WO2024026536A1 - Composés antiviraux et leurs utilisations - Google Patents

Composés antiviraux et leurs utilisations Download PDF

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WO2024026536A1
WO2024026536A1 PCT/AU2023/050725 AU2023050725W WO2024026536A1 WO 2024026536 A1 WO2024026536 A1 WO 2024026536A1 AU 2023050725 W AU2023050725 W AU 2023050725W WO 2024026536 A1 WO2024026536 A1 WO 2024026536A1
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ring
group
optionally substituted
alkyl
compound
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PCT/AU2023/050725
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English (en)
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Mark Von Itzstein
Ibrahim EL-DEEB
Larissa DIRR
Patrice GUILLON
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Griffith University
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Priority claimed from AU2022902183A external-priority patent/AU2022902183A0/en
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Publication of WO2024026536A1 publication Critical patent/WO2024026536A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • 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.
  • 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.
  • 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.
  • hPIV-1 and 3 human parainfluenza viruses types 1 and 3
  • hPIV-3 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.
  • 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.
  • HN haemagglutinin-neuraminidase
  • F viral surface fusion
  • 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.
  • the present disclosure provides for a compound of Formula I, or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:
  • 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
  • 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.
  • the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.
  • 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.
  • 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.
  • a fifth aspect of the present disclosure provides for a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • an 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.
  • “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.
  • 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.
  • 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-
  • “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
  • 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.
  • basic ion exchange resins such
  • 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.
  • 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,
  • 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.
  • groups RI 2 and/or R13 groups RI 2 and/or R13, as defined herein.
  • “optionally substituted amino, heterocyclic, aryl” means all of the amino, heterocyclic and aryl groups may be optionally substituted.
  • 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.
  • 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.
  • cycloalkyl refers to optionally substituted non-aromatic mono- cyclic, bicyclic or tricyclic carbon groups.
  • 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.
  • cycloalkenyl 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.
  • 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.
  • heterocyclic refers 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, imidazoliny
  • 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.
  • 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.
  • 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, pyr
  • “Substituted heteroaryl” means a heteroaryl having one or more non- interfering groups as substituents and including those defined under ‘optionally substituted’ .
  • 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, thiazo
  • 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.
  • amine may refer to -NH2, “alkylamine” and “dialkylamine” as defined above.
  • protected OH 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.
  • 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.
  • N-linked 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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,
  • 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 haloalky
  • the compound of Formula I is a compound of Formula (II), or an N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer thereof:
  • Ri, R3, R4, R6, R7 and R8 are as described for Formula I.
  • 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.
  • Ri, R3, R4, R6, R7 and R8 are as described for Formula I.
  • ring A of R3 is formed with the two carbon atoms of the pyrazole ring to which it is attached.
  • 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.
  • 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.
  • 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.
  • ring A may be selected from 6-membered aryl, 5- or 6- membered heteroaryl, and 5- or 6-membered heterocyclic ring.
  • 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.
  • ring B may be selected from a 5- or 6-membered heteroaryl ring, and a 5- or 6-membered heterocyclic ring.
  • 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.
  • 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.
  • 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 haloalkylsulfony
  • 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.
  • 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.
  • 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.
  • 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.
  • ring B is absent.
  • R3 may be selected from the group consisting of:
  • 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
  • R12 and R13 are independently selected the group consisting of hydrogen, azido, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R63, -O-R63, -S-R63.
  • R3 may be selected from the group consisting of:
  • R3 is selected from:
  • 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.
  • 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(O)-R53,
  • 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.
  • Ri is selected from COOH, or a salt thereof, and C(O)OR11 wherein R11 is selected from methyl, ethyl and propyl.
  • R11 is selected from methyl, ethyl and propyl.
  • Ri is a salt of COOH then it may a sodium or potassium salt.
  • Ri is COOH, or a salt thereof.
  • 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,
  • 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.
  • 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.
  • 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
  • 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.
  • R4 is NHC(O)R17 and R17 is selected from C3-C6 heterocyclyl, and C5 or C6 heteroaryl
  • 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.
  • R4 is NHC(O)R17 and R17 is selected from C3-C6 heterocyclyl, C5 orC6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl
  • 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.
  • 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.
  • 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.
  • 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.
  • R4 is -NR20R21 wherein R20 and R21 are independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl.
  • 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.
  • 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.
  • 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.
  • R4 is selected from the group consisting of:
  • 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.
  • 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 ary
  • 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.
  • 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.
  • R12 and R13 are independently selected from the group consisting of Br, F and Cl, preferably Br and Cl.
  • 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 -
  • 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
  • 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.
  • R12 is selected from the group consisting of Br, F and Cl, preferably Br and Cl.
  • R12 is Br.
  • 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:
  • 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
  • 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, -(
  • 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;
  • 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:
  • the compound of Formula I is a compound of Formula IVA and/or Formula IVB, or an N-oxide.
  • 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.
  • each R12 and R17 as as defined for any embodiment of Formula I, II and III.
  • 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.
  • 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.
  • R12 is selected from hydrogen, Br and Cl.
  • R12 is selected from hydrogen and Br.
  • each R12 is hydrogen.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the haemagglutinin- neuraminidase inhibitor is an influenza or parainfluenza haemagglutinin and/or neuraminidase inhibitor or blocker.
  • 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.
  • 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.
  • 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.
  • the pharmaceutical composition is for the treatment or prophylaxis of a disease, disorder or condition caused by a viral infection.
  • 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.
  • the present disclosure also provides a pharmaceutical composition
  • 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.
  • the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75.
  • the compound is selected from IE2076-37, IE2124-57 and IE2124-75.
  • 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.
  • 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.
  • 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.
  • Dosage forms may include tablets, dispersions, mists, aerosols, suspensions, injections, solutions, syrups, troches, capsules and the like.
  • 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.
  • 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).
  • compositions such as a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present disclosure, combined with a pharmaceutically acceptable carrier, diluent or excipient.
  • 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.
  • 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).
  • 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, sorb
  • 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.
  • 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.
  • aqueous carriers include 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a fifth aspect of the present disclosure provides for a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • the disease, disorder or condition is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia.
  • the disease, disorder or condition is parainfluenza and/or influenza.
  • the disease, disorder or condition is an infection caused by an influenza and/or parainfluenza virus.
  • 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).
  • influenza A virus influenza A virus
  • influenza B virus influenza B virus
  • influenza C virus influenza D virus
  • parainfluenza virus influenza D virus
  • parainfluenza virus respiratory syncytial virus
  • hMPV human metapneumovirus
  • influenza When the disease, disorder or condition is influenza then it may be influenza
  • 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.
  • 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.
  • 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.
  • the subject is a domestic or livestock animal or a human.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure also provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the modulating involves inhibiting the viral haemagglutinin and/or neuraminidase functions or viral haemagglutinin-neuraminidase enzyme.
  • 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.
  • 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.
  • 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 selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124- 75, or N-oxides.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 haloalky
  • 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,
  • 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.
  • Ri is selected from COOH, or a salt thereof, and C(O)OR11 wherein R11 is selected from methyl, ethyl and propyl.
  • 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
  • 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.
  • 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.
  • 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 .
  • 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 .
  • R4 is selected from the group consisting of:
  • 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.
  • ring A is selected from 6-membered aryl, 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic ring.
  • ring A is selected from 6-membered aryl, a 5- or 6-membered N-heteroaryl, and a 5- or 6-membered N- heterocyclic ring.
  • ring B is selected from 5- or 6-membered heteroaryl, and 5- or 6-membered heterocyclic ring.
  • 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.
  • 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.
  • 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.
  • 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,
  • Y is a heteroatom selected from N, O and S;
  • 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, -(
  • 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
  • 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)-C
  • 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.
  • 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.
  • 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,
  • 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;
  • R3 is selected from the group consisting of:
  • 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.
  • 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.
  • 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:
  • 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 haloalky
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • JC2040-110 [0196] 2,6-Anhydro-4-(6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5- isobutyramido-D-glycero-D-galacto -non-2-enonic acid (JC2040-110) .
  • 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.
  • 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.
  • CB2045-104 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).
  • JC2094-88 (60 mg, 0.102 mmol) in anh.
  • DCM (3 mL) was added acetic acid (150 ⁇ L), followed by benzaldehyde (51 ⁇ L. 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).
  • 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.
  • EMEM Eagle's minimal essential medium
  • FBS fetal bovine serum
  • 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).
  • hPIV3 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 Try ⁇ LE 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.
  • GNTE buffer glycine 200 mM, NaCl 200 mM, Tris-HCl 20 mM, EDTA 2 mM, pH 7.4
  • 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.
  • 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.
  • HAI Hemagglutination inhibition assay
  • 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 ⁇ L per well, IX final).
  • Each dilution (25 ⁇ L) is first mixed with 50 ⁇ L of 1% human red blood cells (hRBC) then 25 ⁇ L 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.
  • NIA Neuraminidase inhibition assay
  • 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.
  • IC50 values 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 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.
  • 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 ⁇ L), and the reaction was stopped after 3 - 5 min by addition of 1 M H 2 SO 4 (50 ⁇ L).
  • 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.
  • Table 1 Biological evaluation of example compounds for inhibition of hPIV neuraminidase activity, and of virus growth.
  • HBM honeybee melittin signal peptide
  • 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.
  • 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 ⁇ L. 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.
  • NA neuraminidase activity
  • 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 ⁇ L preincubated stock solution using the hanging drop vapour diffusion method.
  • the drop was equilibrated against a 500 ⁇ L 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.
  • 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).

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Abstract

La présente invention concerne un composé de formule (I), ou un N-oxyde, un sel pharmaceutiquement acceptable, un promédicament ou un stéréoisomère de celui-ci. La présente invention concerne également des compositions pharmaceutiques comprenant le composé. La présente invention concerne en outre des procédés et des utilisations du composé dans le traitement ou la prévention d'une maladie, d'un trouble ou d'un état provoqué par une infection virale chez un sujet.
PCT/AU2023/050725 2022-08-03 2023-08-03 Composés antiviraux et leurs utilisations WO2024026536A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001029021A1 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
WO2002076971A1 (fr) * 2001-03-08 2002-10-03 Biocryst Pharmaceuticals, Inc. Composes d'inhibition de la neuraminidase de paramyxovirus
WO2016033660A1 (fr) * 2014-09-05 2016-03-10 Griffith University Agents antiviraux et leurs utilisations
WO2021016670A1 (fr) * 2019-07-30 2021-02-04 Griffith University Agents antiviraux et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001029021A1 (fr) * 1999-10-19 2001-04-26 Abbott Laboratories Inhibiteurs de la neuraminidase
WO2002076971A1 (fr) * 2001-03-08 2002-10-03 Biocryst Pharmaceuticals, Inc. Composes d'inhibition de la neuraminidase de paramyxovirus
WO2016033660A1 (fr) * 2014-09-05 2016-03-10 Griffith University Agents antiviraux et leurs utilisations
WO2021016670A1 (fr) * 2019-07-30 2021-02-04 Griffith University Agents antiviraux et leurs utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATRICE GUILLON, LARISSA DIRR, IBRAHIM M. EL-DEEB, MORITZ WINGER, BENJAMIN BAILLY, THOMAS HASELHORST, JEFFREY C. DYASON, MARK VON : "Structure-guided discovery of potent and dual-acting human parainfluenza virus haemagglutinin–neuraminidase inhibitors", NATURE COMMUNICATIONS, vol. 5, pages 5268, XP055440108, DOI: 10.1038/ncomms6268 *

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