whole number integer value in between, i.e. wherein x is 1, 2 , 3, 4, or 5.

[0030] Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

Selected Definitions

[0031] As used herein, “effective amount” refers to the administration of an amount of the relevant active agent sufficient to prevent the occurrence of symptoms of the condition being treated, or to bring about a halt in the worsening of symptoms or to treat and alleviate or at least reduce the severity of the symptoms. The effective amount will vary in a manner which would be understood by a person of skill in the art with patient age, sex, weight etc. An appropriate dosage or dosage regime can be ascertained through routine trial.

[0032] “Pharmaceutically acceptable carrier, diluent or excipient”, or like terms, refers to any ingredient other than the compounds described herein (for example, a vehicle capable of suspending, complexing, or dissolving the active compound) and having the properties of being substantially nontoxic in a subject. Excipients may include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxy toluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (com), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E (alpha-tocopherol), vitamin C, xylitol, and other species disclosed herein.

[0033] “Pharmaceutically acceptable salt” includes both acid and base addition salts. Lists of suitable salts may be found in Remington ’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977). Acid addition salts are those which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzene sulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor- 10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1,2-disulfonic acid, ethanesulfonic acid, 2- hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo- glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene- 1,5 -disulfonic acid, naphthalene-2- sulfonic acid, 1 -hydroxy-2 -naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like. Base addition salts are those which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N- ethylpiperidine, polyamine resins and the like.

[0034] As used herein, “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[0035] The terms “substituted” and “optionally substituted” in each incidence of its use herein, and in the absence of an explicit listing for any particular moiety, refers to substitution of the relevant moiety, for example an alkyl chain or ring structure, with one or more groups selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy (such as trifluoromethoxy, trifluoroethoxy and the like), CN, OH, azido, oxo, -CH(COOR28)NH ₂ , NH ₂ , NR28R28' -C(O)-NR28R28’, -O-C(O)-R28, -O-C(O)-O-R28, -C(O)-O-R28, (wherein R28 and R28' are independently selected, as appropriate, from hydrogen, optionally substituted C1-C9 alkyl, optionally substituted aryl, -(CH ₂ ) _n - CH(C00H)NH ₂ , R ₂ 9C=O, R ₂ 9SO ₂ , and R ₂ 9NHC=O wherein R29 is C1-C9 alkyl and n is an integer from 0 to 2), halo (including Cl, F, Br, and I), carboxy, sulfone including C1- C6 alkylsulfonyl, C1-C6haloalkylsulfonyl, and arylsulfonyl; aryl and heterocyclyl which latter two moieties may themselves be optionally substituted. In relation to any 5- to 7- membered aryl, heteroaryl or heterocyclic rings of the compounds herein then the optional substitution may be with one or more of the groups recited in this paragraph and/or with groups RI ₂ and/or R13, as defined herein. When the term is used before the recitation of a number of functional groups then it is intended to apply to all of the listed functionalities unless otherwise apparent. For example, “optionally substituted amino, heterocyclic, aryl” means all of the amino, heterocyclic and aryl groups may be optionally substituted.

[0036] The term “alkyl” refers to a straight-chain or branched alkyl substituent containing from, for example, 1 to about 12 carbon atoms, preferably 1 to about 8 carbon atoms, more preferably 1 to about 6 carbon atoms, even more preferably from 1 to about 4 carbon atoms, still yet more preferably from 1 to 2 carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, pentyl, isoamyl, 2-methylbutyl, 3 -methylbutyl, hexyl, heptyl, 2-methylpentyl, 3- methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3 -ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The number of carbons referred to relates to the carbon backbone and carbon branching but does not include carbon atoms belonging to any substituents, for example the carbon atoms of an alkoxy substituent branching off the main carbon chain.

[0037] The term “cycloalkyl” refers to optionally substituted non-aromatic mono- cyclic, bicyclic or tricyclic carbon groups. Where appropriate, the cycloalkyl group may have a specified number of carbon atoms, for example, C3-C6 cycloalkyl is a carbocyclic group having 3, 4, 5 or 6 carbon atoms. Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0038] The term “cycloalkenyl,” as used herein, generally has the same meaninas the term “cycloalkyl,” however one or more double bonds are present within the ring. Examples of such substituents include cyclobutenyl, cyclopentenyl and cyclohexenyl.

[0039] The term “aryl” refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art. It is understood that the term aryl applies to cyclic substituents that are planar and comprise 4n+2 p electrons, according to Huckel's Rule. C-5 and/or C-6 aryl (such as phenyl) is preferred. The aryl may be connected by a linking group such as a C1-C6 alkyl group and so “aryl” may be considered to include C1-C6 alkyl-aryl, including C1-C6 alkyl- C5-aryl and C1-C6 alkyl- C5-aryl.

[0040] The terms “heterocyclic”, “heterocycle”, and “heterocyclyl” as used herein specifically in relation to certain ‘R’ groups refer to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which may have 5 to 7 atoms in the ring and of those atoms between 1 to 4 are heteroatoms, said ring being isolated or fused to a second ring wherein said heteroatoms are independently selected from O, N and S. Heterocyclic, heterocycle, and heterocyclyl includes aromatic heterocyclyls and non-aromatic heterocyclyls but preferably relates to non-aromatic rings when differentiating from heteroaryl rings. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Heterocyclic systems may be attached to another moiety via any number of carbon atoms or heteroatoms of the radical and may be both saturated and unsaturated. Non-limiting examples of heterocyclic may be selected from pyrazole, imidazole, indole, isoindole, triazole, benzotriazole, tetrazole, pyrimidine, pyridine, pyrazine, diazine, triazine, tetrazine, pyrrolidinyl, pyrrolinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxathiolyl, isoxathiolyl, dioxanyl, dioxinyl, oxazinyl, azepinyl, diazepinyl, thiazolidinyl, isothiazolidinyl thiazepinyl, oxepinyl and thiapinyl, imidazolinyl, thiomorpholinyl, and the like. The term "heterocycloalkyl" means a non- aromatic, monocyclic or polycyclic ring comprising carbon and hydrogen atoms and at least one heteroatom, preferably, 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur. A heterocycloalkyl group can have one or more carbon-carbon double bonds or carbon-heteroatoms double bonds in the ring as long as the ring is not rendered aromatic by their presence. Examples of heterocycloalkyl groups include aziridinyl, pyrrolidinyl, pyrrolidino, piperidinyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. A heterocycloalkyl group can be unsubstituted or substituted with one or two suitable substituents. The term heterocycloalkyl may be used interchangeably with heterocyclic herein when used in relation to non-aromatic heterocycles.

[0041] The terms “heteroaryl” or “aromatic heterocyclyl” refers to an aryl group containing from one or more (particularly one to four) non-carbon atom(s) (particularly N, O or S) or a combination thereof, which heteroaryl group is optionally substituted at one or more carbon or nitrogen atom(s). Heteroaryl rings may also be fused with one or more cyclic hydrocarbon, heterocyclic, aryl, or heteroaryl rings. Heteroaryl includes, but is not limited to, 5-membered heteroaryls having one hetero atom (e.g., thiophenes, pyrroles, furans); 5 membered heteroaryls having two heteroatoms in the 1,2 or 1,3 positions (e.g., oxazoles, pyrazoles, imidazoles, thiazoles, purines); 5-membered heteroaryls having three heteroatoms (e.g., triazoles, thiadiazoles); 5-membered heteroaryls having four heteroatoms (e.g., tetrazoles); 6-membered heteroaryls with one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrine, 5,6- cycloheptenopyridine); 6-membered heteroaryls with two heteroatoms (e.g., pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines); 6-membered heretoaryls with three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryls with four heteroatoms. “Substituted heteroaryl” means a heteroaryl having one or more non- interfering groups as substituents and including those defined under ‘optionally substituted’ . Examples of heteroaryl include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, IH-indazole, purine, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isooxazole, furazane, phenoxazine, 2-, 3- or 4-pyridyl, 2-, 3-, 4-, 5-, or 8-quinolyl, 1-, 3- , 4-, or 5-isoquinolinyl 1-, 2-, or 3-indolyl, and 2-, or 3-thienyl. The group may be a terminal group or a bridging group.

[0042] The terms “alkylamine” and “dialkylamine” refer to -NHR and -NRR’ type groups, respectively, wherein “R” and “R” (which may be numbered R groups, i.e. Rx and Rx’) are alkyl, optionally substituted, and may be independently as defined above. That is, R and R’ may be, but are not necessarily, the same alkyl moiety.

[0043] The term “amine” may refer to -NH2, “alkylamine” and “dialkylamine” as defined above.

[0044] The term “protected OH” or “protected hydroxy” refers to a hydroxyl group which is protected with a common protecting group such as an acyl group, ether group or ester group including C1-C3 acyl, C1-C4 alkyl groups to form the ether or aryl, such as benzyl, forming the ether or C1-C4 ester.

[0045] The term “N-linked” as used herein with reference to compounds of the first aspect including compounds of formula (I), (II), and for example “N-linked pyrazole”, refers to the moiety attached at the C-4 position of the dehydroneuraminic acid-like core (R3 in formulae (I), (II), and (III)) and limits that attachment to involving a direct attachment between a ring carbon and nitrogen atom. Preferably, it refers to the

R3 moiety being linked to the dehydroneuraminic acid core via a nitrogen atom which itself forms part of the pyrazole ring.

[0046] Whenever a range of the number of atoms in a structure is indicated (e.g., a C1-C12, C1-C10, C1-C9, C1-C6, C1-C4, alkyl, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used. Thus, for instance, the recitation of a range of 1-12 carbon atoms (e.g., C1- C12), 1-9 carbon atoms (e.g., C1-C9), 1-6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as used with respect to any chemical group (e.g., alkyl, etc.) referenced herein encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well as any sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms, 1-12 carbon atoms, 2- 3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms, and/or 4-12 carbon atoms, etc., as appropriate).

[0047] As used herein, the terms “subject” or “individual” or “patient” may refer to any subject, particularly a vertebrate subject, and even more particularly a mammalian subject, for whom therapy is desired. Suitable vertebrate animals include, but are not restricted to, primates, avians, livestock animals (e.g., sheep, cows, horses, donkeys, pigs), laboratory test animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs) and captive wild animals (e.g., foxes, deer, dingoes). A preferred subject is a human in need of treatment for a disease or condition caused by a viral infection. However, it will be understood that the aforementioned terms do not imply that symptoms are necessarily present.

[0048] As used herein, the terms “treatment” or “treating” of a subject include the application or administration of the compound of the present disclosure, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof, as described herein to a subject with the purpose of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, less worsening, ameliorating, improving, or affecting the viral infection, the symptom(s) of the viral infection, or the risk of (or susceptibility to) the viral infection. The term “treating” refers to any indication of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement; remission; lessening of the rate of worsening; lessening severity of the disease; stabilization, diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; or improving a subject's physical or mental well-being.

[0049] As used herein, the terms “prophylaxis”, “prevention” or “preventing” are intended to refer to at least the reduction of likelihood of the risk of (or susceptibility to) acquiring a viral infection (i.e., causing at least one of the clinical symptoms of the viral infection not to develop in a patient that may be exposed to or predisposed to the viral infection but does not yet experience or display symptoms of the viral infection). Biological and physiological parameters for identifying such patients are provided herein and are known in the art.

[0050] References herein to “haemagglutinin-neuraminidase”, “haemagglutinin- neuraminidase protein” and the like may be considered interchangeable with “haemagglutinin and/or neuraminidase functions”. They may be considered to incorporate one or both of blocking of the haemagglutination function or inhibition of the neuraminidase (enzyme) function. The blocking of the haemagglutination function may therefore involve modulation, blocking or inhibition of the haemagglutinin- neuraminidase protein which may, without wishing to be bound by any theory, be one mechanism of action of the compounds described herein.

Compounds

[0051] In embodiments, the compounds of the present disclosure may provide for advantages over other select prior art compounds including one or more of: improved efficacy; beneficial pKa properties; reduced toxicity; and improved in vivo clearance. Further, compounds of the present disclosure may provide significant advantages in terms of the ability to tailor substitutions at the R3 position of formula I. Particularly, the present inventors have found that the cyano substituted compounds of the present disclosure, such as R3 cyanoindazoles, allow for a high degree of regiospecificity in substitution of the indazole rings. This has allowed for convenient investigation of the optimal substitution pattern for a given compound and for a high degree of confidence in selection and synthesis of the desired actives.

[0052] In one broad form of a first aspect, the present disclosure provides for a compound of Formula I, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein, Ri is selected from the group consisting of COOH, or a salt thereof,

C(0)NR9RIO, and C(O)OR11, wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

R3 is wherein ring A, together with the carbons to which which it is attached, forms an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring; and ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring;

R4 is selected from the group consisting of sulfonamide; urea; -NHC(0)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkylamino, C1-C6 alkyl-NHC(0)R17’, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and carbon of the C(O) group, which ring may be optionally fused with a further ring, each of which foregoing groups and rings may be optionally substituted;

R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’, -C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, -NH(C=0)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 to 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein any R19 group is optionally substituted.

[0053] In embodiments of the first aspect, the compound of Formula I is a compound of Formula (II), or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:

wherein, Ri, R3, R4, R6, R7 and R8 are as described for Formula I.

[0054] In embodiments of the first aspect, the compound of Formula I or Formula II is a compound of Formula III, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein, Ri, R3, R4, R6, R7 and R8 are as described for Formula I. [0055] Any reference herein to ‘embodiments’, in relation to the compounds of the first aspect may be considered a reference to any embodiment of a compound of each of Formula I, I and III.

[0056] It will be appreciated that ring A of R3 is formed with the two carbon atoms of the pyrazole ring to which it is attached. [0057] In embodiments, ring A, together with the carbons to which which it is attached, forms an optionally substituted 5- to 6-membered aryl ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6- membered heterocyclic ring.

[0058] In embodiments, ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6-membered heterocyclic ring.

[0059] In embodiments wherein ring A and/or ring B are a heteroaryl and/or a heterocyclic ring then the heteroatoms of each ring may be selected from one or more of N, O and S.

[0060] In embodiments, ring A may be selected from 6-membered aryl, 5- or 6- membered heteroaryl, and 5- or 6-membered heterocyclic ring.

[0061] In embodiments, ring A may be selected from 6-membered aryl, a 5- or 6- membered N-heteroaryl, and a 5- or 6-membered N-heterocyclic ring.

[0062] In embodiments, ring B may be selected from a 5- or 6-membered heteroaryl ring, and a 5- or 6-membered heterocyclic ring.

[0063] In embodiments, ring B may be selected from a 5- or 6-membered N, O or S-heteroaryl ring, and a 5- or 6-membered N, O or S -heterocyclic ring.

[0064] In embodiments, ring A and/or ring B may be substituted with one or more substituents independently selected from R12 and R13, as defined herein. It will be appreciated that ring A may comprise one or more R12 groups, wherein each R12 may be the same or different, and ring B may comprise one or more R13 groups, wherein each R13 may be the same or different, as described herein.

[0065] In embodiments, ring A and/or ring B may be optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O-R63, -S-R63, - C(O)-R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)- NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, OXO, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR63)NH2, -(CH2)n- CH(COOH)NH2 wherein n is an integer from 0 to 2, halogen or halo (such as Cl, F, Br, or I), aryl optionally substituted by at least one R62 and heterocyclyl optionally substituted by at least one R62, each of which groups may be optionally substituted as appropriate; wherein R61 and R61 ' are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, -C(O)-C1-C9 alkyl, -C(O)-N-CI-C9 alkyl or dialkyl, and -S(O) ₂ -C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein R62 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR51R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O) ₂ -C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate.

[0066] In embodiments, ring A may be selected from the group consisting of a benzene ring, a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a tetrahydrothiophene ring, and a thiophene ring, each of which may be optionally substituted. In some embodiments, ring A is a benzene ring, which may be optionally substituted. The optional substituent may be halo. The halo may be selected from F, Br and Cl, and is preferably selected from Br and Cl. In some embodiments, ring A is a benzene ring substituted with halo, preferably wherein halo is selected from Br and Cl. In some embodiments, ring A is an unsubstituted benzene ring. In some embodiments, ring A is a benzene ring substituted with Br and Cl. In some embodiments, ring A is a benzene ring substituted with Br.

[0067] In embodiments, ring B may be selected from the group consisting of a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a dioxolane ring, a tetrahydrothiophene ring, and a thiophene ring, each of which may be optionally substituted.

[0068] In embodiments, ring B is absent.

[0069] In embodiments of Formulae I, II or III, R3 may be selected from the group consisting of:

wherein, ring A and ring B are as defined for any embodiment of Formula I, II, and III, optionally wherein ring A is selected from the group consisting of a benzene ring, a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, atetrahydrofuran ring, a furan ring, a tetrahydrothiophene ring, and a thiophene ring and optionally wherein ring B is selected from the group consisting of a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a dioxolane ring, a tetrahydrothiophene ring, and a thiophene ring, all of which rings may be optionally substituted; Y is a heteroatom selected from N, O and S; and

R12 and R13 are independently selected the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O-R63, -S-R63. - C(O)-R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)- NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, oxo, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COORe3)NH2, -(CH2)n- CH(COOH)NH2 wherein n is an integer from 0 to 2, halogen or halo (such as Cl, F, Br, or I), aryl optionally substituted by at least one Re2 and heterocyclyl optionally substituted by at least one R62, each of which groups may be optionally substituted as appropriate; wherein R61 and R61 ' are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, -C(O)-C1-C9 alkyl, -C(O)-N-CI-C9 alkyl or dialkyl, and -S(O) ₂ -C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein R62 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR51R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O) ₂ -C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate; and N-oxide analogs thereof.

[0070] In embodiments of Formulae I, II or III, R3 may be selected from the group consisting of:

and N-oxide analogs thereof.

[0071] In embodiments of Formulae I, II or III, R3 is selected from:

preferably selected from and N-oxide analogs thereof.

[0072] It will be appreciated that the N-oxide analogs of R3 will present the oxygen of the N-oxide on the nitrogen of the pyrazole of the ring which is not attached to the core dehydroneuraminic acid-like ring (the oxygen-containing core). That is, the nitrogen at the 2-position of the pyrazole ring will present the N-oxide. For example, the corresponding N-oxide of the R3 group below: [0073] In embodiments of Formula I, II and III, Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11 wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl and heterocyclyl; wherein said C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R50; wherein R50 is selected from the group consisting of: R53, -O-R53, - S-R53, -C(O)-R53, -C(S)-R53, -C(O)-O-R53, -O-C(O)-R53, -O-C(S)-R53, -C(S)-O-R53, CN, OH, oxo, NR51R51’, Cl, F, Br, I, aryl optionally substituted by at least one R52 and heterocyclyl optionally substituted by at least one R52; wherein R51 and R51’ are independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2- C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-CI-C9 alkyl; wherein R52 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR51R51’, Cl, F, Br and I; wherein R53 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl.

[0074] In embodiments of Formula I, II and III, Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(0)0R11 wherein R9, Rio and R11 are independently selected from hydrogen and C1-C6 alkyl.

[0075] In embodiments of Formula I, II and III, Ri is selected from COOH, or a salt thereof, and C(O)OR11 wherein R11 is selected from methyl, ethyl and propyl. In embodiments wherein Ri is a salt of COOH then it may a sodium or potassium salt. In some embodiments, Ri is COOH, or a salt thereof.

[0076] In embodiments, R4 is selected from the group consisting of sulfonamide; urea; NHC(O)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1- C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C4 alkylamino, C1-C4 alkyl-NHC(O)R17 , C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; wherein said R17 groups may be optionally substituted by one or more R75; wherein R75 is selected from the group consisting of R78, -O-R78, -S-R78, -C(O)-R78, -C(S)-R78, -C(O)-O-R78, - O-C(O)-R78, -O-C(S)-R78, -C(S)-O-R78, CN, OH, oxo, NR76R76’, Cl, F, Br, I, aryl optionally substituted by at least one R77 and heterocyclyl optionally substituted by at least one R77; wherein R76 and R76’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R77 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR76R76’, Cl, F, Br and I; wherein R78 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and the carbon of the C(O) group, which ring may be optionally substituted and/or fused with a further ring.

[0077] In embodiments, R4 may be selected from the group consisting of NH- C(O)R17, -NHS(O) ₂ R27 wherein R27 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl, all of which may be optionally substituted, such as by one or more R75 as previously defined, and -NHC(O)NHR17 wherein R17 may be as previously defined.

[0078] In embodiments, R4 is NHC(O)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl; wherein said C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl may be optionally substituted, for example by one or more R75.

[0079] In any embodiment wherein R4 is NHC(O)R17 and R17 is selected from C3- C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl, then each of these groups may be connected to the carbonyl carbon by a C1-C6 alkyl chain or a C1-C4 alkyl chain or by ethyl or methyl.

[0080] When R4 is NHC(O)R17 and R17 is selected from C3-C6 heterocyclyl, and C5 or C6 heteroaryl then the heterocyclic atoms may be selected from one or more of N, O and S and, particularly, with 2 heteroatoms independently selected from N, O and S.

[0081] When R4 is NHC(O)R17 and R17 is selected from C3-C6 heterocyclyl, C5 orC6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl, then non-limiting examples of such groups may include where R17 is selected from benzyl, phenyl, furanyl, thiophenyl, isooxazolyl, pyridinyl, imidazolyl, pyrrolyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0082] In embodiments, R4 is NHC(O)R17 wherein R17 is C1-C6 alkyl or C1-C6 haloalkyl, including where R17 is -C(CH3)3, -CCI3, -CH-(CH3)2 or -CF3. [0083] In embodiments, R4 is selected from the group consisting of -NHAc, - NHC(O)C(CH ₃ )3, -NHC(O)CCh, -NHC(O)CH(CH ₃ )2, -NHC(O)CF ₃ and - NHC(O)CH2CH3. In embodiments, R4 is selected from the group consisting of - NHC(O)C(CH ₃ )3, -NHC(O)CCh and -NHC(O)CH(CH ₃ )2. In embodiments, R ₄ is NHC(O)C(CH3)3. In embodiments, R4 is -NHC(O)CC13. In embodiments, R4 is - NHC(O)CH(CH ₃ )2.

[0084] In embodiments wherein R4 is -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.

[0085] In embodiments wherein R4 is -NR20R21, one of R20 and R21 is hydrogen and the other is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0086] In embodiments wherein R4 is -NR22C(O)R23 wherein R22 and R23 together form a 5 -membered ring then R22 and R23 may, together with the N and C(O) group, form a pyrrolidone ring, which ring may be optionally substituted and/or fused with a further ring.

[0087] In embodiments, the further ring which is fused with the 5-membered ring formed by R22 and R23 together with the N and C(O) group is a 6-membered aryl ring. It will be appreciated that two of the carbon atoms of the fused 6-membered aryl ring will be shared with the nitrogen-containing ring, such as a pyrrolidone ring.

[0088] In embodiments, R4 is selected from the group consisting of:

[0089] R6, R? and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, - NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein each R19 group is independently optionally substituted.

[0090] In embodiments, R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, - OC(O)R18, -C(O)OR18, -NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 to 2 and each R18 and R18’ are independently selected from hydrogen, R19 optionally substituted by one or more R80 and C1-C9 alkanoyl optionally substituted by one or more R80; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl; wherein R80 is selected from the group consisting of R83, -O-R83, -S-R83, -C(O)-R83, -C(S)-R83, -C(O)- O-R83, -O-C(O)-R83, -O-C(S)-R83, -C(S)-O-R83, CN, OH, oxo, NR81R81’, Cl, F, Br, I, aryl optionally substituted by at least one R82 and heterocyclyl optionally substituted by at least one R82; wherein R81 and R81’ are independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O- C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-CI-C9 alkyl; wherein R82 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1- C6 haloalkoxy, CN, OH, oxo, NR76R76’, Cl, F, Br and I; wherein R83 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2- C6 alkynyl, and C2-C6 haloalkynyl.

[0091] In embodiments, R6, R7 and R8 are independently selected from the group consisting of OH and O-R19 wherein R19 is C1-C6 alkyl, such as forming -OAc, or C1-C6 haloalkyl. In embodiments, R6, R7 and R8 are each OH.

[0092] In embodiments, R12 and R13 are independently selected from the group consisting of hydrogen, azido, R63, -O-R63, -S-R63, - C(O)-R63, -C(S)-R63, -C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)-NR61R61’, -O-C(O)-R63, -O-C(S)-R63, - C(S)-O-R63, CN, OH, oxo, NR61R61’, Cl, F, and Br; wherein R61 and R61’ are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C ₂ -C ₆ haloalkynyl, C ₅ -C ₆ aryl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl, and -S(O)2-C1-C6 alkyl; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C6 aryl, C5-C6 heteroaryl, C5-C6 heterocyclyl, C5-C6 cycloalkyl and C5-C6 cycloalkenyl.

[0093] In embodiments, R12 and R13 are independently selected from the group consisting of: R63, -O-R63, -C(O)-O-R63, -C(O)-OH (or a salt thereof), Cl, F, and Br; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, -C(O)-C1-C6 alkyl, -C(O)- N-C1-C6 alkyl or dialkyl, -S(O)2-C1-C6 alkyl, C2-C6 haloalkynyl (especially C1-C6 alkyl or C1-C6 haloalkyl) and -(CH2)n-CH(COOR63)NH2 wherein n is an integer from 0 to 2.

[0094] In embodiments, R12 and R13 are independently selected from the group consisting of OH, CN, N3, 1, Br, F, Cl, -OCH3, COOH or a salt thereof, S(O)2CH3, CFs, CH3, -CH(COOH)NH2, and -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2. In embodiments, R12 and R13 are independently selected from the group consisting of Br, F and Cl, preferably Br and Cl.

[0095] In embodiments where ring B and R13 are absent, R12 may be independently selected from the group consisting of hydrogen, azido, R63, -O-R63, -S-R63, - C(O)-R63, - C(S)-R63, -C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)-NR61R61’, -O-C(O)-R63, -O- C(S)-R63, - C(S)-O-R63, CN, OH, OXO, NR61R61’, Cl, F, and Br; wherein R51 and R61’ are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C ₆ haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C ₅ -C ₆ aryl, -C(O)-C1-C6 alkyl, -C(0)- N-C1-C6 alkyl or dialkyl, and -S(0)2-C1-C6 alkyl; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C6 aryl, C5-C6 heteroaryl, C5-C6 heterocyclyl, C5- C6 cycloalkyl and C5-C6 cycloalkenyl.

[0096] In embodiments where ring B and R13 are absent, R12 may be independently selected from the group consisting of: R63, -O-R63, -C(O)-O-R63, -C(0)-0H (or a salt thereof), Cl, F, and Br; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, -C(O)- C1-C6 alkyl, -C(O)-N- C1-C6 alkyl or dialkyl, -S(O)2-C1-C6 alkyl, C2-C6 haloalkynyl (especially C1-C6 alkyl or C1-C6 haloalkyl) and -(CH2)n-CH(COOR63)NH2 wherein n is an integer from 0 to 2.

[0097] In embodiments where ring B and R13 are absent, R12 may be independently selected from the group consisting of OH, CN, N3, 1, Br, F, Cl, -OCH3, COOH or a salt thereof, S(O) ₂ CH ₃ , CF ₃ , CH ₃ , -CH(C00H)NH ₂ , and -(CH ₂ ) _n -CH(COOH)NH2 wherein n is an integer from 0 to 2. In embodiments, R12 is selected from the group consisting of Br, F and Cl, preferably Br and Cl. In embodiments, R12 is Br.

[0098] In one embodiment, the present disclosure provides for a compound of Formula I, or Formula II or III as previously defined, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:

Formula I wherein,

Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11 wherein R9, Rio and R11 are independently selected from hydrogen and C1-C6 alkyl, optionally wherein Ri is selected from COOH, or a salt thereof, and C(O)OR11 wherein R11 is selected from methyl, ethyl and propyl;

R3 is as defined in any of paragraphs [0051] to [0071] as described herein, optionally R3 is selected from the group consisting of: wherein, ring A and ring B are as defined for any embodiment of Formula I, II, and III, optionally wherein ring A is selected from the group consisting of a benzene ring, a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, atetrahydrofuran ring, a furan ring, a tetrahydrothiophene ring, and a thiophene ring and wherein ring B is selected from the group consisting of a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a dioxolane ring, a tetrahydrothiophene ring, and a thiophene ring, all of which rings may be optionally substituted; Y is a heteroatom selected from N, O and S; and

R12 and R13 are independently selected from the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O- R63, -S-R63, -C(O)-R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)-NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, oxo, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, CH(COOR63)NH2, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, halogen or halo (such as Cl, F, Br, or I), aryl optionally substituted by at least one Re2 and heterocyclyl optionally substituted by at least one Rr>2. each of which groups may be optionally substituted as appropriate; wherein R61 and R61’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2- C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, -C(O)-C1-C9 alkyl, -C(O)-N-C1- C9 alkyl or dialkyl, and -S(O)2-C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein R52 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR61R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-CI-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate; and N-oxide analogs thereof;

R4 is NHC(0)R17 wherein R17 is selected from the group consisting of C1- C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3- C6 cycloalkyl; wherein said C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl may be optionally substituted, for example by one or more R75, optionally R4 is NHC(0)R17 wherein R17 is C1-C6 alkyl or C1-C6 haloalkyl, including where R17 is -CH-(CH3)2 or -CF3, optionally R4 is selected from the group consisting of:

R6, R? and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, - NH(C=O)R18, - C(=O)NR18R18’, and S(O) _n R18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 optionally substituted by one or more R80 and C1-C9 alkanoyl optionally substituted by one or more R80; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl; wherein R80 is selected from the group consisting of: R83, -O-R83, -S-R83, -C(O)-R83, -C(S)-R83, -C(O)-O-R83, -O-C(O)-R83, -O- C(S)-R83, -C(S)-O-R83, CN, OH, OXO, NR81R81’, Cl, F, Br, I, aryl optionally substituted by at least one R82 and heterocyclyl optionally substituted by at least one R82; wherein R81 and R81’ are independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2- C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=0-C1-C9 alkyl, SO2- C1-C9 alkyl and C=0-NH-CI-C9 alkyl; wherein R82 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR76R76’, Cl, F, Br and I; wherein R83 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl, optionally R6, R7 and R8 are independently selected from the group consisting of OH and O-R19 wherein R19 is C1-C6 alkyl, such as forming -OAc, or C1-C6 haloalkyl.

[0099] In certain examples, the compound of Formula I is a compound of Formula IVA and/or Formula IVB, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein, each R12 is independently selected from the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O-R63, -S-R63. - C(O)-R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)- NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, OXO, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COORe3)NH2, -(CH2)n- CH(C00H)NH2 wherein n is an integer from 0 to 2, halogen or halo (such as Cl, F, Br, or I), aryl optionally substituted by at least one Re2 and heterocyclyl optionally substituted by at least one Re2, each of which groups may be optionally substituted as appropriate; wherein R51 and R51’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, -C(O)-C1-C9 alkyl, -C(O)-N-CI-C9 alkyl or dialkyl, and -S(O) ₂ -C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein R62 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR61R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O) ₂ -C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate; and

R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted.

[0100] In certain embodiments of the compound of Formula IVA and/or Formula IVB, each R12 and R17 as as defined for any embodiment of Formula I, II and III.

[0101] In certain embodiments of the compound of Formula IVA and/or Formula IVB, each R12 is independently selected from the group consisting of hydrogen, halo, haloalkyl, carboxy, aryl, heterocyclic, heteroaryl, alkoxy, cyano and alkylsulfonyl, each of which may be optionally substituted. In some embodiments, each R12 is independently selected from hydrogen and halo. The halo may be selected from the group consisting of F, Br and Cl, preferably Br and Cl. In embodiments, R12 is selected from hydrogen, Br and Cl. In some embodiments, R12 is selected from hydrogen and Br. In some embodiments, each R12 is hydrogen.

[0102] In certain embodiments of the compound of Formula IVA and/or Formula IVB, R17 is selected from the group consisting of -C(CH3)3, -CCI3, -CH-(CH3)2 and - CF3. In some embodiments, R17 is selected from the group consisting of -C(CH3)3, -CCl3 and -CH-(CH ₃ )2. In some embodiments, R17 is -C(CH3)3. In some embodiments, R17 is - CCI3. In some embodiments, R17 is -CH-(CH3)2. [0103] In embodiments, the compound of Formula I, II, and/or III is selected from the group consisting of:

CB2160-6 IE2076-45 IE2076-47 and N-oxides. pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms thereof, including acetyl replacing hydrogen at the free hydroxyls, all C-2 analogues thereof wherein the C-2 carboxy group is in the protonated form, sodium salt form or prodrug form and wherein each compound may be considered to have close analogues disclosed wherein the R4 position is explicitly replaced with any - NHC(O)R group wherein R is C1-C4 alkyl or haloalkylthereof.

[0104] Particularly, each compound shown in the preceding paragraph is considered to be explicitly reproduced with the nitrogen of the pyrazole ring which is not attached to the oxygen-containing ring being in the form of an N-oxide.

[0105] In some embodiments, the compound of the first aspect is selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof. Accordingly, the present disclosure also provides a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof. In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37 and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0106] As is described in the examples, the compounds of the first aspect may be accessed via a synthetic approach which initially forms the corresponding N-oxide, as described above. The N-oxide material, or a portion of it, may then be reduced and so the N-oxide forms and reduced forms of the compounds of the first aspect may be achieved in any desired relative amounts.

[0107] It will be appreciated by a person of skill in the art of synthetic chemistry that the COOH group can be readily interchanged with a salt form or an ester protecting group, for example a methyl ester group, and so all such forms are considered to be disclosed herein with reference to the compounds of the first aspect.

[0108] The prodrug form of the above compounds may be explicitly considered to include C1-C20 ester, or C1-C12 ester, or C1-C6 ester or ester comprising a cycloalkyl, or aryl moiety. The aryl moiety may include substituted phenyl or fused 2-3 cyclic aromatic rings.

[0109] In one embodiment, the compound of the first aspect is a haemagglutinin- neuraminidase modulator. That is, the compound of the first aspect is a modulator of haemagglutinin and/or neuraminidase functions. Preferably, the compound of the first aspect is a haemagglutinin-neuraminidase inhibitor. That is, an inhibitor of haemagglutinin and/or neuraminidase functions. This may include blocking of the haemagglutination function through modulation of the haemagglutinin protein.

[0110] In one embodiment, it may be preferred that the haemagglutinin- neuraminidase inhibitor is an influenza or parainfluenza haemagglutinin and/or neuraminidase inhibitor or blocker. Put another way, in one embodiment, it may be preferred that the inhibitor of haemagglutinin and/or neuraminidase functions is an inhibitor of influenza or parainfluenza haemagglutinin and/or neuraminidase functions. This may include blocking of the influenza or parainfluenza haemagglutination function and so modulation of the influenza haemagglutinin protein or parainfluenza haemagglutinin-neuraminidase protein.

[0111] A number of synthetic pathways can be employed to access the compounds of the first aspect. The experimental section details certain pathways by which certain compounds were synthesised to use as reference compounds. Relevant further synthetic techniques, which may also be applied to synthesis of compounds of the first aspect, are disclosed in Nature Scientific Reports, 7:4507, 03 July 2017; Angew. Chem. Int. Ed. 2015, 54, 2936-2940; Nature Scientific Reports, Q-.24138, 07 April 2016; Med. Chem. Commun, 2017, 8, 130-134; J. Med. Chem. 2014, 57, 7613-7623; Carbohydr. Res. 244, 181 -185 (1993); Nature Communications, 5:5268, 20 Oct 2014; Viruses, 2019, 1 1, 417, 05 May 2019; Carbohydr. Res. 342, 1636-1650 (2007); Bioorg. Med. Chem. Lett. 16, 5009-5013 (2006); PCT application W02002076971 (US publication equivalent US20030187063); and PCT application W02016033660 (US publication equivalent US20170290809), each of which is hereby incorporated by reference in their entirety. Such techniques and synthetic approaches can be employed to access all of the compounds of the first aspect.

Compositions

[0112] According to a second aspect of the present disclosure there is provided a pharmaceutical composition comprising an effective amount of a compound of any embodiment or formulae of the first aspect, or N-oxides. pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

[0113] Suitably, the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0114] In embodiments of the second aspect, the compound of the first aspect may be selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof. Accordingly, the present disclosure also provides a pharmaceutical composition comprising an effective amount of a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides, pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient. In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37 and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0115] The pharmaceutical composition may include more than one compound of formula (I). When the composition includes more than one compound then the compounds may be in any ratio. The composition may further comprise known co- actives, delivery vehicles or adjuvants.

[0116] The compound of any embodiment or formulae of the first aspect is present in the pharmaceutical composition in an amount sufficient to inhibit or ameliorate the disease, disorder or condition which is the subject of treatment. Suitable dosage forms and rates of the compounds and the pharmaceutical compositions containing such may be readily determined by those skilled in the art.

[0117] Dosage forms may include tablets, dispersions, mists, aerosols, suspensions, injections, solutions, syrups, troches, capsules and the like.

[0118] The compositions, such as a pharmaceutical composition, comprising a compound of the present disclosure can be formulated for administration via any accepted mode of administration of small molecule drugs. The pharmaceutical compositions of the present disclosure may be formulated into preparations in solid, semi-solid, liquid or aerosol/gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intradermal, intrastemal injection or infusion techniques. The compositions administered to a subject may be in the form of one or more dosage units, where for example, a tablet or injectable liquid volume may be a single dosage unit. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000).

[0119] Therefore, embodiments of the present disclosure provide a composition (such as a pharmaceutical composition) comprising a compound of the present disclosure, combined with a pharmaceutically acceptable carrier, diluent or excipient.

[0120] In general terms, the pharmaceutically acceptable carrier, diluent or excipient may be a solid or liquid filler, binder, diluent, encapsulating substance, emulsifier, wetting agent, solvent, suspending agent, coating or lubricant that may be safely administered to any subject, e.g., a human. Depending upon the particular route of administration, a variety of acceptable carriers, known in the art may be used, as for embodiment described in Remington's Pharmaceutical Sciences (Mack Publishing Co. N.J. USA, 1991).

[0121] Pharmaceutically acceptable carriers, diluents and excipients will have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a subject. Some examples of compounds which can be used as pharmaceutically acceptable carriers, fillers or constituents thereof are sugars, such as, for example, lactose, glucose, trehalose and sucrose; starches, such as, for example, com starch or potato starch; dextrose; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, com oil and oil from theobroma; polyols, such as, for example, polypropylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; and alginic acid.

[0122] Formulation of compounds of the disclosure to be administered will vary according to the route of administration and formulation (e.g., solution, emulsion, capsule) selected. An appropriate pharmaceutical composition comprising a compound of the disclosure to be administered can be prepared in a physiologically acceptable carrier. For solutions or emulsions, suitable carriers include, for embodiment, aqueous or alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles can include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. A variety of appropriate aqueous carriers are known to the skilled artisan, including water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), dextrose solution and glycine. Intravenous vehicles can include various additives, preservatives, or fluid, nutrient or electrolyte replenishers (See, generally, Remington's Pharmaceutical Science, 16th Edition, Mack, Ed. 1980). The compositions can optionally contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents and toxicity adjusting agents, for embodiment, sodium acetate, sodium chloride, potassium chloride, calcium chloride and sodium lactate.

[0123] Compositions comprising a compound of the disclosure may be formulated in unit dosage form. The therapeutically effective or prophylactically effective dose for any particular patient will depend upon a variety of factors including the severity and identify of a disorder being treated; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific pharmaceutical composition employed; the duration of the treatment; drugs used in combination or coincidental with the specific pharmaceutical composition employed; and like factors well known in the medical arts.

[0124] Compositions comprising a compound of the disclosure described herein may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. They may be administered together in a single composition or administered separately in different compositions.

Methods of Treatment and Uses

[0125] A third aspect of the present disclosure resides in a method of treating and/or preventing a disease, disorder or condition caused by a viral infection in a subject including the step of administering an effective amount of a compound of any embodiment or formulae of the first aspect, or an N-oxide. pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect to the subject.

[0126] A fourth aspect of the present disclosure provides for a compound of any embodiment or formulae of the first aspect, or an N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect for use in the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection in a subject.

[0127] A fifth aspect of the present disclosure provides for a pharmaceutical composition comprising a compound of any embodiment or formulae of the first aspect, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof, for use in the treatment or prophylaxis of a disease, disorder or condition caused by viral infection in a subject.

[0128] A sixth aspect of the present disclosure provides for use of a compound of any embodiment or formulae of the first aspect, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof, or the pharmaceutical composition of the second aspect, for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0129] A seventh aspect of the present disclosure provides for use of a compound of any embodiment or formulae of the first aspect, or an N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect, in the manufacture of a medicament for the treatment or prophylaxis of a disease, disorder or condition in a subject caused by a viral infection.

[0130] In embodiments of the third, fourth, fifth, sixth or seventh aspects, the disease, disorder or condition is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia.

[0131] In embodiments of the third, fourth, fifth, sixth or seventh aspects, the disease, disorder or condition is parainfluenza and/or influenza.

[0132] In embodiments of the third, fourth, fifth, sixth or seventh aspects, the disease, disorder or condition is an infection caused by an influenza and/or parainfluenza virus.

[0133] The infection may be caused by one or more of an influenza A virus, influenza B virus, influenza C virus, influenza D virus, parainfluenza virus, respiratory syncytial virus (RSV) and human metapneumovirus (hMPV).

[0134] When the disease, disorder or condition is influenza then it may be influenza

A, B, C or D.

[0135] When the disease, disorder or condition is parainfluenza viral infection, it may be selected from the group consisting of an hPIV-1, -2, -3 and -4 virus. These may include all viral subtypes, e.g. 4a and 4b.

[0136] When the disease, disorder or condition is caused by RSV then it may be the A and/or B subtypes, for example, hRSV-A and hRSV-B.

[0137] When the disease, disorder or condition is caused by hMPV then it may be caused by any one or more of the hMPV Al, A2, Bl and B2 subtypes.

[0138] Preferably, the subject is a domestic or livestock animal or a human.

[0139] In embodiments of the third, fourth, fifth, sixth or seventh aspects, the compound of the first aspect is selected from the group consisting of IE2076-14, IE2076- 37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including Woxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof. [0140] In embodiments of the third, fourth, sixth or seventh aspects, the pharmaceutical composition of the second aspect comprises a compound selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof.

[0141] Accordingly, the present disclosure also provides a method of treating and/or preventing a disease, disorder or condition caused by a viral infection in a subject including the step of administering an effective amount of a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124- 75, or N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof.

[0142] The present disclosure also provides a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N- oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same, for use in the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection in a subject.

[0143] The present disclosure also provides a pharmaceutical composition comprising a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, for use in the treatment or prophylaxis of a disease, disorder or condition caused by viral infection in a subject.

[0144] The present disclosure also provides for use of a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same, for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

[0145] The present disclosure also provides for use of a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same, in the manufacture of a medicament for the treatment or prophylaxis of a disease, disorder or condition in a subject caused by a viral infection.

[0146] In some embodiments, the compound is selected from IE2076-37, IE2076- 80, IE2124-39, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37 and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0147] A eighth aspect of the present disclosure provides for a method of modulating viral haemagglutinin and/or neuraminidase function including the step of contacting the viral haemagglutinin-neuraminidase with a compound of any embodiment or formulae of the first aspect or an N-oxide. pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect.

[0148] A ninth aspect of the present disclosure provides for a compound of any embodiment or formulae of the first aspect or an N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect, for use in modulating viral haemagglutinin and/or neuraminidase function.

[0149] A tenth aspect of the present disclosure provides for use of a compound of any embodiment or formulae of the first aspect or an N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form thereof, or the pharmaceutical composition of the second aspect, for modulating viral haemagglutinin and/or neuraminidase function. [0150] Preferably, the modulating involves inhibiting the viral haemagglutinin and/or neuraminidase functions or viral haemagglutinin-neuraminidase enzyme.

[0151] In embodiments of the eighth, ninth and tenth aspects, the compound of the first aspect is selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof.

[0152] In embodiments of the eighth, ninth and tenth aspect, the pharmaceutical composition of the second aspect comprises a compound selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof.

[0153] Accordingly, the present disclosure also provides for a method of modulating viral haemagglutinin and/or neuraminidase function including the step of contacting the viral haemagglutinin-neuraminidase with a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124- 75, or N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same.

[0154] The present disclosure also provides for a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same, for use in modulating viral haemagglutinin and/or neuraminidase function.

[0155] The present disclosure also provides for use of a compound selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or N-oxides. pharmaceutically acceptable salts, prodrugs and stereoisomers thereof, or a pharmaceutical composition comprising same, for modulating viral haemagglutinin and/or neuraminidase function.

[0156] In some embodiments, the compound is selected from IE2076-37, IE2076- 80, IE2124-39, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57 and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37 and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

Itemised listing of embodiments

[0157] The present disclosure is further described in detail by reference to the following items:

1. A compound of Formula I, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein,

Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11, wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

R3 is wherein ring A, together with the carbons to which it is attached, forms an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7- membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring; and ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring;

R4 is selected from the group consisting of sulfonamide; urea; -NHC(0)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkylamino, C1-C6 alkyl-NHC(0)R17’, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and carbon of the C(O) group, which ring may be optionally fused with a further ring, each of which foregoing groups and rings may be optionally substituted;

R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, - NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein any R19 group is optionally substituted.

2. The compound of item 1, wherein the compound of Formula I is a compound of Formula (II), or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein, Ri, R3, R4, R6, R7 and R8 are as defined in item 1.

3. The compound of item 1 or item 2 wherein the compound of Formula I or Formula

II is a compound of Formula III, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof: wherein, Ri, R3, R4, R6, R7 and R8 are as defined in item 1. 4. The compound of any one of the preceding items, wherein Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11 wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl and heterocyclyl; wherein said C1- C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted by one or more R50; wherein R50 is selected from the group consisting of R53, -O-R53, - S-R53, -C(O)-R53, -C(S)-R53, -C(O)-O-R53, -O-C(O)-R53, -O-C(S)-R53, -C(S)- O-R53, CN, OH, oxo, NR51R51’, Cl, F, Br, I, aryl optionally substituted by at least one R52 and heterocyclyl optionally substituted by at least one R52; wherein R51 and R51’ are independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2- C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-CI-C9 alkyl; wherein R52 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR51R51’, Cl, F, Br and I; wherein R53 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl.

5. The compound of any one of the preceding items, wherein Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11 wherein R9, Rio and R11 are independently selected from hydrogen and C1-C6 alkyl.

6. The compound of any one of the preceding items, wherein Ri is selected from COOH, or a salt thereof, and C(O)OR11 wherein R11 is selected from methyl, ethyl and propyl.

7. The compound of any one of the preceding items, wherein R4 is selected from the group consisting of sulfonamide; urea; NHC(O)Ri? wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2- C6 alkynyl, C2-C6 haloalkynyl, C1-C4 alkylamino, C1-C4 alkyl-NHC(O) R17 , C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; wherein said R17 groups may be optionally substituted by one or more R75; wherein R75 is selected from the group consisting of R78, -O-R78, -S-R78, - C(O)-R78, -C(S)-R78, -C(O)-O-R78, -O-C(O)-R78, -O-C(S)-R78, -C(S)-O-R78, CN, OH, oxo, NR76R76’, Cl, F, Br, I, aryl optionally substituted by at least one R77 and heterocyclyl optionally substituted by at least one R77; wherein R76 and R76’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O-C1-C9 alkyl, SO2- C1-C9 alkyl and C=0-NH-CI-C9 alkyl; wherein R77 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR76R76’, Cl, F, Br and I; wherein R78 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl- aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and the carbon of the C(O) group, which ring may be optionally substituted and/or fused with a further ring.

8. The compound of any one of the preceding items, wherein R4 is selected from the group consisting of NH-C(0)R17, -NHS(O)2R27 wherein R27 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl, all of which are optionally substituted, optionally by one or more R75, and -NHC(0)NHR17 wherein R17 and R75 are as defined in item 7.

9. The compound of any one of the preceding items, wherein R4 is NHC(0)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl; wherein said C1- C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3- C6 cycloalkyl are optionally substituted, optionally by one or more R75 as defined in item 7. 10. The compound of any one of the preceding items, wherein R4 is NHC(O)R17 wherein R17 is C1-C6 alkyl or C1-C6 haloalkyl, including where R17 is -CH-(CH ₃ )2 or - CF ₃ .

11. The compound of any one of the preceding items, wherein R4 is selected from the group consisting of -NHAc, -NHC(O)C(CH ₃ ) ₃ , -NHC(O)CC1 ₃ , -NHC(O)CH(CH ₃ ) ₂ , - NHC(O)CF ₃ and -NHC(O)CH ₂ CH ₃ .

12. The compound of any one of the preceding items, wherein R4 is selected from the group consisting of:

13. The compound of any one of the preceding items, wherein R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18', -C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, -NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein each R19 group is independently optionally substituted.

14. The compound of any one of the preceding items, wherein R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, -NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 optionally substituted by one or more R80 and C1-C9 alkanoyl optionally substituted by one or more R80; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl; wherein R80 is selected from the group consisting of: R83, -O-R83, -S-R83, -C(O)-R83, -C(S)-R83, -C(O)-O-R83, -O-C(O)-R83, -O- C(S)-R83, -C(S)-O-R83, CN, OH, OXO, NR81R81’, Cl, F, Br, I, aryl optionally substituted by at least one R82 and heterocyclyl optionally substituted by at least one R82; wherein R81 and R81’ are independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2- C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, C=O-C1-C9 alkyl, SO2- C1-C9 alkyl and C=0-NH-CI-C9 alkyl; wherein R82 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR76R76’, Cl, F, Br and I; wherein R83 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl.

15. The compound of any one of the preceding items, wherein R6, R7 and R8 are independently selected from the group consisting of OH and O-R19 wherein R19 is C1-C6 alkyl, such as forming -OAc, or C1-C6 haloalkyl. 16. The compound of any one of the preceding items, wherein R6, R? and R8 are independently selected from OH and OAc.

17. The compound of any one of the preceding items, wherein ring A, together with the carbons to which it is attached, forms an optionally substituted 5- to 6-membered aryl ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6-membered heterocyclic ring.

18. The compound of any one of the preceding items, wherein ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6-membered heterocyclic ring.

19. The compound of any one of the preceding items, wherein ring A and/or ring B are heteroaryl and/or heterocyclic then the heteroatoms of each ring are selected from one or more of N, O and S.

20. The compound of any one of the preceding items, wherein ring A is selected from 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic ring.

21. The compound of any one of the preceding items, wherein ring A is selected from 6-membered aryl, a 5- or 6-membered N-heteroaryl, and a 5- or 6-membered N- heterocyclic ring.

22. The compound of any one of the preceding items, wherein ring B is selected from 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic ring.

23. The compound of any one of the preceding items, wherein ring B is selected from a 5- or 6-membered N, O or S-heteroaryl, and a 5- or 6-membered N, O or S -heterocyclic ring. 24. The compound of any one of the preceding items, wherein ring A is selected from the group consisting of a benzene ring, a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a tetrahydrothiophene ring, and a thiophene ring, each of which is optionally substituted.

25. The compound of any one of the preceding items, wherein ring B is selected from the group consisting of a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a dioxolane ring, a tetrahydrothiophene ring, and a thiophene ring, each of which is optionally substituted.

26. The compound of any one of the preceding items, wherein R3 is selected from the group consisting of: wherein, ring A and ring B are as defined in any one of item 1 to item 25, optionally wherein ring A is selected from the group consisting of a benzene ring, a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a tetrahydrothiophene ring, and a thiophene ring and wherein ring B is selected from the group consisting of a piperidine ring, a pyridine ring, a pyrrolidine ring, a pyrrole ring, a tetrahydrofuran ring, a furan ring, a dioxolane ring, a tetrahydrothiophene ring, and a thiophene ring, all of which rings are optionally substituted;

Y is a heteroatom selected from N, O and S; and

R12 and R13 are independently selected from the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O- R63, -S-R63, -C(O)-R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)-NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, oxo, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, CH(COOR63)NH2, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, halo, aryl optionally substituted by at least one Rr>2 and heterocyclyl optionally substituted by at least one Rei. each of which groups may be optionally substituted as appropriate; wherein Rei and Re i’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, and -S(O) ₂ -C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein R52 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR61R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O) ₂ -C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate; and N-oxide analogs thereof.

27. The compound of item 26, wherein R12 and R13 are independently selected from the group consisting of hydrogen, azido, R63, -O-R63, -S-R63, -C(O)-R63, -C(S)-R63, - C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)-N R61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, oxo, NR61R61’, Cl, F, and Br; wherein R61 and R61’ are independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C ₆ haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl, and -S(O)2-C1-C6 alkyl; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl.

28. The compound of item 26 or item 27, wherein R12 and R13 are independently selected from the group consisting of: R63, -O-R63, -C(O)-O-R63, — C(O)-OH (or a salt thereof), Cl, F, Br, and -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, and C2-C6 haloalkynyl.

29. The compound of any one of item 26 to item 28, wherein R12 and R13 are independently selected from the group consisting of OH, CN, I, Br, F, Cl, -OCH3, COOH or a salt thereof, -S(O)2CH3, CF3 and CH3.

30. The compound of any one of the preceding items, wherein ring A and/or ring B are substituted with one or more substituents independently selected from R12 and R13, which are independently selected from the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O-R63, -S-R63, -C(O)- R63, -C(S)-R63, -C(O)-O-R63, -O-C(O)-O-R63, -C(O)-OH (or a salt thereof), -C(O)- NR61R61’, -O-C(O)-R63, -O-C(S)-R63, -C(S)-O-R63, CN, OH, oxo, NR61R61’, C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR63)NH2, -(CH2)n- CH(COOH)NH2 wherein n is an integer from 0 to 2, halo, aryl optionally substituted by at least one Re2 and heterocyclyl optionally substituted by at least one R62. each of which groups may be optionally substituted as appropriate; wherein R51 and R61’ are independently selected from the group consisting of hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 alkynyl, C2-C9 haloalkynyl, aryl, - C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, and -S(O) ₂ -C1-C9 alkyl, each of which may be optionally substituted as appropriate; wherein Re2 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR61R61’, Cl, F, Br and I, each of which groups may be optionally substituted as appropriate; wherein R63 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, -(CH2)n-CH(COOH)NH2 wherein n is an integer from 0 to 2, -C(0)-C1-C9 alkyl, -C(0)-N-CI-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl and cycloalkenyl, each of which groups may be optionally substituted as appropriate.

31. The compound of any one of the preceding items, wherein ring A and/or ring B are substituted with one or more substituents independently selected from hydrogen, halo, C1-C6 alkoxy, hydroxyl, carboxy, C1-C6 alkyl, C1-C6 haloalkyl, cyano, and sulfone.

32. The compound of any one of the preceding items, wherein R3 is selected from the group consisting of:

and N-oxide analogs thereof.

33. The compound of any one of the preceding items wherein the compound is

5 selected from the group consisting of:

and N-oxides, pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms thereof, including acetyl replacing hydrogen at the free hydroxyls, all C- 2 analogues thereof wherein the C-2 carboxy group is in the protonated form, sodium salt form or prodrug form and wherein each compound may be considered to have close analogues disclosed wherein the R4 position is explicitly replaced with any -NHC(O)R group wherein R is C1-C4 alkyl or haloalkylthereof.

34. A pharmaceutical composition comprising an effective amount of a compound of any one of items 1 to 33, or an N-oxide. pharmaceutically acceptable salt, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier, diluent and/or excipient.

35. The pharmaceutical composition of item 34 wherein the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.

36. A method of treating or preventing a disease, disorder or condition caused by a viral infection in a subject including the step of administering an effective amount of a compound of Formula I, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:

wherein,

Ri is selected from the group consisting of COOH, or a salt thereof, C(0)NR9RIO, and C(O)OR11, wherein R9, Rio and R11 are independently selected from the group consisting of hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclyl;

R3 is wherein ring A, together with the carbons to which which it is attached, forms an optionally substituted 5- to 7-membered aryl ring, an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring; and ring B, when present, together with two ring atoms of ring A, forms an optionally substituted 5- to 7-membered heteroaryl ring, or an optionally substituted 5- to 7-membered heterocyclic ring;

R4 is selected from the group consisting of sulfonamide; urea; -NHC(0)R17 wherein R17 is selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C1-C6 alkylamino, C1-C6 alkyl-NHC(0)R17’, C3-C6 cycloalkyl, C3-C6 heterocyclyl, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may be optionally substituted and wherein R17’ may be selected from the same groups as R17; -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1- C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR22C(O)R23 wherein R22 and R23 together form a 5- or 6-membered ring together with the N and carbon of the C(O) group, which ring may be optionally fused with a further ring, each of which foregoing groups and rings may be optionally substituted;

R6, R7 and R8 are independently selected from the group consisting of H, OH, protected OH, R19, O-R19, NR18R18’,-C(O)R18, -C(S)R18, -OC(O)R18, -C(O)OR18, - NH(C=O)R18, - C(=O)NR18R18’, and S(O)nR18, wherein n = 0 - 2 and each R18 and R18’ are independently selected from hydrogen, R19 and optionally substituted C1-C9 alkanoyl, as appropriate; wherein each R19 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl and heterocyclyl, wherein any R19 group is optionally substituted; or the pharmaceutical composition of item 34 or item 35, to the subject.

37. The method of item 36, wherein the compound is as defined in any one of item 1 to item 33.

38. The method of item 36 or item 37, wherein the disease, disorder or condition is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia. 39. The method of any one of item 36 to item 38, wherein the infection is caused by a vims selected from the group consisting of influenza A vims, influenza B vims, influenza C vims, influenza D vims, parainfluenza vims, respiratory syncytial vims (RSV) and human metapneumovims (hMPV).

40. The method of any one of item 36 to item 39, wherein the disease, disorder or condition is parainfluenza and/or influenza.

41. The method of any one of item 36 to item 40, wherein the disease, disorder or condition is an infection caused by an influenza and/or parainfluenza vims.

42. The method of any one of item 36 to item 41, wherein when the disease, disorder or condition is influenza then it is selected from the group consisting of influenza A, B, C or D.

43. The method of any one of item 36 to item 41, wherein when the disease, disorder or condition is a parainfluenza viral infection it is selected from the group consisting of an hPIV-1, -2, -3 and -4 vims, including all viral subtypes.

44. The method of any one of item 36 to item 41, wherein the subject is a domestic or livestock animal or a human.

45. A method of modulating viral haemagglutinin and/or neuraminidase function including the step of contacting the viral haemagglutinin-neuraminidase with a compound of any one of item 1 to item 33, or an N-oxide, pharmaceutically acceptable salt, prodmg or stereoisomer thereof, or with the pharmaceutical composition of item 34 or item 35. 46. The method of item 45, wherein the modulating is inhibiting the viral haemagglutinin and/or neuraminidase functions or viral haemagglutinin-neuraminidase enzyme.

EXAMPLES

Example 1: General Synthetic Approach

[0158] The N-oxide form of the compounds of the first aspect were obtained by coupling the 4-amine intermediate IE889-89 with the appropriate 2-nitrobenzaldehyde, with a desired substituent - ‘X’, in the presence of TMSCN in glacial acetic acid, followed by stirring of the crude product obtained from the first step with triethylamine in ethanol, as shown in the scheme below. It will be appreciated that a wide variation in the IE889-89 starting substrate is possible.

[0159] The N-oxides IE2076-3 and IE2076-16 were deprotected using LiOH (IM) in acetonitrile at 0 °C to yield the indazole-N-oxides IE2076-45 and IE2076-47, respectively.

[0160] The N-oxide derivatives could be, if desired, reduced to their equivalent indazoles under the effect of zinc dust and in the presence of ammonium chloride in 80% MeOH. The reduced products were deprotected with LiOH to yield the final deprotected indazoles IE2076-12, IE2076-14, IE2076-17, IE2076-37 and IE2076-48 as showed in the scheme below. This approach therefore allows the N-oxide form of all synthesized compounds to be formed and all or a portion of the material to then be reduced to give the reduced form.

Experimental data

General procedure for synthesis of protected indazole-N-oxide:

[0161] To a solution of the starting amine, e.g. 4-amino-Neu5Ibu2en, IE889-89 (100 mg, 0.22 mmol), and the appropriate 2-nitrobenzaldehyde reagent (0.22 mmol) in glac. AcOH (1 mL), was added TMSCN (55 μL, 0.44 mmol). The reaction mixture was stirred at rt o/n, and the reaction solvent was then removed under vacuo. Evaporation of AcOH was assisted by multiple additions and co-evaporation of EtOH (3 x 10 mL). The residue was dissolved in EtOH (3 mL) and triethylamine (20 drops) was added, and the mixture was stirred at rt for 2 h. The reaction mixture was then concentrated and was taken to purification by silica gel chromatography using a suitable solvent system to yield the pure protected indazole N-oxide product.

General procedure for reduction of the indazole-N-oxide; synthesis of protected indazole:

[0162] To a solution ofthe protected indazole-N-oxide in MeOH/H2O (4: 1, 3.0 mL) was added zinc or iron powder (3 equivalents) and ammonium chloride (5 equivalents). The mixture was stirred at 0 °C for 1 h, then silica gel (1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using a suitable solvent system to yield the reduced protected indazole.

General procedure for deprotection of protected indazole:

[0163] To a solution of the reduced protected indazole in acetonitrile (2 mL) at 0 °C was added LiOH solution (1.0 M) dropwise until the pH reached 13-14. The mixture was stirred at 0 °C for 2h, then silica gel (1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using a suitable solvent system to yield the deprotected indazole. IE1963-114

[0164] Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-(3-cyano-2H-indazol-l-oxide -2- yl)-3,4,5-trideoxy-5-isobutyramido-D-glycero-D-ga/acto>-n on-2-enonate (IE1963-114).

[0165] The compound was prepared according to the general procedure from IE889-89 and 2-nitrobenzaldehyde, and the product was purified by silica gel chromatography using hexane/EtOAc (1:2) to yield product IE1963-114 in 52% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ = 0.72 (d, J= 6.9 Hz, 3H), 0.82-0.89 (m, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.12-2.23 (m, 1H), 3.84 (s, 3H), 4.19 (dd, J = 12.6, 6.1 Hz, 1H), 4.56-4.65 (m, 1H), 4.74 (d, J= 10.7 Hz, 1H), 5.42 (td, J= 6.4, 2.6 Hz, 1H), 5.51-5.57 (m, 1H), 6.21 (d, J = 2.5 Hz, 1H), 6.44 (d, J = 9.8 Hz, 1H), 7.42-7.52 (m, 2H), 7.74 (d,J = 8.9 Hz, 2H); ¹³ C NMR (101 MHz, CD3OD): δ= 17.29, 17.85, 19.16, 19.24, 19.36, 34.80, 46.07, 51.75, 54.44, 61.76, 67.16, 70.05, 76.60, 105.13, 109.06, 113.18, 118.51, 122.73, 127.95, 128.29, 128.80, 147.27, 161.15, 169.73, 170.08, 171.00, 178.49; LRMS [C28H32N4O11] (m/z): (+ve ion mode) 623.2 [M+Na]’.

IE2076-2

[0166] Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-(6-bromo-3-cyano-2H-indazol - l-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-D-glycero-D-gal acto>-non-2-enonate

(IE2076-2).

[0167] The compound was prepared according to the general procedure from IE889-89 and 4-bromo-2-nitrobenzaldehyde, and the product was purified by silica gel chromatography using hexane/EtOAc (1 : 1) to yield product IE2076-2 in 44% yield (over 2 steps). ¹ H NMR (400 MHz, CDCl3): δ = 0.82 (d, J= 6.9 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 2.13-2.20 (m, 1H), 3.85 (s, 3H), 4.20 (dd, J = 12.6, 6.6 Hz, 1H), 4.65-4.75 (m, 2H), 4.85 (q, J= 10.0 Hz, 1H), 5.36 (ddd, J= 6.5, 5.4, 2.6 Hz, 1H), 5.49 (dd, J= 5.5, 1.7 Hz, 1H), 5.85 (d, J = 9.6 Hz, 1H), 6.07 (d, J = 2.4 Hz, 1H), 6.38 (d, J = 9.9 Hz, 1H), 7.45 (dd, J= 9.0, 1.6 Hz, 1H), 7.53 (dd, J= 9.1, 0.8 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H); LRMS [C28H31BrN4O11] (m/z): (+ve ion mode) 703.1 [M+Na]'.

IE2076-3

[0168] Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-(3-cyano-5-hydroxy-2H-indaz ol- l-oxide-2 -yl)-3, 4, 5-trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2 -enonate (IE2076-3).

[0169] The compound was prepared according to the general procedure from IE889-89 and 5 -hydroxy-2 -nitrobenzaldehyde, and the product was purified by silica gel chromatography using hexane/EtOAc/MeOH (7:4: 1) to yield product IE2076-3 in 61% yield (over 2 steps). ¹ H NMR (400 MHz, CDCl3): δ = 0.76 (d, J= 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H), 2.06 (s, 3H), 2.09 (s, 6H), 2.18 (q, J = 6.9 Hz, 1H), 3.85 (s, 3H), 4.23 (dd, J = 12.5, 7.5 Hz, 1H), 4.76 (d, J = 10.6 Hz, 1H), 4.83 (dd, J = 12.3, 2.6 Hz, 1H), 5.06 (q, J= 10.2 Hz, 1H), 5.28-5.38 (m, 1H), 5.53-5.65 (m, 1H), 6.16 (d, J= 2.4 Hz, 1H), 6.42 (d, J= 9.8 Hz, 1H), 6.71 (d, J= 2.1 Hz, 1H), 6.98 (dt, J= 9.7, 5.2 Hz, 2H), 7.52 (d, J = 9.4 Hz, 1H), 9.35 (s, 1H); ¹³ C NMR (101 MHz, CDCl3): δ = 18.49, 18.64, 20.46, 20.81, 21.00, 35.58, 45.81, 52.90, 62.08, 67.40, 72.00, 77.23, 90.68, 97.95, 104.88, 110.13, 114.78, 123.92, 124.14, 125.44, 147.17, 157.73, 160.94, 170.09, 170.68, 170.98, 178.95; LRMS [C28H32N4O12] (m/z): (+ve ion mode) 639.1 [M+Na]'.

IE2076-11

[0170] Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-(3-cyano-5-methoxy-2H- indazol-l-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-D-glyce ro-D-galacto-non-2- enonate (IE2076-11).

[0171] The compound was prepared according to the general procedure from IE889-89 and 5-methoxy-2 -nitrobenzaldehyde, and the product was purified by silica gel chromatography using hexane/EtOAc (1:2) to yield product IE2076-11 in 68% yield (over 2 steps). ¹ H NMR (400 MHz, CDCl3): δ = 0.78 (d, J= 6.9 Hz, 3H), 0.93 (d, J= 6.7 Hz, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.13-2.18 (m, 1H), 3.85 (s, 3H), 3.87 (s, 3H), 4.20 (dd, J= 12.5, 6.8 Hz, IH), 4.70 (td, J= 11.4, 10.3, 4.5 Hz, 2H), 4.87 (q, J = 10.1 Hz, IH), 5.36 (ddd, J= 6.8, 5.3, 2.7 Hz, IH), 5.50 (dd, J= 5.4, 1.8 Hz, IH), 5.95 (d, J= 9.7 Hz, IH), 6.09 (d, J= 2.5 Hz, IH), 6.36 (d, J= 10.0 Hz, IH), 6.79 (d, J= 2.1 Hz, IH), 7.03 (dd, J = 9.5, 2.2 Hz, IH), 7.58 (dd, J = 9.5, 0.7 Hz, IH); LRMS [C29H34N4O12] (m/z): (+ve ion mode) 653.2 [M+Na]'.

IE2076-16

[0172] Methyl 7,8,9-Tri-O-acetyl-2,6-anhydro-4-(5-bromo-3-cyano-2H-indazol - l-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-D-glycero-D-gal acto -non-2-enonate (IE2076-16).

[0173] The compound was prepared according to the general procedure from IE889-89 and 5-bromo-2-nitrobenzaldehyde, and the product was purified by silica gel chromatography using hexane/EtOAc (1: 1) to yield product IE2076-16 in 66% yield (over 2 steps). ¹ HNMR (400 MHz, CDCl3): δ = 0.82 (d, J= 6.8 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 2.17 (dd, J= 5.7, 2.0 Hz, 1H), 3.85 (s, 3H), 4.20 (dd, J= 12.5, 6.6 Hz, 1H), 4.65-4.75 (m, 2H), 4.82 (q, J= 10.0 Hz, 1H), 5.36 (td, J= 6.1, 2.5 Hz, 1H), 5.49 (dd, J= 5.5, 1.7 Hz, 1H), 5.76 (d, J = 9.6 Hz, 1H), 6.07 (d, J= 2.5 Hz, 1H), 6.38 (d, J= 9.9 Hz, 1H), 7.42 (dd, J= 9.2, 1.7 Hz, 1H), 7.59 (d, J= 9.3 Hz, 1H), 7.82-7.86 (m, IH); ¹³ CNMR(101 MHz, CDCl3): δ= 18.82, 19.46, 20.66, 20.81, 20.94, 35.65, 45.17, 52.73, 55.22, 62.13, 67.56, 71.41, 73.20, 108.39, 109.61, 111.56, 121.72, 131.68, 132.92, 145.04, 161.56, 169.81, 170.37, 177.00; LRMS [C28H31BrN4O11] (m/z): (+ve ion mode) 703.1 [M+Na]'.

IE2076-45

[0174] 2,6-Anhydro-4-(3-cyano-5-hydroxy-2H-indazol-l-oxide-2-yl)-3, 4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-45).

[0175] To a solution of protected N-oxide IE2076-3 (40 mg, 0.065 mmol) in acetonitrile (2 mL) cooled to 0 °C was added 10 drops of LiOH (IM) while stirring. Stirring was maintained in the ice bath for Ih, and then the solution was then acidified with Amberlite® IR-120 (H+) resin (to pH = 5). The acid resin was then filtered and washed with methanol (10 mL). The combined filtrate and washings were then concentrated under vacuum and the crude residue purified by silica gel chromatography using EtOAc/MeOH/H2O (7:2: 1) as a solvent system to yield pure IE2076-45 (77% yield). ¹ H NMR (400 MHz, CD3OD): δ = 0.82 (d, J= 6.8 Hz, 3H), 0.94 (d, J= 6.8 Hz, 3H), 2.28 (dt, J = 13.6, 7.0 Hz, 1H), 3.62 (dd, J= 9.4, 1.1 Hz, 1H), 3.67 (dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.93 (dq, J = 9.0, 2.8 Hz, 1H), 4.63 (d, J =

10.9 Hz, 1H), 5.75 (s, 1H), 6.35 (d, J= 10.0 Hz, 1H), 6.77-6.85 (m, 1H), 7.05 (dd, J = 9.4, 2.1 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H); LRMS [C21H24N4O9] (m/z): (+ve ion mode) 499.1 [M+Na] ⁺ .

IE2076-47

[0176] 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-l-oxide-2-yl)-3,4, 5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-47).

[0177] The deprotection of IE2076-16 to give IE2076-47 followed a similar procedure to that employed for the synthesis of IE2076-45. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (9:2: 1) as a solvent system. The final deprotected product IE2076-47 was obtained in 70% yield. ¹ H NMR (400 MHz, CD3OD): δ = 0.87 (d, J= 6.9 Hz, 3H), 1.03 (d, J= 6.9 Hz, 3H), 2.28 (p, J =

6.9 Hz, 1H), 3.48 (d, J= 9.3 Hz, 1H), 3.61-3.67 (m, 1H), 3.82 (dd, J= 11.5, 3.0 Hz, 1H), 3.89 (ddd, J= 9.2, 5.4, 2.9 Hz, 1H), 4.54-4.64 (m, 1H), 4.79 (s, 2H), 5.72 (s, 1H), 7.09 (d, J= 8.7 Hz, 1H), 7.39 (d, J= 2.1 Hz, 1H), 7.56 (dd, J= 8.8, 2.2 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ = 18.09, 18.36, 34.90, 54.00, 63.58, 68.62, 70.07, 75.11, 79.09, 101.23, 110.44, 112.50, 113.89, 115.44, 127.77, 137.91, 142.58, 147.93, 150.94, 168.10, 179.16; LRMS [C21H23BrN ₄ O ₈ ] (m/z): (+ve ion mode) 562.8 [M+Na] ⁺ .

IE2076-12

[0178] 2,6-Anhydro-4-(3-cyano-5-hydroxy-2H-indazol-2-yl)-3,4,5-trid eoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-12). [0179] The indazole N-oxide IE2076-3 was reduced according to the general procedure using zinc dust, and then deprotected using LiOH solution. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (7:2: 1) as a solvent system. The final deprotected product IE2076-12 was obtained in 61% yield. ¹ H NMR (400 MHz, D2O): δ = 0.90 (d, J= 6.9 Hz, 3H), 0.97 (d, J= 6.9 Hz, 3H), 2.42 (p, J= 6.9 Hz, 1H), 3.63-3.72 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz, 1H), 4.03 (ddd, J = 9.4, 6.3, 2.6 Hz, 1H), 4.55-4.69 (m, 2H), 5.57-5.66 (m, 1H), 5.94 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 9.3, 2.3 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ= 18.25, 18.55, 35.04, 48.19, 61.61, 68.24, 69.81, 75.25, 97.35, 103.01, 112.57, 118.78, 127.92, 129.34, 143.01, 150.15, 158.61, 164.81, 168.91, 180.34; LRMS [C2iH23N ₄ NaO ₈ ] (m/z): (+ve ion mode) 483.1 [M+H] ⁺ .

IE2076-14

[0180] 2,6-Anhydro-4-(3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-14).

[0181] The indazole N-oxide IE1963-114 was reduced according to the general procedure using zinc dust, and then deprotected using LiOH solution. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (7:2: 1) as a solvent system. The final deprotected product IE2076-14 was obtained in 55% yield. ¹ H NMR (400 MHz, D ₂ O): δ = 0.86 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.42 (p, J= 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.67 (d, J = 7.8 Hz, 2H), 5.73-5.82 (m, 1H), 5.99 (d, J= 2.3 Hz, 1H), 7.42-7.50 (m, 1H), 7.52-7.59 (m, 1H), 7.82-7.89 (m, 2H); ¹³ C NMR (101 MHz, D ₂ O):5 = 18.16, 18.54, 48.33, 62.63, 63.05, 68.22, 69.77, 75.23, 102.40, 107.73, 110.87, 117.95, 118.36, 125.51, 126.30, 128.36, 147.77, 150.47, 168.77, 180.30; LRMS [C21H23N4NaO7] (m/z): (+ve ion mode) 467.1 [M+H] ⁺ .

IE2076-17 [0182] 2,6-Anhydro-4-(6-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideo xy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-17).

[0183] The indazole N-oxide IE2076-2 was reduced according to the general procedure using zinc dust, and then deprotected using LiOH solution. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (9:2: 1) as a solvent system. The final deprotected product IE2076-17 was obtained in 57% yield. ¹ H NMR (400 MHz, D ₂ O):5 = 0.86 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.41 (p, J= 6.9 Hz, 1H), 3.63-3.72 (m, 2H), 3.92 (dd, J= 12.0, 2.7 Hz, 1H), 4.04 (ddd, J= 9.4, 6.3, 2.7 Hz, 1H), 4.66 (d, J= 8.5 Hz, 2H), 5.72-5.80 (m, 1H), 5.99 (d, J= 2.2 Hz, 1H), 7.53 (dd, J= 9.0, 1.6 Hz, 1H), 7.76 (dd, J= 8.9, 0.8 Hz, 1H), 8.08 (dd, J= 1.5, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, D ₂ O): δ = 18.19, 18.53, 34.94, 48.27, 62.92, 63.04, 68.21, 69.75, 75.21, 102.11, 108.40, 110.28, 119.91, 120.37, 121.73, 124.09, 129.72, 148.26, 150.58, 168.69, 180.33; LRMS [C2iH ₂ 3BrN ₄ O7] (m/z): (+ve ion mode) 547.0 [M+H] ⁺ .

IE2076-37

[0184] 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideo xy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-37).

[0185] The indazole N-oxide IE2076-16 was reduced according to the general procedure using zinc dust, and then deprotected using LiOH solution. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (9:2: 1) as a solvent system. The final deprotected product IE2076-37 was obtained in 53% yield. ¹ H NMR (400 MHz, DMSO-d6): δ = 0.76 (d, J= 6.8 Hz, 3H), 0.84 (d, J= 6.9 Hz, 3H), 2.21 (p, J= 6.9 Hz, 1H), 3.36-3.44 (m, 2H), 3.62-3.67 (m, 2H), 4.32-4.40 (m, 1H), 4.48 (d, J = 11.1 Hz, 1H), 5.54 (d, J = 2.1 Hz, 1H), 5.63 (dd, J = 9.1, 2.2 Hz, 1H), 6.72 (s, 1H), 7.52 (dd,J= 9.2, 1.8 Hz, 1H), 7.84 (d,J= 9.1 Hz, 1H), 7.98-8.10 (m, 1H); ¹³ C NMR (101 MHz, DMSO-d6): δ = 19.45, 19.60, 34.75, 48.76, 63.24, 63.83, 68.62, 70.35, 75.10, 100.01, 107.12, 110.60, 119.41, 120.78, 121.50, 126.44, 131.15, 146.17, 152.61, 165.71, 177.29; LRMS [C2iH23BrN ₄ O ₇ ] (m/z): (+ve ion mode) 523.2 [M+H] ⁺ . IE2076-48

[0186] 2,6-Anhydro-3,4,5-trideoxy-5-isobutyramido-4-(5-methoxy-3-cy ano-2H- indazoI-2-yI)-D-glycero-D-galacto-non-2-enonic acid (IE2076-48).

[0187] The indazole N-oxide IE2076-11 was reduced according to the general procedure using zinc dust, and then deprotected using LiOH solution. The deprotected product was purified by silica gel chromatography using EtOAc/MeOH/H2O (7:2: 1) as a solvent system. The final deprotected product IE2076-48 was obtained in 62% yield. ¹ H NMR (400 MHz, D ₂ O): δ = 0.87 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.42 (p, J= 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.91 (s, 4H), 4.04 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.59-4.70 (m, 2H), 5.63-5.76 (m, 1H), 5.98 (d, J= 2.2 Hz, 1H), 7.11-7.25 (m, 2H), 7.74 (dd, J = 9.3, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ = 18.21, 18.55, 34.98, 48.23, 55.63, 62.37, 63.05, 68.22, 69.77, 75.24, 95.52, 102.51, 111.19, 119.48, 122.66, 126.70, 144.42, 150.40, 157.77, 168.79, 180.26; LRMS [C22H ₂ 5N4NaO ₈ ] (m/z): (+ve ion mode) 497.1 [M+H] ⁺ .

RP2066-28

[0188] 2,6-Anhydro-4-(5-carboxy-3-cyano-2H-indazol-2-yl)-3,4,5-trid eoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (RP2066-28).

[0189] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 3-formyl-4-nitrobenzoate (46 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1), yielded the deprotected indazole RP2066-28 in 8% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.62-3.75 (m, 2H), 3.93 (dd, J = 12.0, 2.8 Hz, 1H), 4.04 (ddd, J = 10.5, 5.2, 2.0 Hz, 1H), 4.62-4.73 (m, 2H), 5.78-5.86 (m, 1H), 6.02 (d, J = 2.2 Hz, 1H), 7.87 (dd, J = 9.0, 1.0 Hz, 1H), 7.98 (dd, J = 9.1, 1.6 Hz, 1H), 8.42-8.48 (m, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.18, 18.54, 34.94, 48.38, 62.89, 63.04, 68.20, 69.77, 75.23, 102.32, 110.34, 117.92, 121.14, 124.83, 128.14, 131.42, 148.75, 150.42, 168.60, 172.51, 172.58, 180.34; LRMS [C22H24N4O9] (m/z): (-ve ion mode) 487.1 [M-H]’.

RP2066-29

[0190] 2,6-Anhydro-4-(3-cyano-5-fluoro-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (RP2066-29).

[0191] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole RP2066-29 in 22% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.87 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz, 1H), 4.04 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.59-4.71 (m, 2H), 5.70-5.80 (m, 1H), 5.98 (d, J = 2.2 Hz, 1H), 7.36 (td, J= 9.4, 2.5 Hz, 1H), 7.50 (dd, J= 8.7, 2.4 Hz, 1H), 7.87 (dd, J = 9.4, 4.4 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.16, 18.55, 34.95, 48.31, 62.81, 63.04, 68.21, 69.76, 75.21, 101.69 (d, J = 26.4 Hz), 102.24, 110.58, 119.71 (d, J = 29.1 Hz), 120.59 (d, J= 10.2 Hz), 125.53, 125.66, 125.60 (d,J= 12.9 Hz), 145.18, 150.52, 159.50, 161.94, 168.72, 180.30; LRMS [C21H23FN4O7] (m/z): (+ve ion mode) 461.1 [M-H]’.

RP2066-30

[0192] 2,6-Anhydro-4-(3-cyano-4-fluoro-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (RP2066-30).

[0193] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 2-fluoro-6-nitrobenzaldehyde (37 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole RP2066-30 in 5% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.90 (d, J= 6.9 Hz, 3H), 0.97 (d, J= 6.9 Hz, 3H), 2.44 (p, J = 6.9 Hz, 1H), 3.66-3.72 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.61-4.69 (m, 3H), 5.79 (dd, J = 9.5, 2.3 Hz, 1H), 5.99 (d, J= 2.2 Hz, 1H), 7.13 (dd, J= 10.5, 7.6 Hz, 1H), 7.49 (ddd, J= 8.8, 7.6, 5.1 Hz, 1H), 7.68 (d, J= 8.8 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.14, 18.57, 34.97, 48.38, 62.85, 63.04, 68.21, 69.76, 75.19, 102.10, 105.56, 109.15, 109.31, 114.36, 128.72, 149.82, 150.59, 152.17, 168.70, 180.37; LRMS [C21H23FN4O7] (m/z): (+ve ion mode) 461.1 [M-H]-.

JC2040-107

[0194] 2,6-Anhydro-4-(3-cyano-6-fluoro-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2040-107) .

[0195] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole JC2040-107 in 8% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.90 (d, J= 6.9 Hz, 3H), 0.98 (d, J= 6.9 Hz, 3H), 2.35 (p, J= 6.9 Hz, 1H), 3.61 (d, J= 9.3 Hz, 1H), 3.68 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 3.1 Hz, 1H), 3.95 (ddd, J = 8.9, 5.4, 3.0 Hz, 1H), 4.66 (d, J =

11.2 Hz, 1H), 4.77 (dd, J= 11.1, 9.3 Hz, 1H), 5.79 (dd, J= 9.3, 2.2 Hz, 1H), 5.86 (d, J=

2.2 Hz, 1H), 7.10 (dd, J= 11.2, 7.5 Hz, 1H), 7.31 (td, J = 8.0, 4.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.14, 18.21, 34.94, 48.44, 63.14, 63.42, 68.57, 70.11, 75.39, 100.77, 108.20, 109.99 (d, J= 16.5 Hz), 110.07, 113.98 (d, J= 4.9 Hz), 125.85 (d, J= 6.1 Hz), 128.48 (m), 138.91 (d, J= 17.1 Hz), 151.32, 152.05, 154.60, 178.63; LRMS [C21H23FN4O7] (m/z): (+ve ion mode) 485.1 [M+Na] ⁺ .

JC2040-110 [0196] 2,6-Anhydro-4-(6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2040-110) .

[0197] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-chloro-2 -nitrobenzaldehyde (41 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole JC2040-110 in 2% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.86 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.64-3.73 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.04 (ddd, J = 9.3, 6.2, 2.6 Hz, 1H), 4.62-4.71 (m, 2H), 5.76 (dt, J = 7.5, 2.2 Hz, 1H), 5.98 (d, J= 2.3 Hz, 1H), 7.42 (dd, J= 9.0, 1.7 Hz, 1H), 7.84 (dd, J= 8.9, 0.8 Hz, 1H), 7.91 (dd, J= 1.7, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.19, 18.54, 34.94, 48.27, 62.92, 63.04, 68.21, 69.75, 75.21, 102.15, 108.37, 110.32, 117.02, 119.87, 123.93, 127.43, 133.75, 147.85, 150.56, 168.70, 180.33; LRMS [C21H23CIN4O7] (m/z): (+ve ion mode) 501.0 [M+Na] ⁺ .

JC2040-111

[0198] 2,6-Anhydro-4-(3-cyano-7-fluoro-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2040-111) .

[0199] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole JC2040-111 in 3% yield (over 4 steps). ¹ H NMR (400 MHz, D ₂ O): δ 0.87 (d, J= 6.9 Hz, 3H), 0.96 (d, J= 6.9 Hz, 3H), 2.43 (p, J = 6.9 Hz, 1H), 3.65-3.74 (m, 2H), 3.93 (dd, J = 11.9, 2.7 Hz, 1H), 4.05 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.68 (d, J= 7.5 Hz, 2H), 5.74-5.86 (m, 1H), 6.00 (d, J = 2.3 Hz, 1H), 7.23 (dd, J= 11.4, 7.6 Hz, 1H), 7.39 (td, J= 8.1, 4.3 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H); ¹³ C NMR (101 MHz, D ₂ O): δ 18.16, 18.53, 34.95, 48.32, 63.04, 63.18, 68.21, 69.76, 75.24, 102.02, 103.82, 110.34, 111.27 (d, J = 15.6 Hz), 114.53, 126.70, 138.83 (d, J= 17.3 Hz), 150.68, 151.15, 153.69, 168.70, 180.37; LRMS [C21H23FN4O7] (m/z) (+ve ion mode) 485.0 [M+Na] ⁺ .

JC2040-112

[0200] 2,6-Anhydro-4-(5-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2040-112) .

[0201] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5 -chloro-2 -nitrobenzaldehyde (41 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole JC2040-112 in 1% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.86 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.64-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.8 Hz, 1H), 4.04 (ddd, J= 9.3, 6.2, 2.7 Hz, 1H), 4.63-4.71 (m, 2H), 5.76 (d, J= 8.8 Hz, 1H), 5.99 (d, J= 2.2 Hz, 1H), 7.49 (dd, J= 9.2, 1.9 Hz, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.90 (d, J= 1.3 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.17, 18.55, 34.94, 48.31, 62.85, 63.04, 68.20, 69.75, 75.20, 102.16, 107.50, 110.39, 117.30, 119.68, 125.87, 129.54, 131.90, 146.21, 150.55, 168.70, 180.30; LRMS [C21H23CIN4O7] (m/z): (+ve ion mode) 501.0 [M+Na] ⁺ .

JC2094-3

[0202] 2,6-Anhydro-4-(4-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2094-3).

[0203] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-chloro-6-nitrobenzaldehyde (41 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole JC2094-3 in 10% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.94 (d, J= 6.9 Hz, 3H), 1.00 (d, J= 6.8 Hz, 3H), 2.38 (p, J= 6.8 Hz, 1H), 3.61 (d, J= 9.2 Hz, 1H), 3.68 (dd, J= 11.4, 5.4 Hz, 1H), 3.84 (dd, J = 11.4, 3.0 Hz, 1H), 3.95 (ddd, J = 8.7, 5.4, 2.9 Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H), 4.73 (t, J= 10.2 Hz, 1H), 5.79 (dd, J = 9.1, 2.2 Hz, 1H), 5.85 (d, J= 2.3 Hz, 1H), 7.31-7.40 (m, 2H), 7.76 (d, J= 8.0 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.15, 18.31, 34.98, 48.50, 62.70, 63.43, 68.57, 70.07, 75.33, 99.99, 101.00, 107.56, 110.30, 117.64, 123.63, 123.71, 125.05, 127.42, 148.71, 151.14, 178.62; LRMS [C21H23CIN4O7] (m/z) (+ve ion mode) 501.0 [M+Na] ⁺ .

CB2045-38

[0204] 2,6-Anhydro-4-(6-carboxy-3-cyano-2H-indazol-2-yl)-3,4,5-trid eoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-38).

[0205] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 3-formyl-4-nitrobenzoate (46 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1), yielded the deprotected indazole CB2045-38 in 12% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.85 (d, J= 6.8 Hz, 3H), 0.95 (d, J= 7.0 Hz, 3H), 2.41 (p, J = 6.9 Hz, 1H), 3.65-3.72 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.65-4.73 (m, 2H), 5.77-5.86 (m, 1H), 6.01 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 1.0 Hz, 2H), 8.31 (t, J = 1.1 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 20.75, 21.05, 37.49, 50.87, 65.52, 65.60, 70.77, 72.32, 77.78, 104.79, 113.22, 120.72, 121.63, 128.80, 129.25, 139.29, 150.05, 153.06, 171.27, 177.31, 182.90; LRMS [C22H24N4O9] (m/z): (+ve ion mode) 511.1 [M+Na] ⁺ .

CB2045-43 [0206] 2,6-Anhydro-4-(3-cyano-6-methylsulfonyl-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-43).

[0207] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-(methylsulfonyl)-2 -nitrobenzaldehyde (50 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole CB2045-43 in 9% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.86 (d, J= 6.9 Hz, 3H), 0.93 (d, J= 7.0 Hz, 3H), 2.27 (p, J= 6.7 Hz, 1H), 3.19 (s, 3H), 4.26 (dt, J= 12.6, 2.8 Hz, 1H), 4.56-4.69 (m, 4H), 5.52 (d, J= 1.7 Hz, 1H), 5.70-5.80 (m, 1H), 6.08 (d, J= 2.3 Hz, 1H), 7.83 (dd, .7= 8.9, 1.5 Hz, 1H), 8.01 (d, J= 8.7 Hz, 1H), 8.51 (d, J= 1.4 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 17.71, 18.22, 34.89, 42.72, 50.59, 61.63, 63.74, 67.39, 70.27, 75.60, 103.55, 109.43, 120.05, 120.45, 122.10, 127.16, 140.14, 146.38, 169.83, 170.08, 171.03, 178.28; LRMS [C22H26N4O9S] (m/z): (+ve ion mode) 545.0 [M+Na] ⁺ .

CB2045-44

[0208] 2,6-Anhydro-4-(3-cyano-6-trifluoromethyl-2H-indazol-2-yl)-3, 4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-44).

[0209] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-4-(trifluoromethyl)benzaldehyde (48 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole CB2045-44 in 7% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.89 (d, J= 6.8 Hz, 3H), 0.98 (d, J= 6.9 Hz, 3H), 2.35 (p, J= 6.9 Hz, 1H), 3.62 (d, J= 9.3 Hz, 1H), 3.68 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J = 8.8, 5.4, 3.0 Hz, 1H), 4.67 (d, J = 11.1 Hz, 1H), 4.76 (dd, J= 11.0, 9.2 Hz, 1H), 5.83 (dd, J= 9.3, 2.1 Hz, 1H), 5.90 (d, J= 2.2 Hz, 1H), 7.56 (dd, J = 8.9, 1.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.13, 18.23, 34.92, 48.54, 63.25, 63.38, 68.51, 70.11, 75.45, 101.24, 108.42, 109.57, 114.35, 117.10, 119.82, 120.98, 126.59, 129.00, 127.79 (d, J = 242.0 Hz), 129.32, 146.47, 167.31, 178.60; LRMS [C22H23F3N4O7] (m/z): (+ve ion mode) 535.1 [M+Na] ⁺ .

CB2045-50

[0210] 2,6-Anhydro-4-(4,5 -dichloro-3 -cyano-2H-indazol-2-yl)-3 ,4,5 -trideoxy-5 - isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-50).

[0211] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2,3-dichloro-6-nitrobenzaldehyde (48 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole CB2045-50 in 18% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.95 (d, J= 6.8 Hz, 3H), 1.00 (d, J= 6.9 Hz, 3H), 2.38 (p, J= 6.9 Hz, 1H), 3.60 (d, J= 9.4 Hz, 1H), 3.67 (dd, J= 11.3, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 9.0, 5.4, 2.9 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 4.71 (dd, J= 11.1, 9.0 Hz, 1H), 5.76 (dd, J = 9.2, 2.2 Hz, 1H), 5.84 (d, J= 2.2 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.15, 18.32, 34.97, 48.48, 63.12, 63.45, 68.60, 70.01, 75.25, 100.59, 108.02, 110.00, 118.98, 121.25, 124.25, 129.04, 129.41, 146.93, 151.39, 167.78, 178.57; LRMS [C21H22CI2N4O7] (m/z): (+ve ion mode) 537.0 [M+Na] ⁺ .

CB2045-51

[0212] 2,6-Anhydro-4-(3-cyano-2H-pyrazolo[4,3-b]pyridin-2-yl)-3,4,5 -trideoxy- 5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-51).

[0213] To a solution of protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) and 3-nitropicolinaldehyde (33 mg, 0.22 mmol) in EtOH (2 mL) was added Amberlite IR-120 resin (200 mg) followed by TMSCN (55 μL, 0.44 mmol) and the mixture was stirred at rt o/n. The reaction mixture was filtered, concentrated under vacuum and the residue was diluted with ethyl acetate and washed with water. The organic was washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was dissolved in absolute ethanol (3 mL) and to the stirred solution was added triethylamine (20 drops). The reaction mixture was stirred at rt for 2 h, then silica gel (1 g) was added to the mixture. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography using hexane:ethyl acetate (1:3) to yield the pure protected indazole-N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1), yielded the deprotected indazole CB2045-51 in 16% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.90 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 7.2 Hz, 3H), 2.36 (p, J= 6.9 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.67 (dd, J= 11.3, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J= 8.8, 5.3, 2.9 Hz, 1H), 4.66 (d, J= 11.0 Hz, 1H), 4.75 (t, J= 10.2 Hz, 1H), 5.82 (d, J= 9.1 Hz, 1H), 5.87 (s, 1H), 7.48 (dd, J= 8.8, 4.3 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.71 (d, J = 4.2 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 19.56, 19.67, 36.34, 49.94, 58.78, 64.85, 69.99, 71.41, 76.76, 102.23, 110.19, 110.54, 124.05, 129.19, 142.06, 142.64, 152.57, 152.70, 169.00, 179.99; LRMS [C20H23N5O7] (m/z): (+ve ion mode) 468.1 [M+Na] ⁺ .

IE2076-69

[0214] 2,6-Anhydro-4-(4-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideo xy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-69).

[0215] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-bromo-6-nitrobenzaldehyde (50 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-69 in 15% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.93 (d, J= 6.9 Hz, 3H), 0.97 (d, J= 7.0 Hz, 3H), 2.45 (p, J = 6.9 Hz, 1H), 3.62-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz, 1H), 4.04 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.59 (t, J = 10.2 Hz, 1H), 4.66-4.72 (m, 1H), 5.80 (dd, J= 9.3, 2.3 Hz, 1H), 6.01 (d, J= 2.1 Hz, 1H), 7.39 (dd, J= 8.8, 7.3 Hz, 1H), 7.60 (d, J= 7.3 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.18, 18.68, 35.01, 48.50, 62.66, 63.04, 68.22, 69.76, 75.15, 102.07, 110.67, 111.22, 117.61, 125.02, 128.99, 129.48, 148.18, 150.60, 168.72, 180.26; LRMS [C2iH23BrN ₄ O ₇ ] (m/z): (+ve ion mode) 547.0 [M+Na] ⁺ .

IE2076-78

[0216] 2,6-Anhydro-4-(5-bromo-3-cyano-6-fluoro-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-78).

[0217] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-bromo-4-fluoro-2-nitrobenzaldehyde (55 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-78 in 21% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.58 (dd, J = 9.4, 1.0 Hz, 1H), 3.66 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.93 (ddd, J = 9.6, 5.5, 2.9 Hz, 1H), 4.60-4.67 (m, 1H), 4.72 (dd, J = 11.1, 9.1 Hz, 1H), 5.73 (dd, J = 92, 2.2 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 7.63 (d,J = 9.0 Hz, 1H), 8.13 (d, J= 6.5 Hz, 1H); ¹³ CNMR (101 MHz, CD3OD): 5 18.19, 18.26, 34.93, 48.42, 63.19, 63.50, 68.65, 69.96, 75.26, 100.59, 103.36 (d, J = 262 Hz), 109.45, 109.98 (d, J = 26.5 Hz), 122.84, 123.14, 146.70 (d, J = 12.2 Hz), 151.42, 157.59 (d, J= 246.5 Hz), 167.79, 178.59; LRMS [C2iH22BrFN ₄ O ₇ ] (m/z): (+ve ion mode) 565.1 [M+Na] ⁺ .

IE2076-80 [0218] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-80).

[0219] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-bromo-4-chloro-2-nitrobenzaldehyde (58 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-80 in 26% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 6.9 Hz, 3H), 2.35 (p, J= 6.9 Hz, 1H), 3.59 (dd, J= 9.6, 0.9 Hz, 1H), 3.66 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.4, 2.9 Hz, 1H), 3.90-3.97 (m, 1H), 4.64 (d, J= 11.0 Hz, 1H), 4.72 (dd, J= 11.1, 9.1 Hz, 1H), 5.74 (dd, J = 9.2, 2.2 Hz, 1H), 5.82 (d, J= 2.2 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.18, 18.25, 34.92, 48.45, 63.33, 63.50, 68.65, 69.95, 75.26, 100.47, 107.40, 109.38, 119.58, 119.82, 122.82, 124.86, 133.01, 146.85, 151.47, 167.76, 178.53; LRMS [C2iH22BrClN ₄ O7] (m/z): (+ve ion mode) 581.0 [M+Na] ⁺ .

IE2076-92

[0220] 2,6-Anhydro-4-(3-cyano-2H-benzo [g] indazol-2-yl)-3 ,4,5 -trideoxy-5 - isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-92).

[0221] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with l-nitro-2 -naphthaldehyde (44 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-92 in 22% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.87 (d, J= 6.9 Hz, 3H), 0.96 (d, J= 6.9 Hz, 3H), 2.34 (p, J = 6.9 Hz, 1H), 3.58-3.72 (m, 2H), 3.86 (dd, J = 11.5, 2.9 Hz, 1H), 3.96 (ddd, J= 9.5, 5.5, 2.9 Hz, 1H), 4.68 (d, J= 11.1 Hz, 1H), 4.76-4.81 (m, 1H), 5.80 (dd, J= 9.4, 2.3 Hz, 1H), 5.91 (d, J= 2.2 Hz, 1H), 7.57-7.70 (m, 4H), 7.88-7.94 (m, 1H), 8.57 (dd, J = 13, 1.9 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.21, 34.97, 48.49, 62.18, 63.55, 68.75, 70.00, 75.45, 101.34, 108.13, 110.20, 115.20, 122.05, 123.63, 125.17, 127.24, 127.30, 127.65, 128.40, 132.43, 145.62, 151.20, 168.01, 178.67; LRMS [C25H26N4O7] (m/z): (+ve ion mode) 517.2 [M+Na] ⁺ .

IE2076-97

[0222] 2,6-Anhydro-4-(3-cyano-5,7-dichloro-2H-indazol-2-yl)-3,4,5-t rideoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-97).

[0223] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3, 5 -dichloro-2 -nitrobenzaldehyde (48 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yileded the deprotected indazole IE2076-97 in 18% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.9 Hz, 3H), 0.98 (d, J= 6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.60 (dd, J= 9.4, 1.0 Hz, 1H), 3.67 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 9.5, 5.4, 2.9 Hz, 1H), 4.63-4.69 (m, 1H), 4.75 (dd, J= 11.1, 9.3 Hz, 1H), 5.78 (dd, J= 9.4, 2.2 Hz, 1H), 5.86 (d, J = 2.2 Hz, 1H), 7.50 (d, J= 1.7 Hz, 1H), 7.76 (d, J= 1.7 Hz, 1H); ¹³ CNMR (101 MHz, CD3OD): 8 18.23, 34.94, 48.39, 63.48, 63.77, 68.63, 69.99, 75.36, 100.38, 108.35, 109.17, 116.03, 125.52, 126.80, 127.31, 130.95, 143.87, 151.56, 167.72, 178.64; LRMS [C21H22CI2N4O7] (m/z): (+ve ion mode) 535.1 [M+Na] ⁺ .

IE2076-98

[0224] 2,6-Anhydro-4-(3,5 -dicyano-2H-indazol-2-yl)-3 ,4,5 -trideoxy-5 - isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-98).

[0225] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3-formyl-4-nitrobenzonitrile (39 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N- oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-98 in 20% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.90 (d, J= 6.9 Hz, 3H), 0.98 (d, J= 6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.59 (dd, J= 9.3, 1.0 Hz, 1H), 3.66 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J= 9.5, 5.5, 2.8 Hz, 1H), 4.63 ? 4.68 (m, 2H), 4.75 (dd, J= 11.1, 9.0 Hz, 2H), 5.77-5.85 (m, 2H), 7.60 (dd, J = 9.0, 1.5 Hz, 1H), 7.98 (dd, J = 9.0, 1.0 Hz, 1H), 8.36 (t, J = 1.2 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.17, 18.24, 34.91, 48.51, 63.49, 63.59, 68.63, 69.97, 75.28, 100.42, 108.83, 109.16, 109.46, 118.25, 120.35, 124.35, 125.71, 127.72, 147.89, 151.55, 167.75, 178.57; LRMS [C22H23N5O7] (m/z): (+ve ion mode) 492.2 [M+Na] ⁺ .

IE2076-112

[0226] 2,6-Anhydro-4-(3-cyano-5-trifluoromethyl-2H-indazol-2-yl)-3, 4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-112).

[0227] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-5-(trifluoromethyl)benzaldehyde (48 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-112 in 23% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.90 (d, J= 6.8 Hz, 3H), 0.98 (d, J= 7.0 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.60 (dd, J= 9.5, 1.0 Hz, 1H), 3.67 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J= 11.5, 2.8 Hz, 1H), 3.94 (ddd, J= 9.5, 5.5, 2.9 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.76 (dd, J= 11.1, 9.3 Hz, 1H), 5.82 (dd, J= 9.3, 2.2 Hz, 1H), 5.85 (d, J = 2.2 Hz, 1H), 7.62 (dd, J = 9.2, 1.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 8.13-8.18 (m, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.15, 18.23, 34.93, 48.50, 63.37, 63.48, 68.63, 69.98, 75.35, 100.73, 109.38, 116.78 (d, J = 5.2 Hz), 120.23, 122.75 (d, J = 3.4 Hz), 124.11, 125.36 (d, J= 40.2 Hz), 126.77, 127.26 (q, J= 32.3 Hz), 127.74, 148.27, 151.33, 167.64, 178.59; LRMS [C22H23F3N4O7] (m/z): (+ve ion mode) 535.2 [M+Na] ⁺ . IE2124-9

[0228] 2,6-Anhydro-4-(5-bromo-3-cyano-6-methoxy-2H-indazol-2-yl)-3, 4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-9).

[0229] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5 -bromo-4-methoxy-2 -nitrobenzaldehyde (60 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2124-9 in 22% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 5.7 Hz, 3H), 2.34 (dd, J = 13.9, 6.5 Hz, 1H), 3.58 (d, J = 9.5 Hz, 1H), 3.63-3.73 (m, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.94 (s, 4H), 4.63 (d, J = 11.1 Hz, 1H), 4.68-4.76 (m, 1H), 5.68 (d, J = 9.3 Hz, 1H), 5.82 (s, 1H), 7.22 (s, 1H), 7.98 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.21, 18.26, 34.96, 48.38, 55.56, 62.37, 63.51, 68.67, 69.98, 75.37, 96.96, 101.27, 106.70, 109.86, 114.90, 121.19, 121.67, 148.11, 150.98, 155.40, 167.64, 178.59; LRMS [C22H ₂ 5BrN4O ₈ ] (m/z): (+ve ion mode) 577.1 [M+Na] ⁺ .

IE2124-14

[0230] 2,6-Anhydro-4-(3-cyano-5 ,7-dibromo-2H-indazol-2-yl)-3 ,4,5 -trideoxy-5 - isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-14).

[0231] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3, 5 -dibromo-2 -nitrobenzaldehyde (68 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2124-14 in 12% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.9 Hz, 3H), 0.99 (d, J= 7.0 Hz, 3H), 2.35 (p, J= 6.8 Hz, 1H), 3.59 (d, J= 9.5 Hz, 1H), 3.64-3.71 (m, 1H), 3.84 (dd, J = 11.4, 3.0 Hz, 1H), 3.93 (ddd, J = 8.9, 5.3, 2.9 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 4.68-4.75 (m, 1H), 5.74 (dd, J= 9.2, 2.3 Hz, 1H), 5.83 (d, J= 2.2 Hz, 1H), 8.19 (s, 1H), 8.25 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.19, 18.25, 34.93, 48.47, 63.27, 63.47, 68.61, 70.00, 75.33, 100.77, 105.51, 107.44, 109.37, 121.61, 122.49, 123.14, 123.32, 125.27, 147.22, 151.20, 178.55; LRMS [C2iH ₂ 2Br ₂ N4O7] (m/z): (+ve ion mode) 625.1 [M+Na] ⁺ .

IE2124-51

[0232] 2,6-Anhydro-4-(3-cyano-5,6-dibromo-2H-indazol-2-yl)-3,4,5-tr ideoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-51).

[0233] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3, 4-dibromo-2 -nitrobenzaldehyde (68 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc dust and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H ₂ O (10:2: 1), yielded the deprotected indazole IE2124-51 in 12% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.91 (d, J= 6.8 Hz, 3H), 0.99 (d, J= 7.0 Hz, 3H), 2.35 (p, J= 6.8 Hz, 1H), 3.59 (d, J= 9.6 Hz, 1H), 3.64-3.70 (m, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.93 (ddd, J= 9.0, 5.4, 2.8 Hz, 1H), 4.64 (d, J= 11.1 Hz, 1H), 4.72 (dd, J= 11.1, 9.2 Hz, 1H), 5.73 (dd, J = 9.2, 2.2 Hz, 1H), 5.81 (d, J= 2.1 Hz, 1H), 8.19 (s, 1H), 8.25 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.18, 18.25, 34.93, 48.45, 63.31, 63.48, 68.63, 69.98, 75.27, 100.52, 107.42, 109.37, 121.59, 122.49, 123.13, 123.31, 124.09, 125.27, 147.21, 151.42, 178.55; LRMS [C ₂ iH ₂₂ Br ₂ N ₄ O7] (m/z): (+ve ion mode) 625.2 [M+Na] ⁺ .

IE2076-76

[0234] 2,6-Anhydro-4-(3-cyano-7-phenyl-2H-indazol-2-yl)-3,4,5-tride oxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2076-76). [0235] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-[l,l'-biphenyl]-3-carbaldehyde (50 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2076-76 in 18% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.83 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.31 (p, J = 6.9 Hz, 1H), 3.61 (dd, J = 9.3, 1.1 Hz, 1H), 3.66 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 9.5, 5.5, 2.9 Hz, 1H), 4.64-4.70 (m, 1H), 4.82 (d, J= 9.8 Hz, 1H), 5.85 (dd, J= 9.5, 2.3 Hz, 1H), 5.89 (d, J = 2.3 Hz, 1H), 7.33-7.39 (m, 1H), 7.44 (dd, J = 8.3, 7.0 Hz, 3H), 7.56 (dd, J = 7.1, 1.0 Hz, 1H), 7.71 (dd, J = 8.4, 1.0 Hz, 1H), 7.94-8.00 (m, 2H); ¹³ C NMR (101 MHz, CD3OD): δ 18.17, 18.19, 34.93, 48.44, 62.58, 63.50, 68.67, 70.05, 75.60, 101.71, 107.22, 110.26, 116.76, 125.39, 125.92, 126.94, 127.55, 127.96, 128.79, 132.33, 137.16, 146.21, 150.66, 167.54, 178.76; LRMS [C27H28N4O7] (m/z): (+ve ion mode) 543.1 [M+Na] ⁺ .

IE2124-1

[0236] 2,6-Anhydro-4-(3-cyano-7 -(2-fluorophenyl)-2H-indazol-2-yl)-3 ,4,5 - trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-1).

[0237] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2'-fluoro-2-nitro-[l,l'-biphenyl]-3-carbaldehyde (54 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2124-1 in 16% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.83 (d, J= 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.30 (p, J= 6.9 Hz, 1H), 3.59 (dd, J= 9.3, 1.1 Hz, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.83 (dd, J= 11.5, 2.9 Hz, 1H), 3.92 (ddd, J = 9.4, 5.4, 2.9 Hz, 1H), 4.65 (d, J= 11.0 Hz, 1H), 4.78 (dd, J= 11.1, 9.5 Hz, 1H), 5.83 (dd, J= 9.6, 2.2 Hz, 1H), 5.90 (d, J= 2.2 Hz, 1H), 7.16-7.28 (m, 2H), 7.37-7.47 (m, 2H), 7.49 (dt, J= 7.0, 1.4 Hz, 1H), 7.74-7.82 (m, 2H); ¹³ C NMR (101 MHz, CD3OD): δ 18.17, 18.18, 34.92, 48.40, 62.65, 63.47, 68.61, 70.02, 75.69, 101.98, 107.18, 110.12, 115.24, 115.46, 117.55, 123.67 (d, J= 3.6 Hz), 124.80 (d, J= 14.2 Hz), 125.45, 126.67 (d, J= 13.5 Hz), 127.82 (d, J= 3.8 Hz), 129.45 (d, J= 8.2 Hz), 132.21 (d, J= 3.1 Hz), 146.33, 150.30, 158.67, 161.13, 167.12, 178.81; LRMS [C27H27FN4O7] (m/z): (+ve ion mode) 561.2 [M+Na] ⁺ .

IE2124-5

[0238] 2,6-Anhydro-4-(3-cyano-7-(2,3-difluorophenyl)-2H-indazol-2-y l)-3,4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-5).

[0239] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2%'-difluoro-2-nitro-| 1. 1 '-biphenyl |-3-carbaldchydc (58 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2124-5 in 13% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.83 (d, J= 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.30 (p, J= 6.9 Hz, 1H), 3.59 (dd, J= 9.4, 1.1 Hz, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.83 (dd, J= 11.5, 2.9 Hz, 1H), 3.92 (ddd, J = 9.4, 5.4, 2.9 Hz, 1H), 4.65 (d, J= 11.0 Hz, 1H), 4.78 (dd, J= 11.1, 9.4 Hz, 1H), 5.82 (dd, J= 9.6, 2.3 Hz, 1H), 5.87 (d, J= 2.3 Hz, 1H), 7.19-7.34 (m, 2H), 7.46 (dd, J= 8.3, 7.0 Hz, 1H), 7.52 (dt, J = 7.0, 1.4 Hz, 1H), 7.57 (ddt, J= 7.8, 6.2, 1.8 Hz, 1H), 7.81 (dd, J= 8.4, 1.1 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.16, 34.91, 48.38, 62.86, 63.49, 68.64, 70.02, 75.58, 101.44, 107.39, 110.01, 116.29 (d, J= 17.5 Hz), 118.21, 123.74, 123.79 (dd, J= 7.3, 4.7 Hz), 123.85, 125.39, 125.47 (d, J = 2.9 Hz), 126.55, 127.10 (d, J = 3.9 Hz), 127.22, 127.95 (d, J= 3.7 Hz), 146.06, 146.70 (d, J= 13.2 Hz), 149.40 (dd, J= 43.3, 13.1 Hz), 150.77, 152.06 (d, J= 13.4 Hz), 167.48, 178.73; LRMS [C27H26F2N4O7] (m/z): (+ve ion mode) 579.1 [M+Na] ⁺ .

IE2124-6 [0240] 2,6-Anhydro-4-(3-cyano-7-(3-methoxyphenyl)-2H-indazol-2-yl)- 3,4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (IE2124-6).

[0241] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3'-methoxy-2-nitro-[l,r-biphenyl]-3-carbaldehyde (56 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole IE2124-6 in 2% yield (over 4 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.86 (d, J= 6.9 Hz, 3H), 0.97 (d, J= 6.9 Hz, 3H), 2.33 (p, J= 6.9 Hz, 1H), 3.61 (d, J= 9.3 Hz, 1H), 3.67 (dd, J= 11.4, 5.4 Hz, 1H), 3.85 (m, 4H), 3.94 (ddd, J= 8.9, 5.4, 2.8 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.80 (d, J= 10.2 Hz, 1H), 5.85 (dd, J = 9.5, 2.2 Hz, 1H), 5.96 (d, J= 2.2 Hz, 1H), 6.92 (dd, J= 8.2, 2.6 Hz, 1H), 7.34 (t, J= 7.9 Hz, 1H), 7.40-7.51 (m, 2H), 7.60 (d, J= 7.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.74-7.79 (m, 1H); ¹³ CNMR (101 MHz, CD3OD): δ 18.18, 18.20, 34.96, 48.64, 54.54, 62.31, 63.45, 68.58, 70.01, 75.67, 102.81, 107.40, 110.28, 114.03, 114.08, 116.85, 120.46, 125.25, 125.95, 126.82, 128.92, 132.00, 138.28, 146.28, 149.75, 159.66, 178.76; LRMS [C28H30N4O8] (m/z): (+ve ion mode) 573.3 [M+Na] ⁺ .

JC2094-64

[0242] 2,6-Anhydro-4-(3 -cyano-7-(3 -hydroxyphenyl)-2H-indazol-2-yl)-3 ,4,5 - trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2094-64).

[0243] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3'-hydroxy-2-nitro-[l,l'-biphenyl]-3-carbaldehyde (53 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1), yielded the deprotected indazole JC2094-64 in 7% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.74 (d, J= 6.8 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 2.35 (p, J= 6.9 Hz, 1H), 3.67 (dd, J= 12.2, 7.3 Hz, 2H), 3.92 (d, J= 11.4 Hz, 1H), 4.04 (dd, J= 9.0, 5.5 Hz, 1H), 4.67 (d, J = 11.0 Hz, 2H), 5.75 (d, J= 9.7 Hz, 1H), 5.98 (d, J= 2.4 Hz, 1H), 6.97 (d, J= 6.5 Hz, 1H), 7.36-7.50 (m, 4H), 7.54 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H); ¹³ C NMR (101 MHz, D ₂ O): δ 18.18, 18.43, 30.20, 34.93, 48.05, 63.05, 68.24, 69.75, 75.37, 102.34, 107.44, 110.83, 115.24, 115.72, 117.66, 121.03, 126.46, 126.67, 126.93, 130.19, 131.09, 138.46, 145.89, 150.38, 155.60, 168.74, 180.37; LRMS [C27H28N4O8] (m/z): (+ve ion mode) 559.2 [M+Na] ⁺ .

JC2094-65

[0244] 2,6-Anhydro-4-(3-cyano-7-(2-hydroxyphenyl)-2H-indazol-2-yl)- 3,4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2094-65).

[0245] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2'-hydroxy-2-nitro-[l,l'-biphenyl]-3-carbaldehyde (53 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1), yielded the deprotected indazole JC2094-65 in 9% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.75 (d, J= 6.9 Hz, 3H), 0.89 (d, J = 6.9 Hz, 3H), 2.32 (p, J= 6.8 Hz, 1H), 3.61-3.72 (m, 2H), 3.91 (dd, J= 12.1, 2.7 Hz, 1H), 4.02 (ddd, J= 9.2, 6.2, 2.6 Hz, 1H), 4.64 (d, J= 10.9 Hz, 1H), 4.69-4.75 (m, 1H), 5.69 (dd, J = 9.3, 2.2 Hz, 1H), 5.95 (d, J= 2.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 7.33-7.51 (m, 4H), 7.80 (d, J = 7.8 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 18.34, 18.40, 34.91, 47.93, 63.05, 63.26, 68.21, 69.76, 75.35, 102.24, 110.76, 116.23, 117.81, 120.72, 124.43, 126.39, 126.56, 128.56, 128.72, 129.99, 131.53, 146.47, 150.40, 152.96, 168.60, 180.39; LRMS [C27H28N4O8] (m/z): (+ve ion mode) 559.2 [M+Na] ⁺ .

CB2045-78

[0246] 2,6-Anhydro-4-(3-cyano-7-(3,5-difluorophenyl)-2H-indazol-2-y l)-3,4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-78).

[0247] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3\5'-difluoro-2-nitro-| 1. 1 '-biphenyl |-3-carbaldchydc (58 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1), yielded the deprotected indazole CB2045-78 in 11% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.64-0.80 (m, 3H), 0.83-0.96 (m, 3H), 2.28-2.44 (m, 1H), 3.61-3.78 (m, 2H), 3.93 (dd,J= 10.9, 1.7 Hz, 1H), 4.00-4.11 (m, 1H), 4.61-4.71 (m, 2H), 5.70-5.84 (m, 1H), 5.92-6.06 (m, 1H), 7.02 (t, J= 9.9 Hz, 1H), 7.43- 7.56 (m, 3H), 7.57-7.68 (m, 1H), 7.80-7.93 (m, 1H); LRMS [C27H26F2N4O7] (m/z): (+ve ion mode) 579.2 [M+Na] ⁺ .

CB2045-83

[0248] 2,6-Anhydro-4-(3-cyano-7-(pyrimidin-5-yl)-2H-indazol-2-yl)-3 ,4,5- trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (CB2045-83).

[0249] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-3-(pyrimidin-5-yl)benzaldehyde (50 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using iron powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1), yielded the deprotected indazole CB2045-83 in 9% yield (over 4 steps). ¹ H NMR (400 MHz, D2O): δ 0.74 (d, J= 7.0 Hz, 3H), 0.89 (d, J= 6.9 Hz, 3H), 2.36 (p, J = 6.9 Hz, 1H), 3.65-3.73 (m, 2H), 3.92 (dd, J = 11.9, 2.7 Hz, 1H), 4.04 (ddd, J= 9.3, 6.3, 2.7 Hz, 1H), 4.65-4.70 (m, 1H), 4.74 (s, 1H), 5.80 (dd, J= 9.5, 2.3 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.5, 7.1 Hz, 1H), 7.71 (dd, J= 7.2, 1.0 Hz, 1H), 7.94 (dd, J= 8.6, 1.0 Hz, 1H), 9.15 (s, 1H), 9.31 (s, 2H); ¹³ CNMR (101 MHz, D2O): 8 18.18, 18.41, 34.91, 48.14, 63.05, 63.26, 68.22, 69.75, 75.32, 102.15, 110.54, 119.66, 123.88, 126.43, 126.72, 127.58, 131.31, 145.45, 150.56, 155.63, 156.26, 156.37, 168.71, 180.36; LRMS [C25H26N6O7] (m/z): (+ve ion mode) 523.2 [M+H] ⁺ .

JC2094-118 [0250] 2,6-Anhydro-4-(3-cyano-5-chloro-7-(2-difluorophenyl)-2H-inda zol-2-yl)-

3,4,5-trideoxy-5-isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2094-118).

[0251] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-chloro-2'-fluoro-2-nitro-[l, 1'-biphenyl]-3-carbaldehyde (62 mg, 0.22 mmol), according to the general procedure to give the protected indazole N-oxide. Reduction of the protected indazole N-oxide using zinc powder and subsequent deprotection according to the general procedures, followed by purification by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1), yielded the deprotected indazole JC2094-118 in 7% yield (over 4 steps). ‘H NMR (400 MHz, CD3OD): δ 0.94 (d, J= 6.7 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 2.38 (p, J= 6.7 Hz, 1H), 3.66 (dd, J= 19.7, 8.2 Hz, 2H), 3.85 (d, J = 11.0 Hz, 1H), 3.96 (d, J = 8.9 Hz, 1H), 4.68 (t, J = 14.5 Hz, 2H), 5.81 (d, J= 8.9 Hz, 1H), 5.90 (s, 1H), 7.20 (t, J= 9.0 Hz, 1H), 7.28 (t, J= 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.47 (q, J = 6.8 Hz, 1H), 7.79 (s, 1H), 7.94 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 18.21, 18.29, 34.98, 48.54, 62.96, 63.40, 68.53, 70.14, 75.47, 101.45, 107.25, 109.73, 114.95, 115.17, 117.77, 121.30, 123.88, 123.92, 125.43, 126.64, 126.80, 130.19, 130.27, 131.34, 131.37, 131.88, 135.17, 146.42, 158.57, 161.02, 178.72; LRMS [C27H26CIFN4O7] (m/z): (+ve ion mode) 595.1 [M+Na] ⁺ .

Procedure for the formation of methyl 7,8,9-tri-0-acetyl-5-amino-2,6-anhydro-4-(5- bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-D-gly cero-D-galacto -non- 2-enonate (IE2124-20).

[0252] To a solution of protected 4-azido-5-NHBoc-Neu2en (1.0 g, 1.95 mmol) in MeOH/LLO (4: 1, 20 mL) was added zinc powder (0.38 g, 3 eq, 5.85 mmol) and ammonium chloride (0.52 g, 5 eq, 9.75 mmol). The mixture was stirred at rt for 1 h, then filtered over celite. The combined filtrate and washing were concentrated under vacuum and purified by silica gel chromatography using hexane:ethyl acetate (1: 1) to yield pure 4-amino-5-NHBoc-Neu2en (IE927-82, 840 mg, 88% yield).

[0253] To a solution of IE927-82 (800 mg, 1.64 mmol) and 5-bromo-4-chloro-2- nitrobenzaldehyde (430 mg, 1.64 mmol) in glacial acetic acid (10 mL) was added TMSCN (225 μL, 1.8 mmol) and the mixture was stirred at rt o/n. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was dissolved in absolute ethanol (20 mL) and to the stirred solution was added triethylamine (0.5 mL). The reaction mixture was stirred at rt for 2 h, then silica gel (2.0 g) was added to the mixture. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography using hexane:ethyl acetate (3:2) to yield the pure protected indazole-N-oxide.

[0254] To a solution of the protected indazole-N-oxide in McOH/HiO (4: 1, 10 mL) was added zinc powder (3 equivalents) and ammonium chloride (5 equivalents). The mixture was stirred at rt for 1 h, then silica gel (2 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using hexane: acetone (3:2) to yield the reduced protected indazole IE2124-19 at 58% yield (over 3 steps).

[0255] To a solution of the indazole IE2124-19 (100 mg, 0.14 mmol) in anh. DCM

(3 mL) under argon was added TFA (0.4 mL, 5.6 mmol) dropwise while stirring. The reaction was stirred at rt for 1 :30 h, then diluted with DCM (20 mL) and washed with sat aq NaHCO3 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to yield the 5-amino derivative IE2124-20 (92% yield), which was of sufficient purity to be used in the following 5-N-functionalisation step without further purification. ¹ H NMR (400 MHz, CD3OD): δ 2.04 (s, 3H), 2.09 (s, 3H), 2.14 (s, 3H), 3.78-3.83 (s, 3H), 4.31 (dd, J = 12.6, 5.3 Hz, 1H), 4.37 (dd, J = 10.5, 1.3 Hz, 1H), 4.61 (dd, J = 12.6, 2.4 Hz, 1H), 5.48-5.58 (m, 2H), 5.68 (dd, J= 7.5, 1.3 Hz, 1H), 6.07 (d, J= 2.3 Hz, 1H), 8.06 (s, 1H), 8.23 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): 8 20.54, 20.61, 20.78, 51.21, 53.00, 63.12, 65.36, 69.24, 71.16, 79.93, 108.68, 110.79, 120.70, 121.28, 124.55, 125.92, 134.76, 146.81, 148.48, 163.12, 171.48, 172.34, 172.42; LRMS [C24H24BrClN ₄ O9] (m/z): (+ve ion mode) 651.1 [M+Na] ⁺ .

Procedure for the formation of methyl 7,8,9-tri-O-acetyl-5-amino-2,6-anhydro-4-(5- bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-D-glycero-D-ga lacto -non-2-enonate (JC2094-88)

[0256] To a solution of 4-amino-5-NHBoc-Neu2en (IE927-82; 800 mg, 1.64 mmol) and 5 -bromo-2 -nitrobenzaldehyde (380 mg, 1.64 mmol) in glacial acetic acid (10 mL) was added TMSCN (225 μL, 1.8 mmol) and the mixture was stirred at rt o/n. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was dissolved in absolute ethanol (20 mL) and to the stirred solution was added triethylamine (0.5 mL). The reaction mixture was stirred at rt for 2 h, then silica gel (2.0 g) was added to the mixture. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography using hexane: ethyl acetate (3:2) to yield the pure protected indazole-N-oxide.

[0257] To a solution of the protected indazole-N-oxide in Me0H/H20 (4: 1, 10 mL) was added zinc powder (3 equivalents) and ammonium chloride (5 equivalents). The mixture was stirred at rt for 1 h, then silica gel (2 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using hexane: acetone (3:2) to yield the reduced protected indazole JC2094-86 in 46% yield (over 3 steps). [0258] To a solution of the reduced indazole (100 mg, 0.144 mmol) in anh. DCM (3 mL) under argon was added TFA (0.41 mL, 5.76 mmol) dropwise while stirring. The reaction was stirred at rt for 1 :30 h, then diluted with DCM (20 mL) and washed with sat aq NaHCO3 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to yield 5 -amino derivative JC2094-88 (quantitative yield), which was of sufficient purity to be used in the following 5 -N- functionalisation step without further purification. ¹ H NMR (400 MHz, CDCl3): δ 2.07 (s, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 3.45 (s, 1H), 3.81 (s, 4H), 4.24 (dt, J= 12.7, 6.4 Hz, 1H), 4.32 (dd, J = 12.7, 4.6 Hz, 1H), 4.60 (dd, J= 12.8, 2.1 Hz, 1H), 5.38-5.54 (m, 2H), 5.59 (d, J= 7.2 Hz, 1H), 6.04 (d, J = 2.3 Hz, 1H), 7.48 (dd, J= 9.2, 1.8 Hz, 1H), 7.68-7.72 (m, 1H), 7.94 (dd, J= 1.8, 0.8 Hz, 1H); LRMS [C24H2 ₅ BrN ₄ O9] (m/z): (+ve ion mode) 616.9 [M+Na] ⁺ .

General procedure for 5- N-acylation of protected 5-amino-4-indazole:

[0259] To a solution of the protected 5-amino-4-indazole-Neu2en derivative (0.08 mmol) in anhydous DCM (3 mL) was added diisopropylethylamine (70 μL, 0.4 mmol) followed by the appropriate acid chloride (0.24 mmol). The reaction mixture was stirred under argon at rt o/n, then silica gel ( 1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using a suitable solvent system.

CB2045-102

[0260] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5- cyclopentanecarboxamido-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2045-102).

[0261] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclopentanecarbonyl chloride (29 μL. 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate :MeOH:H2O (10:2: 1), yielded the deprotected indazole CB2045-102 in 42% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 1.32 (dd, J = 14.4, 8.6 Hz, 1H), 1.45-1.62 (m, 5H), 1.74 (tdd, J= 21.1, 14.9, 8.3 Hz, 2H), 2.54 (p, J= 7.8 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.68 (dd, J= 11.4, 5.4 Hz, 1H), 3.84 (dd, J= 11.7, 3.0 Hz, 1H), 3.94 (dt, J= 8.8, 3.9 Hz, 1H), 4.63 (d, J= 11.0 Hz, 2H), 5.74 (t, J= 7.9 Hz, 1H), 5.83 (s, 1H), 8.05 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 26.82, 31.51, 46.50, 49.98, 64.28, 64.81, 69.94, 71.45, 76.73, 102.11, 110.77, 111.10, 120.87, 121.26, 125.23, 126.22, 128.10, 134.47, 148.25, 169.08, 179.18; LRMS [C23H24BrClN ₄ O7] (m/z): (+ve ion mode) 607.1 [M+Na] ⁺ .

CB2045-103

[0262] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5- cyclobutanecarboxamido-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2045-103).

[0263] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclobutanecarbonyl chloride (28 μL, 0.24 mmol) according to the general procedure for N-acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1) yielded the deprotected indazole CB2045-103 in 38% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 1.70 (dddt, J= 10.3, 8.2, 5.3, 2.9 Hz, 1H), 1.86-1.94 (m, 2H), 1.97-2.04 (m, 1H), 2.04-2.11 (m, 2H), 2.95-3.06 (m, 1H), 3.57 (d, J= 9.3 Hz, 1H), 3.67 (dd, J= 11.5, 5.4 Hz, 1H), 3.83 (dd, J= 11.5, 2.9 Hz, 1H), 3.93 (ddd, J= 9.5, 5.4, 2.9 Hz, 1H), 4.60-4.73 (m, 2H), 5.71 (dd, J = 9.1, 2.3 Hz, 1H), 5.82 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 17.48, 24.34, 24.95, 39.30, 48.65, 63.29, 63.43, 68.54, 69.99, 75.27, 100.56, 107.48, 109.33, 119.58, 119.84, 122.84, 124.83, 133.04, 146.89, 151.43, 167.76, 176.21; LRMS [C22H22BrClN4O7] (m/z): (+ve ion mode) 593.3 [M+Na] ⁺ .

CB2045-104 [0264] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-(2-hydroxyacetamido)-D-glycero-D-galacto -non-2-enonic acid (CB2045- 104).

[0265] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with acetoxyacetyl chloride (26 μL. 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1) yielded the deprotected indazole CB2045-104 in 34% yield (over 2 steps). ‘H NMR (400 MHz, CD3OD): δ 3.20 (q, J= 7.3 Hz, 1H), 3.62 (d, J= 9.4 Hz, 1H), 3.68 (dd, J= 11.5, 5.5 Hz, 1H), 3.82 (q,J= 2.3, 1.7 Hz, 1H), 3.85-3.89 (m, 1H), 3.92-3.96 (m, 1H), 4.75 (d, J= 6.1 Hz, 2H), 5.84 (d, J= 2.2 Hz, 1H), 5.87-5.93 (m, 1H), 8.05 (s, 1H), 8.20 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.98, 62.45, 64.10, 64.88, 69.92, 71.40, 76.62, 102.42, 108.89, 110.56, 120.93, 121.18, 124.41, 126.29, 134.45, 148.30, 152.58, 175.50, 177.66; LRMS [C19H18BrC1N4O8] (m/z): (+ve ion mode) 567.2 [M+Na] ⁺ .

CB2045-110

[0266] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5- cyclopropanecarboxamido-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2045-110).

[0267] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclopropanecarbonyl chloride (22 μL, 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1) yielded the deprotected indazole CB2045-110 in 39% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.36-0.46 (m, 1H), 0.62-0.77 (m, 3H), 1.50 (tt, J = 8.2, 3.8 Hz, 1H), 3.60-3.73 (m, 2H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.94 (ddd, J= 9.8, 5.4, 2.8 Hz, 1H), 4.62-4.72 (m, 2H), 5.70-5.78 (m, 1H), 5.82 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 7.40, 7.77, 14.91, 50.45, 64.77, 64.90, 70.01, 71.39, 76.67, 101.92, 110.68, 121.04, 121.17, 124.16, 126.23, 134.38, 148.33, 152.84, 176.39; LRMS [C2iH2oBrClN ₄ 07] (m/z): (+ve ion mode) 579.0 [M+Na] ⁺ .

CB2045-111

[0268] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-propionamido-D-glycero-D-galacto -non-2-enonic acid (CB2045-111).

[0269] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with propionyl chloride (21 μL, 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole CB2045-111 in 50% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.96 (t, J= 7.6 Hz, 3H), 2. 12 (q, J= 7.7 Hz, 2H), 3.60 (d, J = 9.3 Hz, 1H), 3.67 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.4, 2.9 Hz, 1H), 3.94 (ddd, J= 9.3, 5.6, 2.9 Hz, 1H), 4.66 (dd, J= 7.9, 2.0 Hz, 2H), 5.73 (dt, J= 7.9, 1.9 Hz, 1H), 5.82 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 10.08, 30.15, 50.12, 64.65, 64.86, 69.97, 71.36, 76.63, 101.99, 108.86, 110.76, 120.95, 121.23, 124.32, 126.26, 134.46, 148.29, 152.84, 169.15, 176.89; LRMS [C20H20BrC1N4O7] (m/z): (+ve ion mode) 567.0 [M+Na] ⁺ .

CB2045-112

[0270] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-(2-phenylacetamido)-D-glycero-D-galacto -non-2-enonic acid (CB2045-112).

[0271] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with phenylacetyl chloride (32 μL. 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole CB2045-112 in 37% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.36 (s, 2H), 3.57 (d, J= 9.4 Hz, 1H), 3.63 (dd, J= 11.2, 5.4 Hz, 1H), 3.83 (dd, J= 11.6, 3.1 Hz, 1H), 3.93 (ddd, J= 9.0, 5.5, 2.9 Hz, 1H), 4.62 (d, J= 11.1 Hz, 1H), 4.77 (dd, J= 11.1, 9.5 Hz, 1H), 5.71 (dd, J= 9.5, 2.3 Hz, 1H), 5.78 (d, J= 2.3 Hz, 1H), 7.00-7.06 (m, 2H), 7.09-7.17 (m, 3H), 7.94 (s, 1H), 8.02 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 43.88, 49.94, 64.25, 65.00, 70.10, 71.37, 76.78, 97.46, 101.95, 108.90, 110.66, 120.98, 124.55, 125.99, 127.77, 129.40, 129.92, 134.27, 136.25, 148.15, 152.66, 169.05, 173.93; LRMS [C25H22BrClN ₄ O7] (m/z) (+ve ion mode) 629.0 [M+Na] ⁺ .

IE2076-107

[0272] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-trifluoroacetamido-D-glycero-D-galacto -non-2-enonic acid (IE2076-107).

[0273] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trifluoroacetic anhydride (33 μL, 0.24 mmol) according to the general procedure for N-acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2076-107 in 42% yield

(over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.55 (dd, J = 9.6, 1.2 Hz, 1H), 3.68 (dd, J = 11.6, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.8 Hz, 1H), 3.95 (ddd, J = 9.6, 5.4, 2.8 Hz, 1H), 4.72 (dd, J= 11.0, 1.2 Hz, 1H), 4.79 (d, J= 9.3 Hz, 1H), 5.78 (dd, J = 9.2, 2.2 Hz, 1H), 5.84 (d, J= 2.2 Hz, 1H), 8.07 (s, 1H), 8.20 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): 8 49.33, 62.69, 63.36, 68.58, 69.83, 74.79, 100.28, 107.29, 108.94, 115.62 (d, J= 287.2

Hz), 119.53, 120.08, 122.87, 124.89, 133.28, 147.00, 151.60, 157.13, 167.41; LRMS [C19H15BrC1F3N4O7] (m/z): (+ve ion mode) 607.0 [M+Na] ⁺ .

IE2124-27 [0274] 2,6-Anhydro-5-acetamido-4-(5-bromo-6-chloro-3-cyano-2H-indaz ol-2- yl)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124-27).

[0275] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with acetic anhydride (23 μL, 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-27 in 51% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 1.85 (s, 3H), 3.61 (d, J= 9.5 Hz, 1H), 3.68 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J= 9.7, 5.4, 2.8 Hz, 1H), 4.63 (d, J= 6.5 Hz, 2H), 5.73 (dt, J= 5.7, 2.4 Hz, 1H), 5.82 (d, J= 2.2 Hz, 1H), 8.06 (s, 1H), 8.20 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 21.19, 48.96, 63.16, 63.48, 68.59, 69.96, 75.18, 100.67, 107.48, 109.29, 119.55, 119.79, 122.95, 124.87, 133.04, 146.93, 151.37, 167.73, 171.75; LRMS [C19H18BrC1N4O7] (m/z): (+ve ion mode) 552.9 [M+Na] ⁺ .

IE2124-28

[0276] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-(thiophene-2-carboxamido)-D-glycero-D-galacto -non-2-enonic acid

(IE2124-28).

[0277] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with thiophene-2 -carbonyl chloride (26 μL, 0.24 mmol) according to the general procedure for N-acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-28 in 49% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.61-3.74 (m, 2H), 3.82 (dd, J = 11.6, 2.9 Hz, 1H), 3.97 (ddd, J= 9.4, 5.1, 2.8 Hz, 1H), 4.79 (d, J= 11.2 Hz, 2H), 5.87 (h, J= 2.3 Hz, 2H), 7.08 (dd, J= 5.0, 3.8 Hz, 1H), 7.61 (dd, J = 5.0, 1.1 Hz, 1H), 7.65 (dd, J = 3.9, 1.1 Hz, 1H), 8.04 (s, 1H), 8.11 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.35, 63.02, 63.31, 68.53, 69.97, 75.39, 100.72, 107.61, 109.16, 119.50, 119.85, 122.86, 124.72, 127.36, 128.87, 130.94, 133.12, 137.76, 146.96, 151.47, 162.70, 167.63; LRMS [C22H18BrC1N4O7S] (m/z): (+ve ion mode) 620.7 [M+Na] ⁺ .

IE2124-30 [0278] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-(isoxazole-5-carboxamido)-D-glycero-D-galacto -non-2-enonic acid (IE2124-30).

[0279] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with isoxazole-5 -carbonyl chloride (23 μL, 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-30 in 44% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.61-3.73 (m, 2H), 3.82 (dd, J = 11.5, 2.9 Hz, 1H), 3.96 (ddd, J= 9.5, 5.2, 2.8 Hz, 1H), 4.81 (dd, J= 11.1, 1.1 Hz, 2H), 5.84-5.97 (m, 2H), 6.84 (d, J = 1.9 Hz, 1H), 8.05 (s, 1H), 8.15 (s, 1H), 8.46 (d, J= 1.9 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.11, 62.88, 63.33, 68.53, 69.94, 75.21, 101.01, 106.27, 107.40, 109.07, 119.52, 119.93, 122.92, 124.89, 133.16, 146.96, 150.90, 151.16, 156.43, 161.87, 167.21; LRMS [C21H17BrC1N5O8] (m/z): (+ve ion mode) 606.1 [M+Na] ⁺ .

IE2124-31

[0280] 2,6-Anhydro-5-benzamido-4-(5-bromo-6-chloro-3-cyano-2H-indaz ol-2- yl)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124-31).

[0281] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with benzoyl chloride (28 μL, 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-31 in 38% yield (over 2 steps). ¹ HNMR (400 MHz, CD3OD): δ 3.69 (ddd, J= 9.7, 5.6, 3.1 Hz, 2H), 3.83 (dd, J= 11.6, 2.9 Hz, 1H), 3.97 (ddd, J= 9.4, 5.1, 2.9 Hz, 1H), 4.79-4.83 (m, 1H), 4.93 (dd, J = 11.2, 8.9 Hz, 1H), 5.87-5.94 (m, 2H), 7.37-7.43 (m, 2H), 7.47-7.54 (m, 1H), 7.65-7.71 (m, 2H), 8.04 (s, 1H), 8.13 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.42, 63.06, 63.32, 68.56, 69.98, 75.40, 100.87, 107.53, 109.25, 119.50, 119.86, 122.87, 124.77, 127.02, 128.06, 128.09, 131.57, 133.12, 133.37, 146.95, 151.38, 167.59, 168.68;

LRMS [C24H2oBrClN ₄ 07] (m/z) (+ve ion mode) 615.2 [M+Na] ⁺ .

IE2124-34

[0282] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-pivalamido-D-glycero-D-galacto -non-2-enonic acid (IE2124-34).

[0283] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with pivaloyl chloride (30 μL, 0.24 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-34 in 45% yield (over 2 steps). ¹ H NMR (400 MHz, D ₂ O): δ 1.04 (s, 9H), 3.57 (d, J= 9.3 Hz, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 8.9, 5.4, 2.9 Hz, 1H), 4.70 (d, J = 11.1 Hz, 1H), 4.77 (ddd, J = 11.3, 6.7, 2.3 Hz, 1H), 5.82 (dt, J = 9.4, 1.6 Hz, 1H), 5.88 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 8.19 (s, 1H); ¹³ C NMR (101 MHz, D2O): δ 26.24, 38.34, 48.79, 62.84, 63.44, 68.55, 70.02, 75.54, 101.62, 107.42, 109.44, 119.55, 119.89, 122.83, 124.79, 133.09, 146.85, 150.63, 167.01, 179.98; LRMS [C22H24BrC1N4O7] (m/z): (+ve ion mode) 595.1 [M+Na] ⁺ .

IE2124-36

[0284] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-pentafluoropropionamido-D-glycero-D-galacto -non-2-enonic acid (IE2124- 36).

[0285] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with pentafluoropropionyl chloride (44 mg, 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-36 in 37% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.51-3.56 (m, 1H), 3.66 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.95 (ddd, J= 9.5, 5.5, 2.8 Hz, 1H), 4.72 (dd, J= 11.0, 1.2 Hz, 1H), 4.92 (dd, J= 11.0, 9.4 Hz, 1H), 5.79 (dd, J= 9.5, 2.2 Hz, 1H), 5.82 (d, J= 2.2 Hz, 1H), 8.05 (s, 1H), 8.20 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.19, 62.72, 63.41, 68.66, 69.90, 74.83, 100.26, 107.23, 108.91, 118.50 (d, J= 193.7 Hz), 119.53, 120.07, 122.82, 124.91, 126.17 (d, J= 133.1 Hz), 133.25, 146.93, 151.52, 153.73 (d, J= 39.9 Hz), 157.76; LRMS [C2oHi ₅ BrClF ₅ N407] (m/z): (+ve ion mode) 657.0 [M+Na] ⁺ .

IE2124-39

[0286] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( 2,2,2- trichloroacetamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124- 39).

[0287] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trichloroacetyl chloride (27 μL, 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-39 in 53% yield (over 2 steps). ¹ H NMR (400 MHz, D2O): δ 3.62-3.75 (m, 2H), 3.92 (dd, J= 12.1, 2.7 Hz, 1H), 4.05 (ddd, J= 9.3, 6.3, 2.6 Hz, 1H), 4.60-4.68 (m, 1H), 4.73-4.76 (m, 1H), 5.88 (dd, J= 9.6, 2.3 Hz, 1H), 6.04 (d, J= 2.2 Hz, 1H), 7.99 (s, 1H), 8.17 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 50.58, 61.79, 63.32, 68.48, 70.02, 76.06, 105.43, 107.81, 109.12, 119.55, 120.26, 122.94, 124.75, 133.49, 147.06, 147.11, 162.51, 163.72; LRMS [C19H15BrCl4N4O7] (m/z): (+ve ion mode) 656.8 [M+Na] ⁺ .

IE2124-43

[0288] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4 ,5- trideoxy-5-(furane-2-carboxamido)-D-glycero-D-galacto-non-2- enonic acid (IE2124- 43). [0289] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trichloroacetyl chloride (30 μL, 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-43 in 40% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.67 (dd, J = 10.9, 5.6 Hz, 2H), 3.82 (dd, J= 11.6, 2.8 Hz, 1H), 3.96 (ddd, J= 9.0, 5.3, 2.9 Hz, 1H), 4.78 (d, J= 11.0 Hz, 2H), 5.82-5.93 (m, 2H), 6.53 (dd, J= 3.4, 1.8 Hz, 1H), 6.92-7.02 (m, 1H), 7.63 (d, J= 1.8 Hz, 1H), 8.04 (s, 1H), 8.13 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 48.67, 63.08, 63.36, 68.56, 70.01, 75.37, 100.78, 107.49, 109.05, 111.60, 114.63, 119.51, 119.81, 122.90, 124.81, 133.03, 133.07, 145.26, 146.73, 146.92, 159.05; LRMS [C22H18BrC1N4O8] (m/z) (+ve ion mode) 605.2 [M+Na] ⁺ .

IE2124-46

[0290] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( 2,2- dichloroacetamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124- 46).

[0291] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with dichloroacetyl chloride (23 μL, 0.24 mmol) according to the general procedure for N-acylation. to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-46 in 34% yield (over 2 steps). ‘H NMR (400 MHz, CD3OD): δ 3.58-3.70 (m, 2H), 3.85 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J = 9.0, 5.6, 2.9 Hz, 1H), 4.72 (d, J= 11.1 Hz, 1H), 4.76-4.82 (m, 1H), 5.77-5.88 (m, 1H), 6.08 (s, 1H), 8.05 (s, 1H), 8.18 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.35, 62.59, 63.47, 65.78, 68.69, 70.06, 75.07, 100.68, 107.68, 109.23, 119.59, 119.94, 122.90, 124.79, 133.15, 146.98, 151.17, 165.13, 167.44; LRMS [C19H16BrCl3N4O7 ] (m/z) (+ve ion mode) 621.3 [M+Na] ⁺ .

IE2124-82 [0292] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( 2-bromo-

2,2-difluoroacetamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124- 82).

[0293] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with 2-bromo-2,2-difluoroacetyl chloride (45 mg, 0.24 mmol) according to the general procedure for N-acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-82 in 36% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.59 (dd, J= 9.4, 1.2 Hz, 1H), 3.67 (dd, J= 11.5, 5.5 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.95 (ddd, J= 9.5, 5.4, 2.8 Hz, 1H), 4.72 (dd, J= 11.0, 1.2 Hz, 1H), 4.81 (s, 1H), 5.77- 5.87 (m, 2H), 8.07 (s, 1H), 8.21 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 49.28, 62.58, 63.40, 68.67, 69.96, 74.96, 100.41, 109.10, 109.15 (d, J = 330.7 Hz), 113.93, 119.59, 120.06, 122.92, 124.86, 133.26, 147.00, 148.20, 160.48 (t, J= 28.0 Hz), 167.41; LRMS [C19H15Br2ClF2N4O7] (m/z) (+ve ion mode) 666.9 [M+Na] ⁺ .

CB2160-3

[0294] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( 2- ethylbutanamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2160-3).

[0295] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (40 mg, 0.064 mmol) in anh. DCM (2 mL) with triethylamine (45 μL, 0.32 mmol) was reacted with 2- ethylbutyryl chloride (18 μL, 0.13 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole CB2160-3 in 48% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.42 (m, 3H), 0.71 - 0.81 (m, 3H), 1.18 - 1.48 (m, 5H), 3.54 - 3.68 (m, 2H), 3.82 (dd, J = 11.4, 2.9 Hz, 1H), 3.89-3.93 (m, 1H), 4.11-4.17 (m, 1H), 4.29 - 4.39 (m, 1H), 4.51 (d, J = 11.1 Hz, 1H), 5.73 (s, 1H), 8.01 (s, 1H), 8.15 (s, 1H); ¹³ C NMR (101 MHz, CD3OD) 8 12.02, 12.45, 12.59, 20.84, 26.22, 26.76, 51.77, 64.66, 65.03, 67.48, 70.16, 71.31, 77.02, 102.12, 110.66, 120.93, 121.33, 124.21, 126.28, 134.51, 148.17, 152.62, 178.90; LRMS [C23H ₂ 6BrClN ₄ O7] (ESI): m/z 609.1 [M+Na] ⁺ .

CB2160-4

[0296] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( 2,2- dimethylbutanamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2160- 4).

[0297] Protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (40 mg, 0.064 mmol) in anh. DCM (2 mL) with triethylamine (45 μL, 0.32 mmol) was reacted with 2,2- dimethylbutanoyl chloride (18 μL, 0.13 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole CB2160-4 in 42% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.47 (t, J= 7.4 Hz, 3H), 0.96 (s, 3H), 1.00 (s, 3H), 1.31- 1.37 (m, 2H), 3.54 (d, J= 9.5 Hz, 1H), 3.62 (dd, J= 11.4, 5.5 Hz, 1H), 3.8O (dd, J= 11.5, 2.9 Hz, 1H), 3.91 (m, 1H), 4.58 (d, J= 11.1 Hz, 1H), 5.77 (m, 1H), 8.01 (s, 1H), 8.15 (s, 1H), 2 protons were obscured by the solvent peak at 4.86 ppm; ¹³ C NMR (101 MHz, CD3OD) 5 8.01, 23.76, 33.10, 42.27, 48.40, 57.07, 62.98, 63.49, 68.59, 69.98, 75.49, 100.80, 107.42, 109.40, 117.51, 119.53, 119.92, 122.80, 124.80, 133.10, 146.80, 151.32, 167.76, 179.36; LRMS [C23H26BrClN4O7] (ESI): m/z 609.1 [M+Na] ⁺ .

IE2124-57

[0298] 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-5-(2,2,2- trichloroacetamido)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124- 57).

[0299] Protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) in anh. DCM (3 mL) with diisopropylethylamine (74 μL, 0.42 mmol) was reacted with 2,2,2-trichloroacetyl chloride (28 μL, 0.25 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-57 in 56% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.60-3.71 (m, 2H), 3.85 (dd, J= 11.5, 2.9 Hz, 1H), 3.96 (ddd, J= 9.4, 5.6, 2.9 Hz, 1H), 4.80 (dd, J= 11.1, 1.1 Hz, 2H), 5.90 (d, J= 8.6 Hz, 2H), 7.52 (dd, J= 9.2, 1.8 Hz, 1H), 7.75 (d, J= 9.2 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 50.52, 61.99, 63.46, 68.80, 70.04, 75.22, 101.56, 107.10, 109.50, 119.55, 120.25, 120.50, 126.49, 130.94, 146.56, 150.58, 162.35, 166.89; LRMS [C19H16BrCl3N4O7 ] (m/z): (+ve ion mode) 622.9 [M+Na] ⁺ .

IE2124-75

[0300] 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-5-pivalamido -3,4,5- trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124-75).

[0301] Protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) in anh. DCM (3 mL) with diisopropylethylamine (74 μL, 0.42 mmol) was reacted with pivaloyl chloride (32 μL, 0.25 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-75 in 44% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 1.03 (s, 9H), 3.54-3.60 (m, 1H), 3.66 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 8.9, 5.5, 2.9 Hz, 1H), 4.68 (dd, J= 11.0, 1.1 Hz, 1H), 4.75-4.83 (m, 1H), 5.82 (h, J= 2.4 Hz, 2H), 7.51 (dd, J= 9.2, 1.8 Hz, 1H), 7.74 (dd, J = 92, 0.8 Hz, 1H), 7.95 (dd, J= 1.8, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): 8 26.23, 48.74, 62.61, 63.47, 68.62, 70.04, 75.40, 100.99, 106.87, 109.80, 119.38, 120.17, 120.46, 126.50, 130.76, 146.37, 151.26, 167.73, 179.96; LRMS [C22H25BrN4O7] (m/z): (+ve ion mode) 561.1 [M+Na] ⁺ .

IE2124-76

[0302] 2,6-Anhydro-4-(5-bromo-3 -cyano-2H-indazol-2-yl)-3 ,4,5 -trideoxy-5 -(3 - methylbutanamido)-D-glycero-D-galacto -non-2-enonic acid (IE2124-76). [0303] Protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) in anh. DCM (3 mL) with diisopropylethylamine (74 μL, 0.42 mmol) was reacted with isovaleryl chloride (30 mg, 0.25 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-76 in 40% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.71 (d, J = 6.5 Hz, 3H), 0.75 (d, J= 6.6 Hz, 3H), 1.84 (dp, J= 13.7, 6.8 Hz, 1H), 1.90-2.03 (m, 2H), 3.61 (dd, J = 9.5, 1.1 Hz, 1H), 3.65 (dd, J = 11.5, 5.6 Hz, 1H), 3.84 (dd, J= 11.5, 2.9 Hz, 1H), 3.94 (ddd, J= 9.5, 5.5, 2.9 Hz, 1H), 4.59 (dd, J = 11.0, 1.1 Hz, 1H), 4.77-4.82 (m, 1H), 5.74 (dd, J = 9.5, 2.2 Hz, 1H), 5.82 (d, J= 2.2 Hz, 1H), 7.51 (dd, J= 9.1, 1.8 Hz, 1H), 7.75 (dd, J = 9.2, 0.8 Hz, 1H), 7.95 (dd, J= 1.8, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 21.22, 25.71, 44.88, 48.35, 62.86, 63.56, 68.70, 69.97, 75.53, 101.17, 106.97, 109.67, 119.41, 120.21, 120.49, 126.57, 130.78, 146.42, 150.97, 167.49, 174.07; LRMS [C22H25BrN4O7] (m/z): (+ve ion mode) 561.1 [M+Na] ⁺ .

IE2124-77

[0304] Trans 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideo xy-

5-(2-methylbut-2-enamido)-D-glycero-D-galacto-non-2-enoni c acid (IE2124-77).

[0305] Protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) in anh. DCM (3 mL) with diisopropylethylamine (74 μL, 0.42 mmol) was reacted with trans-2-methylbut-2 -enoyl chloride (30 mg, 0.25 mmol) according to the general procedure for N- acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole IE2124-77 in 35% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 1.67-1.73 (m, 6H), 3.62 (d, J= 9.4 Hz, 1H), 3.66-3.72 (m, 1H), 3.83 (dd, J= 11.5, 2.9 Hz, 1H), 3.95 (ddd, J= 9.5, 5.3, 2.9 Hz, 1H), 4.70 (d, J= 11.1 Hz, 1H), 4.77 (dd, J= 11.1, 9.0 Hz, 1H), 5.82 (dd, J= 9.2, 2.3 Hz, 1H), 5.89 (d, J= 2.2 Hz, 1H), 6.29 (ddt, J= 6.9, 5.4, 3.7 Hz, 1H), 7.50 (dd, J= 9.2, 1.8 Hz, 1H), 7.75 (d,J= 9.1 Hz, 1H), 7.94 (d,J= 1.7 Hz, 1H); ¹³ CNMR (101 MHz, CD3OD): δ 10.92, 12.57, 49.03, 62.62, 63.41, 68.56, 69.99, 75.59, 101.66, 107.01, 109.65, 119.37, 120.23, 120.46, 126.48, 130.79, 131.11, 131.50, 146.47, 150.75, 167.22, 170.85; LRMS [C22H23BrN4O7] (m/z) (+ve ion mode) 559.1 [M+Na] ⁺ .

JC2094-91

[0306] 2,6-Anhydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideo xy-5- trifluoroacetamido-D-glycero-D-galacto -non-2-enonic acid (JC2094-91).

[0307] Protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) in anh. DCM (3 mL) with diisopropylethylamine (85 μL, 0.48 mmol) was reacted with trifluoroacetic anhydride (33 μL, 0.25 mmol) according to the general procedure for N-acylation, to yield the protected amide. Deprotection according to the general procedure and purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) yielded the deprotected indazole JC2094-91 in 14% yield (over 2 steps). ¹ H NMR (400 MHz, D2O): δ 3.63-3.74 (m, 2H), 3.88-3.97 (m, 1H), 4.07 (ddd, J= 9.2, 6.3, 2.7 Hz, 1H), 4.71 (q, J= 10.4, 9.2 Hz, 2H), 5.88 (dd, J= 9.3, 2.5 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 7.59 (dd, J = 9.5, 1.7 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 8.05 (d, J= 1.7 Hz, 1H); ¹³ C NMR (101 MHz, D2O): δ 49.57, 62.14, 62.99, 68.10, 69.63, 74.81, 101.90, 107.22, 109.91, 115.24 (d, J = 286.5 Hz), 119.69, 120.09, 120.72, 126.44, 132.11, 146.49, 150.90, 158.49 (d, J = 38.2 Hz), 168.39; LRMS [C19H16BrF3N4O7] (m/z): (+ve ion mode) 571.1 [M+Na] ⁺ .

IE2124-89

[0308] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-

(isobutylamino)-3,4,5-trideoxy-D-glycero-D-galacto-non-2- enonic acid (IE2124-89).

[0309] To a solution of the protected 5-amino-4-indazole-Neu2en derivative

IE2124-20 (60 mg, 0.096 mmol) in anh. DCM (3 mL) was added acetic acid (150 μL), followed by isobutyraldehyde (44 μL, 0.48 mmol) and the reaction mixture was stirred at rt for 30 min. Sodium borohydride (36 mg, 0.96 mmol) was added portionwise, and the mixture was allowed to stirr at rt o/n. The reaction mixture was filtered over celite, and the celite bed was washed with DCM (20 mL x 2). The combined filtrate and washing was washed with sat aq NaHCO3 (20 mL), then with brine solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to yield the crude product. Purification by silica gel chromatography using hexane: acetone (5:2) to yield the protected amine. To a solution of the protected amine in a acetonitrile (2 mL) at 0 °C was added LiOH solution (1.0 M) dropwise until the pH reached 13-14. The mixture was stirred at 0 °C for 2h, then silica gel (1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate :Me0H:H20 (10:2: 1) to yield the deprotected indazole IE2124-89 in 45% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 0.59 (dd, J = 8.5, 6.7 Hz, 6H), 1.20 (dtd, J= 11.0, 6.6, 5.6, 3.2 Hz, 1H), 1.95 (dd, J= 11.7, 6.5 Hz, 1H), 2.46 (dd, J= 11.6, 6.7 Hz, 1H), 3.48 (ddd, J= 10.6, 9.5, 5.1 Hz, 1H), 3.71 (dd, J= 11.5, 5.6 Hz, 1H), 3.85-3.92 (m, 2H), 3.95 (ddd, J= 8.8, 5.4, 2.8 Hz, 1H), 4.37 (d, J= 10.7 Hz, 1H), 5.53 (dd, J= 9.5, 2.1 Hz, 1H), 5.73 (d, J= 2.1 Hz, 1H), 8.06 (s, 1H), 8.22 (s, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 19.16, 19.20, 29.08, 55.23, 56.21, 63.59, 64.77, 68.80, 70.39, 77.59, 101.90, 109.63, 119.32, 119.58, 122.85, 124.41, 133.01, 146.83, 148.02, 150.42, 167.90; LRMS [C2iH24BrClN4O6] (m/z): (+ve ion mode) 545.1 [M+H] ⁺ .

IE2124-106

[0310] 2,6-Anhydro-5-(benzylamino)-4-(5-bromo-6-chloro-3-cyano-2H-i ndazol-

2-yl)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (IE2124-106).

[0311] To a solution of the protected 5-amino-4-indazole-Neu2en derivative

JC2094-88 (60 mg, 0.102 mmol) in anh. DCM (3 mL) was added acetic acid (150 μL), followed by benzaldehyde (51 μL. 0.51 mmol) and the reaction mixture was stirred at rt for 30 min. Sodium borohydride (40 mg, 1.02 mmol) was added portionwise, and the mixture was allowed to stirr at rt o/n. The reaction mixture was filtered over celite, and the celite bed was washed with DCM (20 mL x 2). The combined filtrate and washing was washed with sat aq NaHCO3 (20 mL), then with brine solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4. and concentrated under vacuum to yield the crude product. Purification by silica gel chromatography using hexane: ethylacetate (5:2) to yield the protected amine. To a solution of the protected amine in a acetonitrile (2 mL) at 0 °C was added LiOH solution (1.0 M) dropwise until the pH reached 13-14. The mixture was stirred at 0 °C for 2h, then silica gel (1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2: 1) to yield the deprotected indazole IE2124-106 in 33% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD): δ 3.40-3.54 (m, 2H), 3.71-3.81 (m, 2H), 3.93 (dd, J= 11.5, 2.2 Hz, 1H), 3.99 (s, 2H), 4.37 (d, J = 10.7 Hz, 1H), 5.40 (dd, J = 9.5, 2.1 Hz, 1H), 5.67 (d, J = 2.1 Hz, 1H), 6.69-6.78 (m, 3H), 6.81 (dd, J = 7.7, 1.9 Hz, 2H), 7.47 (dd, J = 9.1, 1.8 Hz, 1H), 7.57 (dd, J = 9.1, 0.8 Hz, 1H), 7.84 (dd, J = 1.8, 0.8 Hz, 1H); ¹³ C NMR (101 MHz, CD3OD): δ 51.07, 54.06, 63.61, 65.08, 68.74, 70.43, 78.10, 101.64, 107.29, 109.87, 118.78, 120.29, 120.42, 126.05, 126.42, 127.06, 127.89, 130.34, 140.00, 145.99, 150.79, 167.94; LRMS [C24H23BrN4O6] (m/z): (+ve ion mode) 545.1 [M+H] ⁺ .

CB2160-6

[0312] 2,6-Anhydro-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-( l- oxoisoindolin-2-yl)-3,4,5-trideoxy-D-glycero-D-galacto -non-2-enonic acid (CB2160-6).

[0313] To a solution of the amine JC2094-88 (50 mg, 0.084 mmol) and phthaldehyde (12 mg, 0.084 mmol) in ethanol (2 mL) at rt, TMSCN (22 μL, 0.17 mmol) was added dropwise, and the reaction mixture was stirred at rt for 3 h. The reaction mixture was concentrated and the residue was subjected to purification by silica gel chromatography using hexane: ethyl acetate (1: 1) to yield the protected isoindolinone. To a solution of the protected C-5 isoindolinone in acetonitrile (2 mL) at 0 °C was added LiOH solution (1.0 M) dropwise until the pH reached 13-14. The mixture was stirred at 0 °C for 2h, then silica gel (1 g) was added to the mixture and the mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2: 1) to yield the deprotected indazole CB2160-6 in 25% yield (over 2 steps). ¹ H NMR (400 MHz, CD3OD) 8 3.40 (d, J= 9.4 Hz, 1H), 3.65 (dd, J = 11.6, 5.0 Hz, 1H), 3.78 (dd, J= 11.6, 3.0 Hz, 1H), 3.97 (ddd, J= 8.9, 5.0, 3.0 Hz, 1H), 4.59 (broad s, 1H), 5.92 (s, 1H), 7.40 - 7.55 (m, 2H), 7.54 - 7.66 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.85 (s, 1H), 4 protons were obscured by the solvent peak at 4.86 ppm; ¹³ C NMR (101 MHz, CD3OD) 5 48.36, 48.57, 48.79, 49.00, 49.21, 49.28, 49.42, 49.50, 49.64, 49.71, 64.55, 71.27, 102.27, 110.40, 120.93, 121.68, 121.81, 124.35, 129.25, 132.38, 133.37, 143.60, 147.90, 152.78, 171.09; LRMS [C25H2iBrN4O7] (ESI): m/z 591.1 [M+Na] ⁺

Example 2: Biological data

Cells and Viruses

[0314] LLC-MK2 cells and MA104 cells were used for stock amplification of hPIV3 and hPIVl respectively. Cells were grown in Eagle's minimal essential medium (EMEM) supplemented with 1% Glutamine (200 mM) and 2% of fetal bovine serum (FBS) at 37 °C in a humidified atmosphere of 5% CO2. hPIV3 strain C243 was obtained from the American Type Culture Collection. hPIV3 strain CI002 and hPIVl CI002 were isolated from a clinical sample (Gold Coast University Hospital). All hPIV were propagated in cells [LLC-MK2 (hPIV3) or MA104 (hPIVl)] maintained in EMEM supplemented with 1% Glutamine (200 mM) and no FBS at 35 °C in a humidified atmosphere of 5% CO2. hPIV3 strain CI002 and all hPIVl strains also required the addition of 1.6% (v/v) of TryμLE for efficient virus proliferation. Virus-containing culture supernatant was collected 3 to 4 days post-infection, while monitoring cytopathic effects, and clarified from cell debris by centrifugation (3,000 xg. for 15 min). Virus was concentrated at least 10-time using 100 kDa Amicon Ultra filter unit (Millipore, Billerica, MA) for use in HI assays. NI assays experiments used virus that was polyethylene glycol (PEG)-precipitated and then purified as described below. Clarified hPIV supernatant was mixed with PEG6000 (8% final concentration) and NaCl (0.4M final concentration) and then incubated overnight at 4 °C under gentle agitation. PEG6000/hPIV complex was pelleted by centrifugation at 3,000 xg. for 30 min at 4 °C. The supernatant was discarded and a volume of GNTE buffer (glycine 200 mM, NaCl 200 mM, Tris-HCl 20 mM, EDTA 2 mM, pH 7.4) corresponding to at least 1:40 of the initial virus suspension volume was used to resuspend the pellet overnight at 4 °C. The virus suspension was homogenized by up and down pipetting followed by a mechanical disruption of the remaining virus aggregates using a douncer with ‘tight’ pestle. The hPIV homogenate was loaded on top of a 30-60% non-linear sucrose gradient prepared in GNTE buffer and centrifuged at 100,000 xg. for 2 h 30 min at 4 °C without brake for deceleration. The virus was concentrated at the 40-50% sucrose interface and then collected and stored at -80 °C for NI assays. hPIV Inhibitors

[0315] Each compound was provided as a lyophilised powder which was then solubilised in sterile water or DMSO to generate a 10 mM stock solution. Solutions were sonicated for 15 min to ensure complete dissolution. The stock solution was stored in an amber glass vial at -20 °C and freshly diluted in appropriate buffer before use.

Hemagglutination inhibition assay (HIA) with concentrated hPIV:

[0316] The hPIV HN inhibitors are assessed in duplicate in a U-bottom 96 well plate. Compounds are diluted in PBS as a 4X solution for each concentration tested (25 μL per well, IX final). Each dilution (25 μL) is first mixed with 50 μL of 1% human red blood cells (hRBC) then 25 μL of a 4 hemagglutination units ofhPIV3 or hPIVl dilution (1 HAU final). The plate is then incubated for 1 h at room temperature before reading the extent of hemagglutination. The hemagglutination inhibition assay (HIA) IC50 value is considered as the concentration of inhibitor that reduced the haemagglutinin binding activity (hemagglutination) by 50% compared to those of a mock-treated virus suspension and equivalent to the hemagglutination observed when 0.5 HAU of the virus is used for the assay.

Neuraminidase inhibition assay (NIA) with purified hPIV:

[0317] Viral neuraminidase inhibition (NIA) assay was conducted with purified hPIV3 in hPIV3 NIA reaction buffer (NaOAc 50 mM, CaC12 5 mM, pH 4.6) and purified hPIVl in hPIVl NIA reaction buffer (NaOAc 50 mM, CaC12 5 mM, pH 5.0). To be considered statistically relevant, the amount of purified virus used per experiment in this assay was calculated to score a maximal fluorescence signal (positive control) at least 4 to 5 times higher than the fluorescence background (negative control). Purified hPIV3, inhibitor and MUNANA were prepared and diluted in NIA Reaction Buffer. For each concentration tested, 2 μL of purified hPIV and 4 μL of 2.5X inhibitor solution (IX final) was added to each well. The plate was kept at room temperature for 20 min before 4 μL of 5 mM MUNANA (2 mM final) was added to each well. The plate was then incubated at 37 °C for 30 min with agitation (1,000 rpm). The enzymatic reaction was stopped by the addition of 50 μL of glycine buffer to each well (glycine, 0.25 M, pH 10.4). A negative control was included by the addition of MUNANA to virus and then the enzymatic reaction stopped at t = 0. Relative fluorescence (RF) from each well was measured with a Tecan M200 reader. Data were processed by background subtraction (negative control RF) and then analysed with GraphPad Prism 4 (GraphPad Software Inc., Ua Jolla, CA) to calculate IC50 values [nonlinear regression (curve fit), Dose- response - inhibition, 4 parameters logistic]. The concentration of inhibitor that reduced neuraminidase activity by 50% compared to those of a non-treated virus suspension was considered to be the NIA IC50 value.

Virus growth inhibition assay - In situ ELISA

[0318] Virus growth inhibition assay - In situ EUISA is a technique used to evaluate virus growth inhibition by measuring expression levels ofhPIV HN at the cell surface of an infected cell monolayer. The expression level is directly correlated with the ability of a non-immobilized virus to infect novel target cells. Infection was performed with 100 FFU/well ofhPIV for 1 h at 37 °C with gentle agitation every 15 min on a confluent cell monolayer [UUC-MK2 (hPIV3), MA104 (hPIVl)] seeded in a 96 well plate. Assay was performed in triplicate. Inocula were removed and replaced with respective compound dilutions. hPIV3 strain CI002 and hPIVl strain CI002 also required the addition of 1.6% (v/v) of TrypUE for efficient virus proliferation. Infected cell monolayers were kept for 36 - 40 h at 35.5 °C, 5% CO ₂ for virus proliferation. Virus was inactivated and cells were fixed by treatment with 3.7% formaldehyde in PBS for 20 min. Next, endogenous peroxidases were inactivated by treatment with 0.3% H ₂ O ₂ /PBS for 30 min at 37 °C. The cell monolayers were then incubated with mouse monoclonal IgG anti-hPIV3 HN or anti- hPIV 1 HN in 5% milk/PBS for 1 h at 37 °C. Goat anti- Mouse-IgG(H+L)-HRP conjugate in 5% milk/PBS was added for 1 h at 37 °C. BD OptEIA TMB substrate was added (100 μL), and the reaction was stopped after 3 - 5 min by addition of 1 M H ₂ SO ₄ (50 μL). Raw data was obtained by reading the absorbance of each well at 450 nm using Biorad xMark plate reader. Final values were adjusted by subtracting the absorbance of the negative control to the absorbance of each other well and the data analysed with GraphPad Prism4 to calculate IC ₅₀ values. The virus growth IC ₅₀ value was considered as the concentration of inhibitor that reduced the absorbance at 450 nm by 50%, compared to a non-treated infected cell monolayer.

Results

[0319] Table 1: Biological evaluation of example compounds for inhibition of hPIV neuraminidase activity, and of virus growth.

Example 3: Structural Biology Recombinant HN expression and purification

[0320] The HN protein was expressed using the Bac-to-Bac® baculovirus expression system (Invitrogen, Carlsbad, CA) based on a substantially modified literature procedure. Thus, the nucleotide sequence for a honeybee melittin signal peptide (HBM) was added downstream to the sequence encoding for the HN ectodomain (amino acids 125 to 572). This sequence (HBM+HN) was codon optimised for expression in Spodoptera frugiperda cells (Sf9) and ordered directly through the DNA2.0 gene synthesis service (DNA2.0, Menlo Park, CA) as a gene named HBM-HNhPIV-3opt. HBM- HNhPIV-3opt was amplified by PCR and ligated into a pFastBac/CT-TOPO® vector that provides an additional C-terminal 6-histidine tag (His-Tag) for purification and detection purposes.

[0321] The generation and amplification of recombinant baculovirus containing HBM- HNhPIV-3opt were performed according to the manufacturer's instructions. Sf9 cells (Invitrogen), cultured in Insect-XPRESS protein free insect cell medium (Lonza), were infected with high MOI of HBM-HNhPIV-3opt baculovirus. Four days post- infection the supernatant, containing recombinant HN, was collected to yield the highest protein expression. The supernatant was clarified by centrifugation (3,000 RCF for 15 min) to remove cell debris and then purified on a HisTrap excel 5 mL column (GE Healthcare life sciences, Buckinghamshire, England) following the manufacturer’s protocol. Recombinant HN was eluted with 500 mM imidazole solution and collected fractions were assessed by a neuraminidase activity (NA) assay (see below). The most active fractions were pooled and concentrated with a 10 kDa Amicon Ultra filter unit (Millipore) to a final volume of 800 μL. An additional purification step was performed that employed fast protein liquid chromatography (Amersham Biosciences) over a Superdex 75 gel filtration column (GE Healthcare) at 4 °C and 1 mL fractions were collected with a Frac-920. Protein-containing fractions, as determined by monitoring fraction collection at 280 nm, were assessed in a NA assay as well as subjected to SDS- PAGE. Purified and concentrated recombinant HN protein was stored at 4 °C.

Crystallisation, Data collection and Structure determination

[0322] All hPIV-3 HN complexes were prepared by co-crystallisation (with compounds compounds IE2076-14, IE2076-37, CB2045-50, CB2045-51, IE2076-80, IE2076-76, IE2124-1, IE2124-36, IE2124-39, IE2124-57, IE2124-75 and CB2160-6) where the 4 mg/mL hPIV3 HN protein stock solution was preincubated with a final concentration of 1.5 mM inhibitor in 0.1 M citrate buffer pH 4.6, 0.2 M (NH4)2SO4and 10% PEG 3000 for 30 min. Crystallization trials were set up as 2 μL preincubated stock solution using the hanging drop vapour diffusion method. The drop was equilibrated against a 500 μL reservoir (0.1 M citrate buffer pH 4.6, 0.2 M (NH4)2SO4 and 10% or 15% PEG 3000). The crystals were mounted in nylon loops (Hampton R63 earch) and flash frozen at 100 K in a cryoprotectant solution containing 20% glycerol in addition to the precipitant solution.

[0323] X-ray diffraction data were collected on the MX2 beamline at the Australian Synchrotron using the Blu-Ice software. The datasets were processed using XDS and scaled using Aimless in the CCP4 suite. The structure was solved by molecular replacement using Phaser and the apo hPIV3-HN model (PDB ID: 4XJQ) as template. The model was refined using Phenix.Refine, and structure validation was performed using MolProbity. Structure analyses were performed using Coot ⁶ , and PyMOL (http://www.pymol.org/; DeLano Scientific LLC).