Antiviral compounds and uses thereof

Abstract

The present disclosure relates to compounds of formula (I) or N-oxides, pharmaceutically acceptable salts, prodrugs or stereoisomers thereof. The present disclosure also relates to pharmaceutical compositions comprising said compounds. The disclosure further relates to methods of treating or preventing a disease, disorder or condition caused by a viral infection in a subject and uses of the compounds in treating or preventing the disease, disorder or condition. Formula I.

Description

Technical Field

[0001] This disclosure relates to the medical field. More specifically, this disclosure relates to novel antiviral agents and their use in treating diseases or symptoms caused by viral infections. Background Technology

[0002] Any references to background technology in this article should not be construed as an admission that such technology constitutes common knowledge in Australia or elsewhere.

[0003] Viruses are the culprits behind many diseases in mammals, placing a huge burden on society. The effects of viral infections can range from common flu symptoms to severe respiratory problems and can be fatal, especially among young people, the elderly, and immunocompromised members of the community.

[0004] Orthomyxoviridae viruses (including influenza A, B, and C viruses) and paramyxoviridae viruses are the pathogens that cause a large number of human infections each year.

[0005] For example, in the Paramyxoviridae family, human parainfluenza virus types 1 and 3 (hPIV-1 and 3) are major causes of upper and lower respiratory tract infections in infants and young children, and also affect the elderly and those with weakened immune systems. Notably, it is estimated that in the United States alone, up to 5 million lower respiratory tract infections occur annually in children under the age of 5, and hPIV is isolated in approximately one-third of these cases. hPIV infection is frequently reported in transplant patients, with mortality rates as high as 30% in hematopoietic stem cell transplant recipients. Despite ongoing efforts, there is currently no vaccine or specific antiviral therapy to correspondingly prevent or treat hPIV infection. Some newer approaches focus on entry point blocking and inducing premature viral fusion via small molecules.

[0006] The initial interaction between parainfluenza virus and host cells occurs via its surface glycoprotein hemagglutinin-neuraminidase (HN) and involves the recognition of N-acetylneuraminic acid-containing glycoconjugates. The parainfluenza virus HN is a multifunctional protein that, not only within a single protein but also apparently at a single binding site, encompasses both receptor binding (for cell adhesion) and receptor disruption (promoting viral release). Furthermore, HN is involved in the activation of viral surface fusion (F) proteins essential for initiating infection of target host cells. Therefore, inhibition of hemagglutinin-neuraminidase could provide a target for antiviral drugs.

[0007] Although certain antiviral compounds as regulators of viral hemagglutinin-neuraminidase function have been disclosed in the applicant’s earlier international applications WO 2016 / 033660 (equivalent U.S. Publication US20170290809A) and WO 2021 / 016670 (equivalent U.S. Publication US20220274965), there is still a need for additional compounds that exhibit the desired efficacy and / or physicochemical characteristics. Summary of the Invention

[0008] Embodiments of this disclosure provide antiviral compounds exhibiting an N-linked pyrazole group attached to the C-4 position of a dehydroneuraminic acid-like core ring. The pyrazole ring represents a cyano group and is itself fused with at least one additional ring system. The inventors have found that the compounds provide the useful efficacy described herein.

[0009] Therefore, in a first aspect, this disclosure provides a compound of formula I or its N-oxide, a pharmaceutically acceptable salt, a prodrug, or a stereoisomer:

[0010]

[0011] Formula I

[0012] in

[0013] R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups;

[0014] R3 is

[0015]

[0016] Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and

[0017] When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle;

[0018] R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted;

[0019] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0 to 2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein each R 19 The groups may be substituted.

[0020] According to a second aspect of this disclosure, a pharmaceutical composition is provided comprising an effective amount of the compound of the first aspect or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer, and a pharmaceutically acceptable carrier, diluent and / or excipient.

[0021] Suitable, the pharmaceutical composition is used to treat or prevent diseases, symptoms, or conditions caused by viral infections.

[0022] A third aspect of this disclosure relates to a method for treating or preventing a disease, symptom, or illness of a subject caused by a viral infection, the method comprising the steps of administering to the subject an effective amount of a compound of the first aspect or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer, or a pharmaceutical composition of the second aspect.

[0023] The fourth aspect of this disclosure provides a compound of the first aspect, or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer, or a pharmaceutical composition of the second aspect, for the treatment or prevention of a disease, symptom, or illness caused by a viral infection in a subject.

[0024] The fifth aspect of this disclosure provides a pharmaceutical composition for treating or preventing a disease, symptom, or illness caused by a viral infection in a subject, comprising the compound of the first aspect or its N-oxide, a pharmaceutically acceptable salt, a prodrug, or a stereoisomer.

[0025] The sixth aspect of this disclosure provides the use of the compound of the first aspect or its N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer, or the pharmaceutical composition of the second aspect for the treatment or prevention of diseases, symptoms or conditions caused by viral infection.

[0026] The seventh aspect of this disclosure provides the use of the compound of the first aspect or its N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer or the pharmaceutical composition of the second aspect for the preparation of a medicament for the treatment or prevention of diseases, symptoms or conditions caused by viral infection.

[0027] In embodiments of the third, fourth, fifth, sixth, or seventh aspect, the disease, symptom, or illness is selected from parainfluenza, influenza, croup, bronchiolitis, and pneumonia. In one embodiment of the third, fourth, fifth, sixth, or seventh aspect, the disease, symptom, or illness is parainfluenza and / or influenza.

[0028] The eighth aspect of this disclosure provides a method for regulating the function of viral hemagglutinin and / or neuraminidase, the method comprising the step of contacting viral hemagglutinin-neuraminidase with a compound of the first aspect or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer, or a pharmaceutical composition of the second aspect.

[0029] The ninth aspect of this disclosure provides a compound of the first aspect or its N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form, or a pharmaceutical composition of the second aspect for regulating the function of viral hemagglutinin and / or neuraminidase.

[0030] The tenth aspect of this disclosure provides the use of any embodiment or formula of the first aspect of a compound or its N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form, or a pharmaceutical composition of the second aspect for modulating viral hemagglutinin and / or neuraminidase function.

[0031] The various features and embodiments of this disclosure mentioned in the foregoing chapters are applicable to other chapters as appropriate, with necessary modifications. Therefore, a feature specified in one chapter may be combined with features specified in other chapters where appropriate.

[0032] Further features and advantages of this disclosure will become apparent from the following detailed description. Detailed Implementation

[0033] Overview

[0034] Throughout this specification, unless otherwise expressly stated or required by the context, references to a single step, a composition of substance, a group of steps, or a group of compositions of substance shall be deemed to cover one or more (i.e., one or more) of such steps, compositions of substance, groups of steps, or groups of compositions of substance.

[0035] Those skilled in the art will understand that this disclosure is susceptible to variation and modification, except for the specific variations and modifications described. It should be understood that this disclosure includes all such variations and modifications. This disclosure also includes all steps, features, compositions, and compounds individually or collectively mentioned or indicated in this specification, and any and all combinations of any two or more of said steps or features.

[0036] The scope of this disclosure is not limited to the specific embodiments described herein, which are for illustrative purposes only. Functionally equivalent products, compositions, and methods are obviously within the scope of this disclosure.

[0037] Unless otherwise expressly stated, any embodiment of this disclosure herein, with necessary modifications, should be considered applicable to any other embodiment of this disclosure.

[0038] Unless otherwise expressly stated, all technical and scientific terms used herein should be regarded as having the same meaning as commonly understood by one of ordinary skill in the art (for the examples, the fields of organic synthetic chemistry, cell culture, molecular genetics, immunology, immunohistochemistry, medicinal chemistry, and biochemistry).

[0039] The term “and / or”, such as “X and / or Y”, should be understood to mean “X and Y” or “X or Y”, and should be regarded as providing explicit support for both meanings or either meaning.

[0040] The terms “from” and “to” when referring to a range should be understood to mean that the range includes both the lower and upper limits stated. For example, “x is an integer from 0 to 6” should be understood to include the case where x does not exist (x is 0), the case where x is 6, and the integer value of each integer in between, i.e., where x is 1, 2, 3, 4, or 5.

[0041] Throughout this specification, the word “comprise” or variations such as “comprises” or “comprising” shall be understood to imply inclusion of the stated elements, integers or steps or groups of elements, integers or steps, but not to exclude any other elements, integers or steps or groups of elements, integers or steps.

[0042] Selected definition

[0043] As used herein, "effective amount" means the amount of an active agent administered in sufficient quantity to prevent the onset of symptoms of the treated condition, or to stop the worsening of symptoms, or to treat and relieve symptoms, or at least reduce the severity of symptoms. Effective amounts will vary with patient age, sex, weight, etc., in a manner known to those skilled in the art. Appropriate dosages or dosage regimens can be determined through routine testing.

[0044] "Pharmaceutically acceptable carrier, diluent, or excipient" or similar terms refer to any component other than the compounds described herein (e.g., a medium capable of suspending, complexing, or dissolving an active compound) and having properties that are substantially non-toxic to the subject. Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, and hydrated water. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (binary), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium starch carbonyl acetate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E (α-tocopherol), vitamin C, xylitol, and other substances disclosed herein.

[0045] “Pharmaceutical-acceptable salts” include both acid addition salts and base addition salts. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, PA, 1990, p. 1445 and Journal of Pharmaceutical Science, 66, 2-19 (1977). Acid addition salts are those salts that retain the biological effectiveness and properties of the free base, which are not biologically or otherwise undesirable, and are formed from: inorganic acids, such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; and organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, camphoric acid, camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, carbonic acid, cinnamic acid, citric acid, cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid. Fumaric acid, galactoic acid, gentianic acid, glucohepatic acid, gluconic acid, glucuronic acid, glutamic acid, glutamate, 2-oxoglutamate, glycerophosphate, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucoic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanate, p-toluenesulfonic acid, trifluoroacetic acid, undecenoic acid, etc. Base addition salts are those salts that retain the biological effectiveness and properties of the free acid, and which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts, and magnesium salts.Salts derived from organic bases include, but are not limited to, the following: 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, tannin, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, phenethylbenzylamine, benzathine penicillin, ethylenediamine, glucosamine, methylglucosamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc.

[0046] As used herein, a "stereoisomer" refers to a compound consisting of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This disclosure covers various stereoisomers and mixtures thereof, and includes "enantiomers," which are two stereoisomers whose molecules are mirror images of each other and are not superimposed on each other.

[0047] The terms “substituted” and “optionally substituted”, whenever used herein and unless any particular part is explicitly listed, refer to the substitution of the relevant part (e.g., alkyl chain or cyclic structure) with one or more groups selected from: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy (e.g., trifluoromethoxy, trifluoroethoxy, etc.), CN, OH, azide, oxo, -CH(COOR) 28 NH2, NH2, NR 28 R 28 '、-C(O)-NR 28 R 28 '、-OC(O)-R 28 -OC(O)-OR 28 -C(O)-OR 28 (where R) 28 and R 28 'Independently selected from hydrogen, optionally substituted C1-C9 alkyl, optionally substituted aryl, -(CH2), depending on the context.' n -CH(COOH)NH2、R 29 C=O、R 29 SO2 and R 29 NHC=O, where R 29The radical is C1-C9 alkyl and n is an integer from 0 to 2; halogen (including Cl, F, Br and I); carboxyl; sulfone (including C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl and arylsulfonyl); aryl and heterocyclic, the latter two parts of which may optionally be substituted. For any 5 to 7-membered aryl, heteroaryl or heterocyclic group of the compounds herein, the optional substitution may be one or more of the groups described in this paragraph and / or the group R as defined herein. 12 and / or R 13 The term is used before describing multiple functional groups, and unless otherwise stated, it is intended to apply to all listed functions. For example, "optionally substituted amino, heterocyclic, and aryl" means that all amino, heterocyclic, and aryl groups may be optionally substituted.

[0048] The term "alkyl" refers to a straight-chain or branched alkyl substituent containing, for example, one to about 12 carbon atoms, preferably one to about 8 carbon atoms, more preferably one to about 6 carbon atoms, even more preferably one to about 4 carbon atoms, and still more preferably one to two carbon atoms. Examples of such substituents include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 3-methylbutyl, hexyl, heptyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylbutyl, 3-ethylbutyl, octyl, nonyl, decyl, undecyl, dodecyl, etc. The number of carbons mentioned refers to both the carbon backbone and carbon branches, but does not include carbon atoms belonging to any substituent, such as carbon atoms of alkoxy substituents branching from the main carbon chain.

[0049] The term "cycloalkyl" refers to an optionally substituted non-aromatic monocyclic, bicyclic, or tricyclic carbon group. Where appropriate, a cycloalkyl group may have a specified number of carbon atoms; for example, C3-C6 cycloalkyl groups are carbocyclic groups having 3, 4, 5, or 6 carbon atoms. Non-limiting examples may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0050] As used herein, the term "cycloalkenyl" generally has the same meaning as the term "cycloalkyl," but with one or more double bonds present in the ring. Examples of such substituents include cyclobutenyl, cyclopentenyl, and cyclohexenyl.

[0051] The term "aryl" refers to an unsubstituted or substituted aromatic carbocyclic substituent, as commonly understood in the art. It should be understood that the term aryl, according to Hückel's Rule, applies to planar cyclic substituents containing 4n+2 p electrons. C-5 and / or C-6 aryl groups (such as phenyl) are preferred. Aryl groups can be linked by linking groups such as C1-C6 alkyl groups, and therefore "aryl" can be considered to include C1-C6 alkyl-aryl, including C1-C6 alkyl-C5 aryl and C1-C6 alkyl-C5 aryl.

[0052] As used herein, the terms "heterocyclic," "heterocyclic," and "heterocyclic group," specifically referring to certain "R" groups, refer to a portion obtained by removing hydrogen atoms from the ring atoms of a heterocyclic compound, the ring of which may have 5 to 7 atoms, of which 1 to 4 are heteroatoms, the ring being separate from or fused to a second ring, wherein the heteroatoms are independently selected from O, N, and S. Heterocyclic, heterocyclic, and heterocyclic groups include aromatic and non-aromatic heterocyclic groups, but, when distinguished from heteroaryl rings, preferably refer to non-aromatic rings. A heterocyclic system can be attached to another portion by any number of carbon atoms or heteroatoms of a group, and can be saturated or unsaturated. Non-limiting examples of heterocycles may be selected from pyrazole, imidazole, indole, isoindole, triazole, benzotriazole, tetraazole, pyrimidine, pyridine, pyrazine, diazine, triazine, tetraazine, pyrrolyl, pyrrololinyl, pyranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, dithiolyl, oxothiohexyl, isoxazinyl, dioxinyl, azirphonyl, diazirphonyl, thiazolyl, isothiazolyl, thiazolyl, thiazolyl, oxazolyl, and thiazolyl, imidazolinyl, thiomorpholinyl, etc. The term "heterocyclic alkyl" means a non-aromatic monocyclic or polycyclic ring containing carbon and hydrogen atoms and at least one heteroatom, preferably one to four heteroatoms selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl groups may have one or more carbon-carbon double bonds or carbon-heteroatom double bonds in the ring, provided that the ring does not become aromatic by virtue of its presence. Examples of heterocyclic alkyl groups include aziridinyl, pyrrolyl, pyrrolidine, piperidinyl, piperidinyl, piperazinyl, piperazinyl, morpholinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, and pyranyl. Heterocyclic alkyl groups may be unsubstituted or substituted with one or two suitable substituents. When used with respect to non-aromatic heterocycles, the term heterocyclic alkyl may be used interchangeably with heterocycle herein.

[0053] The term "heteroaryl" or "aromatic heterocyclic group" refers to an aryl group containing one or more (especially one to four) non-carbon atoms (especially N, O, or S) or combinations thereof, wherein the heteroaryl group is optionally substituted at one or more carbon or nitrogen atoms. The heteroaryl ring may also be fused with one or more cyclic hydrocarbons, heterocycles, aryl rings, or heteroaryl rings. Heteroaryl groups include, but are not limited to: 5-membered heteroaryl groups having one heteroatom (e.g., thiophene, pyrrole, furan); 5-membered heteroaryl groups having two heteroatoms at the 1,2 or 1,3 positions (e.g., oxazole, pyrazole, imidazole, thiazole, purine); 5-membered heteroaryl groups having three heteroatoms (e.g., triazole, thiadiazole); 5-membered heteroaryl groups having four heteroatoms (e.g., tetraazole); 6-membered heteroaryl groups having one heteroatom (e.g., pyridine, quinoline, isoquinoline, phenanthrene, 5,6-cycloheptenepyridine); 6-membered heteroaryl groups having two heteroatoms (e.g., pyridazine, cycloheptenyl, phthalazine, pyrazine, pyrimidine, quinazoline); 6-membered heteroaryl groups having three heteroatoms (e.g., 1,3,5-triazine); and 6-membered heteroaryl groups having four heteroatoms. "Substituted heteroaryl" means a heteroaryl group having one or more non-interfering groups as substituents and including those defined under "optionally substituted". Examples of heteroaryl compounds include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzoisothiazole, naphtho[2,3-b]thiophene, furan, isoindazine, xanthone, phenoxazine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, quinoline, isoquinoline, phthalazine, naphthidine, quinoxaline, zoline, and carbazole. The group may include phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane, phenothiazine, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl or 8-quinolinyl, 1-isoquinolinyl, 3-isoquinolinyl, 4-isoquinolinyl or 5-isoquinolinyl, 1-indolyl, 2-indolyl or 3-indolyl, and 2-thiophenyl or 3-thiophenyl. The group may be a terminal group or a bridging group.

[0054] The terms "alkylamine" and "dialkylamine" refer to -NHR and -NRR' type groups, respectively, where "R" and "R" (which can be numbered as R groups, i.e., R) x and R x R' is an alkyl group, optionally substituted, and can be independently defined as above. That is, R and R' can be, but are not necessarily, the same alkyl moiety.

[0055] The term "amine" can refer to -NH2, "alkylamine" as defined above, and "dialkylamine".

[0056] The term “protected OH” or “protected hydroxyl” refers to a hydroxyl group that is protected by a common protecting group (including C1-C3 acyl groups and C1-C4 alkyl groups) such as acyl, ether, or ester groups to form an ether or aryl group (such as benzyl), thereby forming an ether or C1-C4 ester.

[0057] As used herein with respect to compounds of the first aspect (including compounds of formula (I), formula (II), and for example, "N-linked pyrazoles"), the term "N-linked" refers to the portion (R3 in formulas (I), (II), and (III)) linked at the C-4 position of the dehydroneuraminic acid-like core, and restricts said link to a direct link between the cyclic carbon and the nitrogen atom. Preferably, it refers to the R3 portion being linked to the dehydroneuraminic acid core via a nitrogen atom that itself forms part of the pyrazole ring.

[0058] Whenever the range of the number of atoms in a structure is specified (e.g., C1-C), 12 C1-C 10 C1-C9, C1-C6, C1-C4 alkyl, etc.), with particular consideration that any subrange or number of single carbon atoms falling within the specified range may also be used. Thus, for example, 1-12 carbon atoms (e.g., C1-C9, C1-C6, C1-C4 alkyl, etc.) used for any chemical group (e.g., alkyl, etc.) as mentioned herein. 12 The description of ranges of 1-9 carbon atoms (e.g., C1-C9), 1-6 carbon atoms (e.g., C1-C6), 1-4 carbon atoms (e.g., C1-C4), 1-3 carbon atoms (e.g., C1-C3), or 2-8 carbon atoms (e.g., C2-C8) as the case may, encompasses and specifically describes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and / or 12 carbon atoms, and any subrange thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms). Atoms, 1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms, 2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12 carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms and / or 4-12 carbon atoms, as the case may vary.

[0059] As used herein, the terms “subject” or “individual” or “patient” can refer to any subject requiring treatment, specifically a vertebrate subject, and even more specifically a mammal subject. Suitable vertebrates include, but are not limited to, primates, birds, livestock (e.g., sheep, cows, horses, donkeys, pigs), laboratory testing animals (e.g., rabbits, mice, rats, guinea pigs, hamsters), companion animals (e.g., cats, dogs), and captive wild animals (e.g., foxes, deer, wild dogs). Preferred subjects are individuals requiring treatment for illness or symptoms caused by a viral infection. However, it will be understood that the foregoing terms do not necessarily imply the presence of symptoms.

[0060] As used herein, the term "treatment" or "treating" a subject includes the application or administration to a subject of a compound or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer as described herein, with the aim of delaying, slowing, stabilizing, curing, healing, alleviating, relieving, altering, remedying, reducing exacerbation, improving, ameliorating, or influencing the risk (or susceptibility) to a viral infection, symptoms of a viral infection, or viral infection. The term "treatment" refers to any indication of successful treatment or improvement of an injury, pathology, or symptom, including any objective or subjective parameter such as reduction; relief; decrease in the rate of exacerbation; decrease in the severity of the disease; stabilization or disappearance of symptoms or making the injury, pathology, or symptom more tolerable to the subject; slowing the rate of deterioration or decline; making the late stages of exacerbation less debilitating; or improving the physical or mental health of the subject.

[0061] As used herein, the term “prophylaxis (prevention or preventing)” is intended to mean at least a reduction in the likelihood of acquiring a viral infection (or susceptibility) (i.e., preventing a patient who may be exposed to or susceptible to a viral infection but has not yet experienced or shown symptoms of a viral infection from developing at least one of the clinical symptoms of a viral infection). Biological and physiological parameters used to identify such patients are provided herein and are known in the art.

[0062] The references to "hemagglutinin-neuraminidase" and "hemagglutinin-neuraminidase protein" in this article can be considered interchangeable with "hemagglutinin and / or neuraminidase function." They can be considered to include either blocking hemagglutination function or inhibiting neuraminidase (enzyme) function. Therefore, blocking hemagglutination function may involve regulating, blocking, or inhibiting hemagglutinin-neuraminidase protein. Without being bound by any theoretical framework, this may be one mechanism of action of the compounds described herein.

[0063] compound

[0064] In the embodiments, the compounds of this disclosure can provide advantages over other selected prior art compounds, including one or more of the following: improved efficacy; beneficial pKa characteristics; reduced toxicity; and improved in vivo clearance. Furthermore, the compounds of this disclosure can provide significant advantages in terms of the ability to substitute at the R3 position of custom formula I. Specifically, the inventors have found that the cyano-substituted compounds of this disclosure (such as R3 cyanoindazole) allow for highly regiospecific substitution of the indazole ring. This allows for convenient investigation of the optimal substitution mode for a given compound and provides a high degree of confidence in the selection and synthesis of the desired active substance.

[0065] In a broad form of the first aspect, this disclosure provides a compound of formula I or its N-oxide, a pharmaceutically acceptable salt, a prodrug, or a stereoisomer:

[0066]

[0067] Formula I

[0068] in

[0069] R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups;

[0070] R3 is

[0071]

[0072] Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and

[0073] When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle;

[0074] R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17 Select 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)R 17'C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted;

[0075] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0 to 2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein any R 19 All groups are optionally substituted.

[0076] In the embodiments of the first aspect, the compound of formula (II) is a compound of formula (II) or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0077]

[0078] Formula II

[0079] R1, R3, R4, R6, R7 and R8 are described as in Equation I.

[0080] In embodiments of the first aspect, the compound of formula I or formula II is a compound of formula (III) or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0081]

[0082] Formula III

[0083] R1, R3, R4, R6, R7 and R8 are described as in Equation I.

[0084] Any reference in this document to “examples” of compounds relating to the first aspect may be considered as a reference to any example of compounds of Formula I, Formula III, and Formula IV.

[0085] It will be understood that ring A of R3 is formed by the two carbon atoms of the pyrazole ring to which it is attached.

[0086] In the embodiments, ring A together with the carbon to which it is attached forms an optionally substituted 5- to 6-membered aryl ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6-membered heterocycle.

[0087] In the embodiments, when present, ring B, together with the two ring atoms of ring A, forms an optionally substituted 5- to 6-membered heteroaryl ring or an optionally substituted 5- to 6-membered heterocycle.

[0088] In embodiments where ring A and / or ring B are heteroaryl and / or heterocyclic, the heteroatom of each ring may be selected from one or more of N, O, and S.

[0089] In the embodiments, ring A may be selected from 6-membered aryl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocycle.

[0090] In the embodiments, ring A may be selected from 6-membered aryl, 5 or 6-membered N-heteroaryl and 5 or 6-membered N-heterocyclic.

[0091] In the embodiments, ring B may be selected from 5- or 6-membered heteroaryl rings and 5- or 6-membered heterocycles.

[0092] In the embodiments, ring B may be selected from 5- or 6-membered N, O, or S-heteroaryl rings and 5- or 6-membered N, O, or S-heterocyclic rings.

[0093] In the embodiments, as defined herein, ring A and / or ring B may be independently selected from R 12 and R 13 Substituents. It will be understood, as described herein, that ring A may contain one or more R groups.12 Groups, wherein each R 12 They can be the same or different, and ring B can contain one or more R. 13 Groups, wherein each R 13 They can be the same or different.

[0094] In the embodiments, ring A and / or ring B may optionally be substituted by one or more substituents independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated or halogenated (such as Cl, F, Br or I), optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R 62 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate.

[0095] In embodiments, ring A may be selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring, and thiophene ring, each of which may optionally be substituted. In some embodiments, ring A is a benzene ring, which may optionally be substituted. Optional substituents may be halogenated. Halogenation may be selected from F, Br, and Cl, and preferably from Br and Cl. In some embodiments, ring A is a halogenated benzene ring, preferably wherein the halogenation 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 Br-substituted benzene ring.

[0096] In the embodiments, ring B may be selected from the group consisting of piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxane ring, tetrahydrothiophene ring, and thiophene ring, each of which may optionally be substituted.

[0097] In this embodiment, ring B is not present.

[0098] In embodiments of Formula I, Formula II, or Formula III, R3 can be selected from the group consisting of:

[0099]

[0100] Wherein ring A and ring B are as defined in any embodiment of formula I, II and III, wherein ring A is optionally selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring and thiophene ring, and wherein ring B is optionally selected from the group consisting of: piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxane ring, tetrahydrothiophene ring and thiophene ring, and all said rings may optionally be substituted;

[0101] Y is a heteroatom selected from N, O, and S; and

[0102] R 12 and R 13 Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated or halogenated (such as Cl, F, Br or I), optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R62 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n-CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate;

[0103] And its N-oxide analogues.

[0104] In embodiments of Formula I, Formula II, or Formula III, R3 can be selected from the group consisting of:

[0105]

[0106] And its N-oxide analogues.

[0107] In embodiments of Formula I, Formula II, or Formula III, R3 is selected from:

[0108] , and Preferably selected from and ,

[0109] And its N-oxide analogues.

[0110] It will be understood that the N-oxide analogues of R3 present the oxygen of the N-oxide on the nitrogen of the pyrazole ring, which is not attached to the core dehydroneuraminic acid-like ring (oxygen-containing core). That is, the nitrogen at the 2-position of the pyrazole ring will present as an N-oxide. For example, the corresponding N-oxides of the following R3 groups are:

[0111] Will be .

[0112] In the embodiments of Formula I, Formula II and Formula III, R1 is selected from the group consisting of: COOH or its salt, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic groups are optionally composed of one or more R 50 Replace; where R 50 Choose from the following groups: R 53 -OR 53-SR 53 -C(O)-R 53 -C(S)-R 53 -C(O)-OR 53 -OC(O)-R 53 -OC(S)-R 53 -C(S)-OR 53 CN, OH, oxo, NR 51 R 51 ', Cl, F, Br, I, optionally by at least one R 52 Substituted aryl group and optionally with at least one R 52 Substituted heterocyclic groups; wherein R 51 and R 51 'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 52 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 51 R 51 ', Cl, F, Br and I; where R 53 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0113] In the embodiments of Formula I, Formula II and Formula III, R1 is selected from the group consisting of: COOH or its salt, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 It is independently selected from hydrogen and C1-C6 alkyl groups.

[0114] In the embodiments of Formula I, Formula II and Formula III, R1 is selected from COOH or its salts and C(O)OR. 11 , where R 11 The salt is selected from methyl, ethyl, and propyl. In embodiments where R1 is a salt of COOH, it can be a sodium or potassium salt. In some embodiments, R1 is COOH or a salt thereof.

[0115] In the examples, R4 is selected from the group consisting of: sulfonamides; ureas; NHC(O)R 17 , where R 17Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 The same group; wherein the R 17 The group can optionally be surrounded by one or more R 75 Replace; where R 75 Choose from the following groups: R 78 -OR 78 -SR 78 -C(O)-R 78 -C(S)-R 78 -C(O)-OR 78 -OC(O)-R 78 -OC(S)-R 78 -C(S)-OR 78 CN, OH, oxo, NR 76 R 76 ', Cl, F, Br, I, optionally by at least one R 77 Substituted aryl group and optionally with at least one R 77 Substituted heterocyclic groups; wherein R 76 and R 76 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 77 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 78 Selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, and C2-C6 haloynyl; -NR 20 R 21 , where R 20 and R 21Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with carbon atoms of N and C(O) groups, they form 5- or 6-membered rings, which may optionally be substituted and / or fused with other rings.

[0116] In the embodiments, R4 can be selected from the group consisting of: NH-C(O)R 17 ;-NHS(O)2R 27 , where R 27 The group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl, all of which may optionally be substituted, such as by one or more R groups as previously defined. 75 Substitution; and -NHC(O)NHR 17 , where R 17 It can be as defined previously.

[0117] In the embodiment, R4 is NHC(O)R 17 , where R 17 The group selected is from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl may optionally be substituted, for example, by one or more R 75 replace.

[0118] R4 is NHC(O)R 17 And R 17 In any embodiment selected from C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkyl groups, each of these groups may be attached to the carbonyl carbon via a C1-C6 alkyl chain or a C1-C4 alkyl chain or via an ethyl or methyl group.

[0119] When R4 is NHC(O)R 17 And R 17 When the heterocyclic group is selected from C3-C6 heterocyclic group and C5 or C6 heteroaryl group, the heterocyclic atom can be selected from one or more of N, O and S, and specifically has two heteroatoms independently selected from N, O and S.

[0120] When R4 is NHC(O)R 17And R 17 When the group is selected from C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl, then non-limiting examples of such groups may include R. 17 It is selected from benzyl, phenyl, furanyl, thiophene, isoxazolyl, pyridyl, imidazolyl, pyrroleyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0121] In the embodiment, R4 is NHC(O)R 17 , where R 17 It is a C1-C6 alkyl or C1-C6 haloalkyl, including R 17 It can be -C(CH3)3, -CCl3, -CH-(CH3)2 or -CF3.

[0122] In embodiments, R4 is selected from the group consisting of: -NHAc, -NHC(O)C(CH3)3, -NHC(O)CCl3, -NHC(O)CH(CH3)2, -NHC(O)CF3, and -NHC(O)CH2CH3. In embodiments, R4 is selected from the group consisting of: -NHC(O)C(CH3)3, -NHC(O)CCl3, and -NHC(O)CH(CH3)2. In embodiments, R4 is NHC(O)C(CH3)3. In embodiments, R4 is -NHC(O)CCl3. In embodiments, R4 is -NHC(O)CH(CH3)2.

[0123] Where R4 is -NR 20 R 21 In the embodiments, R 20 and R 21 It is independently selected from the group consisting of: hydrogen, C1-C6 alkyl and C1-C6 haloalkyl.

[0124] Where R4 is -NR 20 R 21 In the embodiments, R 20 and R 21 One of them is hydrogen, and the other is selected from the group consisting of C1-C6 alkyl and C1-C6 haloalkyl.

[0125] Where R4 is -NR 22 C(O)R 23 In the embodiments, R 22 and R 23 Together they form a 5-membered ring, then R 22 and R 23 It can form a pyrrolidone ring together with N and C(O) groups, said ring may optionally be substituted and / or fused with other rings.

[0126] In the embodiment, with R 22 and R 23 The other ring fused with the 5-membered ring formed by the N and C(O) groups is a 6-membered aryl ring. It will be understood that the fused 6-membered aryl ring will share two carbon atoms with nitrogen-containing rings (such as pyrrolidone rings).

[0127] In this embodiment, R4 is selected from the group consisting of the following:

[0128] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0129] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18-C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein each R 19 It can be replaced independently and arbitrarily.

[0130] In the embodiments, R6, R7, and R8 are independently selected from the group consisting of: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0 to 2, and each R 18 and R 18 'Independently selected from hydrogen, optionally by one or more R 80 Replacement R 19 and optionally by one or more R 80 Substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic; wherein R 80 Choose from the following groups: R 83 -OR 83 -SR 83 -C(O)-R 83 -C(S)-R 83 -C(O)-OR 83 -OC(O)-R 83 -OC(S)-R 83 -C(S)-OR83 CN, OH, oxo, NR 81 R 81 ', Cl, F, Br, I, optionally by at least one R 82 Substituted aryl group and optionally with at least one R 82 Substituted heterocyclic groups; wherein R 81 and R 81 'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 82 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 83 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0131] In the embodiments, R6, R7, and R8 are independently selected from the group consisting of OH and OR. 19 , where R 19 It is a C1-C6 alkyl group (such as forming -OAc) or a C1-C6 haloalkyl group. In the examples, R6, R7 and R8 are each OH.

[0132] In the embodiment, R 12 and R 13 Independently selected from the following groups: hydrogen, azide, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', Cl, F and Br; where R 61 and R 61'Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C5-C6 aryl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl and -S(O)2-C1-C6 alkyl; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C6 aryl, C5-C6 heteroaryl, C5-C6 heterocyclic, C5-C6 cycloalkyl, and C5-C6 cycloalkenyl.

[0133] In the embodiment, R 12 and R 13 Choose independently from the following groups; R 63 -OR 63 -C(O)-OR 63 -C(O)-OH (or its salts), Cl, F and Br; where R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl, -S(O)2-C1-C6 alkyl, C2-C6 haloynyl (especially C1-C6 alkyl or C1-C6 haloalkyl), and -(CH2). n -CH(COOR 63 )NH2, where n is an integer from 0 to 2.

[0134] In the embodiment, R 12 and R 13 Choose independently from the following groups: OH, CN, N3, I, Br, F, Cl, -OCH3, COOH or their salts, S(O)2CH3, CF3, CH3, -CH(COOH)NH2 and -(CH2). n -CH(COOH)NH2, where n is an integer from 0 to 2. In the embodiment, R 12 and R 13 The following groups are selected independently: Br, F and Cl, preferably Br and Cl.

[0135] In which rings B and R 13 In embodiments where R does not exist 12 It can be independently selected from the following groups: hydrogen, azide, R 63 -OR 63 -SR 63 -C(O)-R63 -C(S)-R 63 -C(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', Cl, F and Br; where R 61 and R 61 'Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C5-C6 aryl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl and -S(O)2-C1-C6 alkyl; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, C5-C6 aryl, C5-C6 heteroaryl, C5-C6 heterocyclic, C5-C6 cycloalkyl, and C5-C6 cycloalkenyl.

[0136] In which rings B and R 13 In embodiments where R does not exist 12 You can independently choose from the following groups: R 63 -OR 63 -C(O)-OR 63 -C(O)-OH (or its salts), Cl, F and Br; where R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl, -S(O)2-C1-C6 alkyl, C2-C6 haloynyl (especially C1-C6 alkyl or C1-C6 haloalkyl), and -(CH2). n -CH(COOR 63 )NH2, where n is an integer from 0 to 2.

[0137] In which rings B and R 13 In embodiments where R does not exist 12The following groups can be selected independently: OH, CN, N3, I, Br, F, Cl, -OCH3, COOH or their salts, S(O)2CH3, CF3, CH3, -CH(COOH)NH2 and -(CH2). n -CH(COOH)NH2, where n is an integer from 0 to 2. In the embodiment, R 12 The following group of elements is selected: Br, F, and Cl, preferably Br and Cl. In the embodiments, R 12 It is Br.

[0138] In one embodiment, this disclosure provides a compound of formula I, II, or III as previously defined, or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0139]

[0140] Formula I

[0141] in

[0142] R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 Independently selected from hydrogen and C1-C6 alkyl groups, optionally wherein R1 is selected from COOH or a salt thereof and C(O)OR 11 , where R 11 Selected from methyl, ethyl, and propyl;

[0143] R3 is defined as in any of the paragraphs

[0051] to

[0071] described herein, and optionally R3 is selected from the group consisting of:

[0144]

[0145] Wherein ring A and ring B are as defined in any embodiment of formula I, II and III, optionally wherein ring A is selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring and thiophene ring, and wherein ring B is selected from the group consisting of: piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxane ring, tetrahydrothiophene ring and thiophene ring, all of which may optionally be substituted;

[0146] Y is a heteroatom selected from N, O, and S; and

[0147] R 12 and R 13Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated or halogenated (such as Cl, F, Br or I), optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R62 is selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n-CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate;

[0148] and its N-oxide analogues;

[0149] R4 is NHC(O)R 17 , where R 17 The group selected is from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl may optionally be substituted, for example, by one or more R 75 Alternatively, R4 may be replaced by NHC(O)R 17 , where R 17 It is a C1-C6 alkyl or C1-C6 haloalkyl, including R 17 R4 can be either -CH-(CH3)2 or -CF3, and optionally R4 can be selected from the following groups:

[0150] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ;

[0151] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O) n R 18 , where n = 0-2, and each R 18 and R 18 'Independently selected from hydrogen, optionally by one or more R 80 Replacement R 19 and optionally by one or more R 80 Substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein R 80 Choose from the following groups: R 83 -OR 83 -SR 83 -C(O)-R 83 -C(S)-R 83 -C(O)-OR 83 -OC(O)-R 83 -OC(S)-R 83 -C(S)-OR 83 CN, OH, oxo, NR 81 R 81 ', Cl, F, Br, I, optionally by at least one R 82 Substituted aryl group and optionally with at least one R 82 Substituted heterocyclic groups; wherein R 81 and R 81'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 82 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 83 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, and C2-C6 haloynyl, and optionally R6, R7, and R8 are independently chosen from the group consisting of: OH and OR. 19 , where R 19 It is a C1-C6 alkyl (such as forming OAc) or a C1-C6 haloalkyl.

[0152] In some instances, a compound of formula I is a compound of formula IVA and / or formula IVB, or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0153]

[0154] Type IVA Type IVB

[0155] in

[0156] Each R 12 Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR)63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated, optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R 62 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate; and

[0157] R 17 The group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl and C3-C6 cycloalkenyl, each of which may optionally be substituted.

[0158] In certain embodiments of the IVA and / or IVB compounds, each R 12 and R 17 As defined in any embodiment of Formula I, Formula II and Formula III.

[0159] In certain embodiments of the IVA and / or IVB compounds, each R12 Independently selected from the group consisting of: hydrogen, halogen, haloalkyl, carboxyl, aryl, heterocyclic, heteroaryl, alkoxy, cyano, and alkylsulfonyl, each of which may optionally be substituted. In some embodiments, each R 12 The derivative is independently selected from hydrogen and halogenated. The halogenated derivative can be selected from the group consisting of F, Br, and Cl, preferably Br and Cl. In the examples, R... 12 Selected from hydrogen, Br, and Cl. In some embodiments, R 12 Selected from hydrogen and Br. In some embodiments, each R 12 It is hydrogen.

[0160] In certain embodiments of the IVA and / or IVB compounds, R 17 Select from the group consisting of: -C(CH3)3, -CCl3, -CH-(CH3)2, and -CF3. In some embodiments, R 17 Select from the group consisting of: -C(CH3)3, -CCl3, and -CH-(CH3)2. In some embodiments, R 17 It is -C(CH3)3. In some embodiments, R 17 -CCl3. In some embodiments, R 17 It is -CH-(CH3)2.

[0161] In the embodiments, the compounds of formula I, formula II and / or formula III are selected from the group consisting of:

[0162]

[0163] And its N-oxides, pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms, including acetyl substitution of the free hydroxyl group for hydrogen, all of its C-2 analogs, wherein the C-2 carboxyl group is in a protonated form, a sodium salt form or a prodrug form, and wherein each compound can be considered to have a publicly known close analog, wherein the R4 position is explicitly replaced by any -NHC(O)R group, wherein R is a C1-C4 alkyl group or a haloalkyl group thereof.

[0164] Specifically, each of the compounds shown in the previous paragraph is considered to be explicitly reproduced, wherein the nitrogen of the pyrazole ring that is not attached to the oxygen-containing ring is in the form of an N-oxide.

[0165] In some embodiments, the compound of the first aspect is selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, including its N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer. Therefore, this disclosure also provides compounds selected from any one or more of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, or their N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer. In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37, and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0166] As described in the examples, the compound of the first aspect can be obtained by a synthetic method that initially forms the corresponding N-oxide, as described above. The N-oxide material or a portion thereof can then be reduced, and thus the N-oxide form and the reduced form of the compound of the first aspect can be achieved in any desired relative amounts.

[0167] Those skilled in the art of synthetic chemistry will understand that the COOH group can be readily interchanged with the salt form or the ester protecting group (e.g., the methyl ester group), and therefore all such forms are considered to be disclosed herein with reference to the compounds of the first aspect.

[0168] The prodrug forms of the above compounds can be definitively considered to include C1-C1. 20 Ester, or C1-C 12Esters, or C1-C6 esters, or esters containing cycloalkyl or aryl moieties. The aryl moieties may include substituted phenyl groups or fused 2- to 3-cyclic aromatic rings.

[0169] In one embodiment, the compound of the first aspect is a hemagglutinin-neuraminidase regulator. That is, the compound of the first aspect is a regulator of the function of hemagglutinin and / or neuraminidase. Preferably, the compound of the first aspect is a hemagglutinin-neuraminidase inhibitor. That is, an inhibitor of the function of hemagglutinin and / or neuraminidase. This may include blocking blood clotting function by regulating the hemagglutinin protein.

[0170] In one embodiment, it may be preferred that the hemagglutinin-neuraminidase inhibitor is an influenza or parainfluenza hemagglutinin and / or neuraminidase inhibitor or blocker. In other words, in one embodiment, it may be preferred that the inhibitor of hemagglutinin and / or neuraminidase function is an inhibitor of influenza or parainfluenza hemagglutinin and / or neuraminidase function. This may include blocking influenza or parainfluenza hemagglutination function and thus modulating influenza hemagglutinin protein or parainfluenza hemagglutinin-neuraminidase protein.

[0171] The compounds described in the first aspect can be obtained through various synthetic routes. The experimental section details some routes for synthesizing certain compounds to be used as reference compounds. The following literature discloses other related synthetic techniques (which can also be applied to the synthesis of compounds in the first aspect): *Nature Scientific Reports*, 7:4507, July 3, 2017; *Angew. Chem. Int. Ed.*, 2015, 54, 2936-2940; *Nature Scientific Reports*, Q-.24138, April 7, 2016; *Med. Chem. Commun.*, 2017, 8, 130-134; *J. Med. Chem.*, 2014, 57, 7613-7623; *Carbohydr. Res.*, 244, 181-185 (1993); *Nature Communications*, 5:5268. October 20, 2014; *Viruses*, 2019, 1 1, 417, May 5, 2019; *Carbohydrate Research* 342, 1636-1650 (2007); *Bioorganic and Medicinal Chemistry Letters* 16, 5009-5013 (2006); PCT application WO 2002076971 (equivalent US publication US20030187063); and PCT application WO 2016033660 (equivalent US publication US20170290809), each of which is hereby incorporated in its entirety by reference. All compounds of the first aspect can be obtained using such techniques and synthetic methods.

[0172] Composition

[0173] According to a second aspect of this disclosure, a pharmaceutical composition is provided comprising an effective amount of a compound or its N-oxide of any embodiment or formula of the first aspect, a pharmaceutically acceptable salt, a prodrug, a stereoisomer, and a protected form, as well as a pharmaceutically acceptable carrier, diluent, and / or excipient.

[0174] Suitable, the pharmaceutical composition is used to treat or prevent diseases, symptoms, or conditions caused by viral infections.

[0175] In embodiments of the second aspect, the compound of the first aspect may be selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, including its N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer. Therefore, this disclosure also provides a pharmaceutical composition comprising an effective amount of one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, or their N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer, and protected form, as well as a pharmaceutically acceptable carrier, diluent, and / or excipient. In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37, and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0176] The pharmaceutical composition may include more than one compound of formula (I). When the composition includes more than one compound, the compounds may be in any proportion. The composition may further include a known synergistic active ingredient, delivery medium, or adjuvant.

[0177] The compounds of any embodiment or formula of the first aspect are present in the pharmaceutical composition in an amount sufficient to inhibit or improve the disease, condition, or symptom to be treated. Those skilled in the art can readily determine suitable dosage forms and ratios of the compounds and pharmaceutical compositions containing such compounds.

[0178] Dosage forms may include tablets, dispersants, sprays, aerosols, suspensions, injections, solutions, syrups, lozenges, capsules, etc.

[0179] Compositions containing compounds of this disclosure (such as pharmaceutical compositions) can be formulated for administration via any acceptable small molecule drug administration modality. The pharmaceutical compositions of this disclosure can be formulated as solid, semi-solid, liquid, or aerosol / gas formulations, such as tablets, capsules, powders, granules, ointments, solutions, suspensions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Typical routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal administration. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intradermal, intrasternal injection, or infusion techniques. Compositions administered to a subject can be in the form of one or more dose units, wherein, for example, a tablet or injectable liquid volume can be a single dose unit. The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000).

[0180] Therefore, embodiments of this disclosure provide a composition (such as a pharmaceutical composition) comprising the compounds of this disclosure, as well as a pharmaceutically acceptable carrier, diluent, or excipient.

[0181] Generally, pharmaceutically acceptable carriers, diluents, or excipients can be solid or liquid fillers, binders, diluents, encapsulating substances, emulsifiers, wetting agents, solvents, suspending agents, coatings, or lubricants that can be safely administered to any subject (e.g., human). Depending on the specific route of administration, a variety of acceptable carriers known in the art may be used, as described in the examples in Remington’s Pharmaceutical Sciences (Mack Publishing Co. NJUSA, 1991).

[0182] Pharmaceutically acceptable carriers, diluents, and excipients will have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to subjects. Some examples of compounds that can be used as pharmaceutically acceptable carriers, fillers, or components thereof are sugars, such as lactose, glucose, trehalose, and sucrose; starches, such as corn starch or potato starch; glucose; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth gum; malt; gelatin; tallow; solid glidants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oils derived from the cocoa genus; polyols, such as polypropylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; and alginic acid.

[0183] The formulation of the compounds of this disclosure to be administered will vary depending on the route of administration and the chosen formulation (e.g., solution, emulsion, capsule). Suitable pharmaceutical compositions comprising the compounds of this disclosure to be administered can be prepared in physiologically acceptable carriers. For solutions or emulsions, suitable carriers include, for the examples, aqueous solutions or alcohol / aqueous solutions, emulsions or suspensions, including saline and buffer media. Parenteral carriers may include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oil. Various suitable aqueous carriers are known to those skilled in the art, including water, buffered water, buffered saline, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol), glucose solutions, and glycine. Intravenous carriers may include various additives, preservatives, or liquids, nutritional or electrolyte supplements (see Remington's Pharmaceutical Sciences, 16th edition, Mack, ed. 1980). The composition may optionally contain pharmaceutically acceptable excipients close to those required for physiological conditions, such as pH adjusters and buffers, as well as toxicity modifiers, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate.

[0184] Compositions containing compounds of this disclosure may be formulated into unit dosage forms. The therapeutic or preventative dose effective for any particular patient will depend on a variety of factors, including the severity and identification of the condition being treated; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the time of administration, route of administration, and the excretion rate of the specific pharmaceutical composition used; the duration of treatment; drugs used in combination with or concurrently with the specific pharmaceutical composition used; and similar factors well known in the medical field.

[0185] The compositions comprising the compounds described herein can be used in combination with one or more other therapeutic, preventative, diagnostic, or imaging agents. They can be administered together in a single composition or separately in different compositions.

[0186] Treatment and usage methods

[0187] A third aspect of this disclosure is a method for treating and / or preventing a disease, symptom, or illness of a subject caused by a viral infection, the method comprising the steps of administering to the subject an effective amount of a compound of any embodiment or formula of the first aspect or its N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer, or protected form, or a pharmaceutical composition of the second aspect.

[0188] The fourth aspect of this disclosure provides a compound or N-oxide thereof, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form of any embodiment or formula of the first aspect for the treatment or prevention of a disease, symptom or illness caused by a viral infection in a subject, or a pharmaceutical composition of the second aspect.

[0189] The fifth aspect of this disclosure provides a pharmaceutical composition for treating or preventing a disease, symptom, or illness caused by a viral infection in a subject, comprising a compound or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer of any embodiment or formula of the first aspect.

[0190] The sixth aspect of this disclosure provides for the use of any embodiment or formula of the first aspect of a compound or its N-oxide, pharmaceutically acceptable salt, prodrug or stereoisomer, or a pharmaceutical composition of the second aspect for the treatment or prevention of a disease, symptom or illness caused by a viral infection.

[0191] The seventh aspect of this disclosure provides the use of any embodiment or formula of the first aspect of a compound or its N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form, or a pharmaceutical composition of the second aspect, for the preparation of a medicament for the treatment or prevention of a disease, symptom or illness caused by a viral infection in a subject.

[0192] In embodiments of the third, fourth, fifth, sixth, or seventh aspect, the disease, symptom, or illness is selected from parainfluenza, influenza, croup, bronchiolitis, and pneumonia.

[0193] In embodiments of the third, fourth, fifth, sixth, or seventh aspect, the disease, symptom, or illness is parainfluenza and / or influenza.

[0194] In embodiments of the third, fourth, fifth, sixth, or seventh aspect, the disease, symptom, or illness is an infection caused by an influenza virus and / or a parainfluenza virus.

[0195] The infection may be caused by one or more of the following viruses: influenza A virus, influenza B virus, influenza C virus, influenza D virus, parainfluenza virus, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV).

[0196] When the disease, symptom, or illness is influenza, it may be influenza A, influenza B, influenza C, or influenza D.

[0197] When the disease, symptom, or illness is a parainfluenza virus infection, it can be selected from the group consisting of: hPIV-1 virus, hPIV-2 virus, hPIV-3 virus, and hPIV-4 virus. These can include all viral subtypes, such as 4a and 4b.

[0198] When the disease, condition, or symptom is caused by RSV, it may be subtype A and / or subtype B, such as hRSV-A and hRSV-B.

[0199] When the disease, condition, or symptom is caused by hMPV, it may be caused by any one or more of the hMPV subtypes A1, A2, B1, and B2.

[0200] Preferably, the subjects are domesticated or livestock animals or humans.

[0201] In embodiments of the third, fourth, fifth, sixth, or seventh aspect, 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 its N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer.

[0202] In embodiments of the third, fourth, sixth, or seventh aspect, the pharmaceutical composition of the second aspect comprises a compound selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, including its N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer.

[0203] Therefore, this disclosure also provides a method for treating and / or preventing a disease, symptom or illness caused by a viral infection in a subject, the method comprising the steps of: administering an effective amount of one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers.

[0204] This disclosure also provides for the treatment or prevention of a disease, condition, or symptom caused by a viral infection in a subject, using one or more of the following compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs, and stereoisomers, or pharmaceutical compositions comprising said compounds.

[0205] This disclosure also provides pharmaceutical compositions for treating or preventing diseases, symptoms, or conditions caused by viral infection in subjects, comprising one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs, and stereoisomers.

[0206] This disclosure also provides the use of any one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers, or pharmaceutical compositions comprising said compounds, for the treatment or prevention of diseases, symptoms or conditions caused by viral infections.

[0207] This disclosure also provides the use of any one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers, or pharmaceutical compositions comprising said compounds, for the preparation of a medicament for the treatment or prevention of a disease, condition or symptom caused by a viral infection in a subject.

[0208] In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37, and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0209] The eighth aspect of this disclosure provides a method for modulating the function of viral hemagglutinin and / or neuraminidase, the method comprising the step of contacting viral hemagglutinin-neuraminidase with a compound or its N-oxide, a pharmaceutically acceptable salt, a prodrug, a stereoisomer or protected form of any embodiment or formula of the first aspect, or a pharmaceutical composition of the second aspect.

[0210] The ninth aspect of this disclosure provides compounds, or N-oxides thereof, pharmaceutically acceptable salts, prodrugs, stereoisomers, or protected forms of any embodiment or formula of the first aspect, for regulating the function of viral hemagglutinin and / or neuraminidase, or pharmaceutical compositions of the second aspect.

[0211] The tenth aspect of this disclosure provides the use of any embodiment or formula of the first aspect of a compound or its N-oxide, pharmaceutically acceptable salt, prodrug, stereoisomer or protected form, or a pharmaceutical composition of the second aspect for modulating viral hemagglutinin and / or neuraminidase function.

[0212] Preferably, the regulation involves inhibiting the function of viral hemagglutinin and / or neuraminidase or viral hemagglutinin-neuraminidase.

[0213] In the embodiments of the eighth, ninth and tenth aspects, the compounds of the first aspect are selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, including their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers.

[0214] In embodiments of the eighth, ninth, and tenth aspects, the pharmaceutical composition of the second aspect comprises a compound selected from the group consisting of IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75, including its N-oxide, pharmaceutically acceptable salt, prodrug, and stereoisomer.

[0215] Therefore, this disclosure also provides a method for regulating the function of viral hemagglutinin and / or neuraminidase, the method comprising the step of contacting viral hemagglutinin-neuraminidase with any one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers, or pharmaceutical compositions comprising said compounds.

[0216] This disclosure also provides one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers, or pharmaceutical compositions comprising said compounds, for regulating the function of viral hemagglutinin and / or neuraminidase.

[0217] This disclosure also provides the use of any one or more compounds selected from IE2076-14, IE2076-37, IE2076-80, IE2124-39, IE2124-57 and IE2124-75, or their N-oxides, pharmaceutically acceptable salts, prodrugs and stereoisomers, or pharmaceutical compositions comprising said compounds, for the regulation of viral hemagglutinin and / or neuraminidase function.

[0218] In some embodiments, the compound is selected from IE2076-37, IE2076-80, IE2124-39, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-37, IE2124-57, and IE2124-75. In some embodiments, the compound is selected from IE2076-80 and IE2124-39. In some embodiments, the compound is selected from IE2124-39 and IE2124-57. In some embodiments, the compound is selected from IE2076-14, IE2076-37, and IE2076-80. In some embodiments, the compound is selected from IE2076-37 and IE2076-80. In some embodiments, the compound is IE2076-14. In some embodiments, the compound is IE2076-37. In some embodiments, the compound is IE2076-80. In some embodiments, the compound is IE2124-39. In some embodiments, the compound is IE2124-57. In some embodiments, the compound is IE2124-75.

[0219] List of items in the example:

[0220] This disclosure is further described in detail with reference to the following items:

[0221] 1. A compound of formula I or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0222]

[0223] Formula I

[0224] in

[0225] R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups;

[0226] R3 is

[0227]

[0228] Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and

[0229] When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle;

[0230] R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted;

[0231] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein any R 19 All groups are optionally substituted.

[0232] 2. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (II) or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0233]

[0234] Formula II

[0235] R1, R3, R4, R6, R7 and R8 are as defined in item 1.

[0236] 3. The compound according to claim 1 or 2, wherein the compound of formula I or the compound of formula II is a compound of formula III or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer:

[0237]

[0238] Formula III

[0239] R1, R3, R4, R6, R7 and R8 are as defined in item 1.

[0240] 4. The compound according to any one of the preceding items, wherein R1 is selected from the group consisting of: COOH or a salt thereof, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic groups are optionally composed of one or more R 50 Replace; where R 50 Choose from the following groups: R 53 -OR 53 -SR 53 -C(O)-R 53 -C(S)-R 53 -C(O)-OR 53 -OC(O)-R 53 -OC(S)-R 53 -C(S)-OR 53CN, OH, oxo, NR 51 R 51 ', Cl, F, Br, I, optionally by at least one R 52 Substituted aryl group and optionally with at least one R 52 Substituted heterocyclic groups; wherein R 51 and R 51 'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 52 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 51 R 51 ', Cl, F, Br and I; where R 53 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0241] 5. The compound according to any one of the preceding items, wherein R1 is selected from the group consisting of: COOH or a salt thereof, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 It is independently selected from hydrogen and C1-C6 alkyl groups.

[0242] 6. The compound according to any one of the preceding items, wherein R1 is selected from COOH or a salt thereof and C(O)OR 11 , where R 11 Selected from methyl, ethyl, and propyl.

[0243] 7. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: sulfonamides; ureas; NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17The same group; wherein the R 17 The group can optionally be surrounded by one or more R 75 Replace; where R 75 Choose from the following groups: R 78 -OR 78 -SR 78 -C(O)-R 78 -C(S)-R 78 -C(O)-OR 78 -OC(O)-R 78 -OC(S)-R 78 -C(S)-OR 78 CN, OH, oxo, NR 76 R 76 ', Cl, F, Br, I, optionally by at least one R 77 Substituted aryl group and optionally with at least one R 77 Substituted heterocyclic groups; wherein R 76 and R 76 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 77 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 78 Selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, and C2-C6 haloynyl; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with carbon atoms of N and C(O) groups, they form 5- or 6-membered rings, which may optionally be substituted and / or fused with other rings.

[0244] 8. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: NH-C(O)R17 ;-NHS(O)2R 27 , where R 27 The following groups are selected: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl, all of which are optionally substituted and optionally converted by one or more R groups. 75 Substitution; and -NHC(O)NHR 17 , where R 17 and R 75 As defined in item 7.

[0245] 9. The compound according to any one of the preceding claims, wherein R4 is NHC(O)R 17 , where R 17 Selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl; wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkyl are optionally substituted, optionally replaced by one or more R as defined in item 7. 75 replace.

[0246] 10. The compound according to any one of the preceding claims, wherein R4 is NHC(O)R 17 , where R 17 It is a C1-C6 alkyl or C1-C6 haloalkyl, including R 17 It is -CH-(CH3)2 or -CF3.

[0247] 11. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of: -NHAc, -NHC(O)C(CH3)3, -NHC(O)CCl3, -NHC(O)CH(CH3)2, -NHC(O)CF3 and -NHC(O)CH2CH3.

[0248] 12. The compound according to any one of the preceding items, wherein R4 is selected from the group consisting of:

[0249] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0250] 13. The compound according to any one of the preceding claims, wherein R6, R7 and R8 are independently selected from the group consisting of: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein each R 19 It can be replaced independently and arbitrarily.

[0251] 14. The compound according to any one of the preceding claims, wherein R6, R7 and R8 are independently selected from the group consisting of: H, OH, protected OH, R 19 OR 19 NR 18 R 18 ',-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0-2, and each R 18 and R 18 'Independently selected from hydrogen, optionally by one or more R 80 Replacement R 19 and optionally by one or more R 80 Substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein R 80 Choose from the following groups: R 83 -OR 83 -SR 83 -C(O)-R 83 -C(S)-R 83 -C(O)-OR 83 -OC(O)-R 83 -OC(S)-R 83 -C(S)-OR 83 CN, OH, oxo, NR 81 R 81 ', Cl, F, Br, I, optionally by at least one R 82 Substituted aryl group and optionally with at least one R 82 Substituted heterocyclic groups; wherein R 81 and R 81 'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 82Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 83 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0252] 15. The compound according to any one of the preceding items, wherein R6, R7 and R8 are independently selected from the group consisting of OH and OR. 19 , where R 19 It is a C1-C6 alkyl (such as forming -OAc) or a C1-C6 haloalkyl.

[0253] 16. The compound according to any one of the preceding items, wherein R6, R7 and R8 are independently selected from OH and OAc.

[0254] 17. The compound according to any one of the preceding items, wherein ring A together with the carbon to which it is attached forms an optionally substituted 5- or 6-membered aryl ring, an optionally substituted 5- or 6-membered heteroaryl ring, or an optionally substituted 5- or 6-membered heterocycle.

[0255] 18. The compound according to any one of the preceding items, wherein ring B, when present, forms an optionally substituted 5- to 6-membered heteroaryl ring or an optionally substituted 5- to 6-membered heterocycle together with the two ring atoms of ring A.

[0256] 19. The compound according to any one of the preceding items, wherein ring A and / or ring B are heteroaryl and / or heterocyclic, wherein the heteroatom of each ring is selected from one or more of N, O and S.

[0257] 20. The compound according to any one of the preceding items, wherein ring A is selected from 6-membered aryl, 5- or 6-membered heteroaryl and 5- or 6-membered heterocycle.

[0258] 21. The compound according to any one of the preceding items, wherein ring A is selected from 6-membered aryl, 5 or 6-membered N-heteroaryl and 5 or 6-membered N-heterocycle.

[0259] 22. The compound according to any one of the preceding items, wherein ring B is selected from 5- or 6-membered heteroaryl and 5- or 6-membered heterocycle.

[0260] 23. The compound according to any one of the preceding items, wherein ring B is selected from 5- or 6-membered N, O, or S heteroaryl groups and 5- or 6-membered N, O, or S heterocycles.

[0261] 24. The compound according to any one of the preceding items, wherein ring A is selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring and thiophene ring, each of which is optionally substituted.

[0262] 25. The compound according to any one of the preceding items, wherein ring B is selected from the group consisting of: piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxane ring, tetrahydrothiophene ring and thiophene ring, each of which is optionally substituted.

[0263] 26. The compound according to any one of the preceding items, wherein R3 is selected from the group consisting of:

[0264]

[0265] Wherein ring A and ring B are as defined in any one of items 1 to 25, wherein optionally ring A is selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring and thiophene ring, and wherein ring B is selected from the group consisting of: piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxanepentane ring, tetrahydrothiophene ring and thiophene ring, and all said rings are optionally substituted;

[0266] Y is a heteroatom selected from N, O, and S; and

[0267] R 12 and R 13 Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n-CH(COOH)NH2, where n is an integer from 0 to 2, halogenated, optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R 62 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate;

[0268] And its N-oxide analogues.

[0269] 27. The compound according to claim 26, wherein R 12 and R 13 Independently selected from the following groups: hydrogen, azide, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63CN, OH, oxo, NR 61 R 61 ', Cl, F and Br; where R 61 and R 61 'Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl and -S(O)2-C1-C6 alkyl; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0270] 28. The compound according to item 26 or 27, wherein R 12 and R 13 Independently select from the following groups: R 63 -OR 63 -C(O)-OR 63 -C(O)-OH (or its salts), Cl, F, Br, and -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2; where R 63 It is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

[0271] 29. The compound according to any one of items 26 to 28, wherein R 12 and R 13 Choose independently from the following groups: OH, CN, I, Br, F, Cl, -OCH3, COOH or their salts, -S(O)2CH3, CF3 and CH3.

[0272] 30. The compound according to any one of the preceding claims, wherein ring A and / or ring B are independently selected from R 12 and R 13 Substituents of R, wherein R 12 and R 13 Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63-OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated, optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R 62 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate.

[0273] 31. The compound according to any one of the preceding items, wherein ring A and / or ring B are substituted by one or more substituents independently selected from hydrogen, halogen, C1-C6 alkoxy, hydroxyl, carboxyl, C1-C6 alkyl, C1-C6 haloalkyl, cyano and sulfone.

[0274] 32. The compound according to any one of the preceding items, wherein R3 is selected from the group consisting of:

[0275]

[0276] And its N-oxide analogues.

[0277] 33. The compound according to any one of the preceding items, wherein the compound is selected from the group consisting of:

[0278]

[0279] And its N-oxides, pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms, including acetyl-substituted free hydroxyl hydrogen, all of its C-2 analogs, wherein the C-2 carboxyl group is in a protonated form, a sodium salt form or a prodrug form, and wherein each compound can be considered to have a publicly known close analog, wherein the R4 position is explicitly replaced by any -NHC(O)R group, wherein R is a C1-C4 alkyl group or a haloalkyl group thereof.

[0280] 34. A pharmaceutical composition comprising an effective amount of the compound or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer according to any one of claims 1 to 33, and a pharmaceutically acceptable carrier, diluent and / or excipient.

[0281] 35. The pharmaceutical composition according to claim 34, wherein the pharmaceutical composition is used to treat or prevent diseases, symptoms or conditions caused by viral infection.

[0282] 36. A method for treating or preventing a disease, symptom, or illness of a subject caused by a viral infection, the method comprising the steps of: administering to the subject an effective amount of a compound of formula I or its N-oxide, a pharmaceutically acceptable salt, a prodrug, or a stereoisomer:

[0283]

[0284] Formula I

[0285] in

[0286] R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups;

[0287] R3 is

[0288]

[0289] Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and

[0290] When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle;

[0291] R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted;

[0292] R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 , where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 alkynyl, C2-C6 haloalkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein any R 19 All groups are optionally substituted;

[0293] Or the pharmaceutical composition according to item 34 or item 35.

[0294] 37. The method according to item 36, wherein the compound is as described in any one of items 1 to 33.

[0295] 38. The method according to item 36 or 37, wherein the disease, symptom or illness is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia.

[0296] 39. The method according to any one of items 36 to 38, wherein the infection is caused by a virus selected from the group consisting of: influenza A virus, influenza B virus, influenza C virus, influenza D virus, parainfluenza virus, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV).

[0297] 40. The method according to any one of items 36 to 39, wherein the disease, symptom or illness is parainfluenza and / or influenza.

[0298] 41. The method according to any one of items 36 to 40, wherein the disease, symptom or illness is an infection caused by an influenza virus and / or a parainfluenza virus.

[0299] 42. The method according to any one of items 36 to 41, wherein when the disease, symptom or illness is influenza, then the disease, symptom or illness is selected from the group consisting of: influenza A, influenza B, influenza C or influenza D.

[0300] 43. The method according to any one of items 36 to 41, wherein when the disease, symptom or illness is a parainfluenza virus infection, the disease, symptom or illness is selected from the group consisting of hPIV-1 virus, hPIV-2 virus, hPIV-3 virus and hPIV-4 virus, including all viral subtypes.

[0301] 44. The method according to any one of items 36 to 41, wherein the subject is a domesticated or livestock animal or a human.

[0302] 45. A method for regulating the function of viral hemagglutinin and / or neuraminidase, the method comprising the steps of: contacting viral hemagglutinin-neuraminidase with a compound or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer, or a pharmaceutical composition according to any one of items 1 to 33, or with any pharmaceutical composition according to item 34 or 35.

[0303] 46. ​​The method according to item 45, wherein the regulation is to inhibit the function of the viral hemagglutinin and / or neuraminidase or viral hemagglutinin-neuraminidase.

[0304] Example

[0305] Example 1: General Synthesis Method

[0306] The N-oxide form of the compound of the first aspect was obtained by coupling the 4-amine intermediate IE889-89 with a suitable 2-nitrobenzaldehyde and a desired substituent 'X' in glacial acetic acid in the presence of TMSCN, followed by stirring the crude product obtained from the first step with triethylamine in ethanol, as shown in the following scheme. It will be understood that the starting substrates for IE889-89 may vary considerably.

[0307]

[0308] N-oxides IE2076-3 and IE2076-16 were deprotected at 0°C using an acetonitrile solution containing LiOH (1M) to produce indazole-N-oxides IE2076-45 and IE2076-47, respectively.

[0309]

[0310] If desired, the N-oxide derivatives can be reduced to their equivalent indazoles in the presence of zinc powder and ammonium chloride in 80% MeOH. The reduced products are then deprotected with LiOH to yield the finally deprotected indazoles IE2076-12, IE2076-14, IE2076-17, IE2076-37, and IE2076-48, as illustrated in the following scheme. Therefore, this method allows for the formation of the N-oxide forms of all synthesized compounds, and then the reduction of all or part of the material to give the reduced form.

[0311]

[0312] Experimental data

[0313] General procedure for synthesizing protected indazole-N-oxides:

[0314] TMSCN (55 μL, 0.44 mmol) was added to a solution of a starting amine (e.g., 4-amino-Neu5Ibu2en) IE889-89 (100 mg, 0.22 mmol) and a suitable 2-nitrobenzaldehyde reagent (0.22 mmol) in glac.AcOH (1 mL). The reaction mixture was stirred overnight at room temperature, and then the reaction solvent was removed under vacuum. The evaporation of AcOH was aided by repeated additions and co-evaporation of EtOH (3 × 10 mL). The residue was dissolved in EtOH (3 mL) and triethylamine (20 drops) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified by silica gel chromatography using a suitable solvent system to yield a pure, protected indazole N-oxide product.

[0315] General procedure for reducing indazole-N-oxides; synthesis of protected indazoles:

[0316] Add zinc or iron powder (3 equivalents) and ammonium chloride (5 equivalents) to a solution of protected indazole-N-oxide in MeOH / H2O (4:1, 3.0 mL). Stir the mixture at 0 °C for 1 hour, then add silica gel (1 g) to the mixture and concentrate the mixture under vacuum and purify it by silica gel chromatography using a suitable solvent system to produce reduced protected indazole.

[0317] The general procedure for deprotecting protected indazoles is as follows:

[0318] LiOH solution (1.0 M) was added dropwise to a solution of reduced protected indazole in acetonitrile (2 mL) at 0 °C until the pH reached 13–14. The mixture was stirred at 0 °C for 2 hours, then silica gel (1 g) was added, and the mixture was concentrated under vacuum and purified by silica gel chromatography using a suitable solvent system to produce deprotected indazole.

[0319] IE1963-114

[0320] 7,8,9-Tri-O-acetyl-2,6-dehydr-4-(3-cyano-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoate (IE1963-114).

[0321] The compound was prepared by IE889-89 and 2-nitrobenzaldehyde according to a general procedure, and the product was purified by silica gel chromatography using hexane / EtOAc (1:2) to produce product IE1963-114 in 52% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ = 0.72 (d, J = 6.9 Hz, 3H), 0.82-0.89 (m, 3H), 2.03 (s, 3H), 2.05 (s, 3H), 2.07 (s, 3H), 2.12-2.23 (m, 1H), 3.84 (s, 3H), 4.19 (dd, J= 12.6, 6.1 Hz, 1H), 4.56-4.65 (m, 1H), 4.74 (d, J = 10.7 Hz, 1H), 5.42 (td,J = 6.4, 2.6 Hz, 1H), 5.51-5.57 (m, 1H), 6.21 (d, J = 2.5 Hz, 1H), 6.44 (d, J= 9.8 Hz, 1H), 7.42-7.52 (m, 2H), 7.74 (d, J = 8.9 Hz, 2H); 13C NMR (101 MHz, CD3OD): δ = 17.29, 17.85, 19.16, 19.24, 19.36, 34.80, 46.07, 51.75, 54.44,61.76, 67.16, 70.05, 76.60, 105.13, 109.06, 113.18, 118.51, 122.73, 127.95,128.29, 128.80, 147.27, 161.15, 169.73, 170.08, 171.00, 178.49; 28 H 32 N4O 11 [m / z] (positive ion mode) 623.2 [M+Na] - .

[0322] IE2076-2

[0323] 7,8,9-Tri-O-acetyl-2,6-dehydr-4-(6-bromo-3-cyano-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoate (IE2076-2).

[0324] The compound was prepared by IE889-89 and 4-bromo-2-nitrobenzaldehyde according to a general procedure, and the product was purified by silica gel chromatography using hexane / EtOAc (1:1) to produce product IE2076-2 in 44% yield (after 2 steps). 1HNMR (400 MHz, CDCl3): δ = 0.82 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 2.13-2.20 (m, 1H), 3.85 (s, 3H), 4.20 (dd, J = 12.6, 6.6 Hz, 1H), 4.65-4.75 (m, 2H), 4.85 (q, J = 10.0 Hz, 1H), 5.36 (ddd, J = 6.5, 5.4, 2.6 Hz, 1H), 5.49 (dd, J = 5.5, 1.7 Hz, 1H), 5.85 (d, J = 9.6 Hz, 1H), 6.07 (d, J = 2.4 Hz, 1H), 6.38 (d, J = 9.9 Hz, 1H), 7.45 (dd, J = 9.0, 1.6 Hz, 1H), 7.53 (dd, J = 9.1, 0.8 Hz, 1H), 7.92 (d, J =0.8 Hz, 1H); LRMS [C 28 H 31 BrN4O 11 [m / z] (positive ion mode) 703.1 [M+Na] - .

[0325] IE2076-3

[0326] 7,8,9-Tri-O-acetyl-2,6-dehydr-4-(3-cyano-5-hydroxy-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoate (IE2076-3).

[0327] The compound was prepared by IE889-89 and 5-hydroxy-2-nitrobenzaldehyde according to a general procedure, and the product was purified by silica gel chromatography using hexane / EtOAc / MeOH (7:4:1) to produce product IE2076-3 in 61% yield (after 2 steps). 1H NMR (400 MHz, CDCl3): δ = 0.76 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8Hz, 3H), 2.06 (s, 3H), 2.09 (s, 6H), 2.18 (q, J = 6.9 Hz, 1H), 3.85 (s, 3H), 4.23 (dd, J = 12.5, 7.5 Hz, 1H), 4.76 (d, J = 10.6 Hz, 1H), 4.83 (dd, J =12.3, 2.6 Hz, 1H), 5.06 (q, J = 10.2 Hz, 1H), 5.28-5.38 (m, 1H), 5.53-5.65(m, 1H), 6.16 (d, J = 2.4 Hz, 1H), 6.42 (d, J = 9.8 Hz, 1H), 6.71 (d, J = 2.1Hz, 1H), 6.98 (dt, J = 9.7, 5.2 Hz, 2H), 7.52 (d, J = 9.4 Hz, 1H), 9.35 (s,1H); 13 C NMR (101 MHz, CDCl3): δ = 18.49, 18.64, 20.46, 20.81, 21.00, 35.58,45.81, 52.90, 62.08, 67.40, 72.00, 77.23, 90.68, 97.95, 104.88, 110.13,114.78, 123.92, 124.14, 125.44, 147.17, 157.73, 160.94, 170.09, 170.68,170.98, 178.95; LRMS [C 28 H 32 N4O 12 [m / z] (positive ion mode) 639.1 [M+Na] - .

[0328] IE2076-11

[0329] 7,8,9-Tri-O-acetyl-2,6-dehydr-4-(3-cyano-5-methoxy-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoate (IE2076-11).

[0330] The compound was prepared by IE889-89 and 5-methoxy-2-nitrobenzaldehyde according to a general procedure, and the product was purified by silica gel chromatography using hexane / EtOAc (1:2) to produce product IE2076-11 in 68% yield (after 2 steps). 1 H NMR (400 MHz, CDCl3): δ = 0.78 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.7Hz, 3H), 2.06 (s, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.13-2.18 (m, 1H), 3.85(s, 3H), 3.87 (s, 3H), 4.20 (dd, J = 12.5, 6.8 Hz, 1H), 4.70 (td, J = 11.4,10.3, 4.5 Hz, 2H), 4.87 (q, J = 10.1 Hz, 1H), 5.36 (ddd, J = 6.8, 5.3, 2.7Hz, 1H), 5.50 (dd, J = 5.4, 1.8 Hz, 1H), 5.95 (d, J = 9.7 Hz, 1H), 6.09 (d, J= 2.5 Hz, 1H), 6.36 (d, J = 10.0 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 7.03 (dd,J = 9.5, 2.2 Hz, 1H), 7.58 (dd,J = 9.5, 0.7 Hz, 1H); LRMS [C 29 H 34 N4O 12 [m / z] (positive ion mode) 653.2 [M+Na] - .

[0331] IE2076-16

[0332] 7,8,9-Tri-O-acetyl-2,6-dehydr-4-(5-bromo-3-cyano-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoate methyl ester (IE2076-16).

[0333] The compound was prepared by IE889-89 and 5-bromo-2-nitrobenzaldehyde according to a general procedure, and the product was purified by silica gel chromatography using hexane / EtOAc (1:1) to produce product IE2076-16 in 66% yield (after 2 steps). 1HNMR (400 MHz, CDCl3): δ = 0.82 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 2.06 (s, 3H), 2.10 (s, 3H), 2.11 (s, 3H), 2.17 (dd, J = 5.7, 2.0 Hz, 1H), 3.85 (s, 3H), 4.20 (dd, J = 12.5, 6.6 Hz, 1H), 4.65-4.75 (m, 2H), 4.82 (q, J= 10.0 Hz, 1H), 5.36 (td, J = 6.1, 2.5 Hz, 1H), 5.49 (dd, J = 5.5, 1.7 Hz,1H), 5.76 (d, J = 9.6 Hz, 1H), 6.07 (d, J = 2.5 Hz, 1H), 6.38 (d, J = 9.9 Hz,1H), 7.42 (dd, J = 9.2, 1.7 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.82-7.86 (m,1H); 13 C NMR (101 MHz, CDCl3): δ = 18.82, 19.46, 20.66, 20.81, 20.94, 35.65,45.17, 52.73, 55.22, 62.13, 67.56, 71.41, 73.20, 108.39, 109.61, 111.56,121.72, 131.68, 132.92, 145.04, 161.56, 169.81, 170.37, 177.00; LRMS[C 28 H 31 BrN4O 11 [m / z] (positive ion mode) 703.1 [M+Na] - .

[0334] IE2076-45

[0335] 2,6-Dehydr-4-(3-cyano-5-hydroxy-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-45).

[0336] While stirring, 10 drops of LiOH (1M) were added to a solution of protected N-oxide IE2076-3 (40 mg, 0.065 mmol) cooled to 0°C in acetonitrile (2 mL). Stirring was maintained in an ice bath for 1 hour, and then the solution was treated with Amberlite. ® The solution was acidified (to pH = 5) with IR-120 (H+) resin. The acidic resin was then filtered, and the solution was washed with methanol (10 mL). The combined filtrate and wash were then concentrated under vacuum, and the crude residue was purified by silica gel chromatography using EtOAc / MeOH / H2O (7:2:1) as a solvent system to produce pure IE2076-45 (77% yield). 1 H NMR (400 MHz, CD3OD): δ = 0.82 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 2.28 (dt, J =13.6, 7.0 Hz, 1H), 3.62 (dd, J = 9.4, 1.1 Hz, 1H), 3.67 (dd, J = 11.5, 5.4Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.93 (dq, J = 9.0, 2.8 Hz, 1H), 4.63 (d, J = 10.9 Hz, 1H), 5.75 (s, 1H), 6.35 (d, J = 10.0 Hz, 1H), 6.77-6.85(m, 1H), 7.05 (dd, J = 9.4, 2.1 Hz, 1H), 7.59 (d, J = 9.4 Hz, 1H); LRMS[C 21 H 24 [N4O9] (m / z): (positive ion mode) 499.1 [M+Na] + .

[0337] IE2076-47

[0338] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazole-1-oxide-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-47).

[0339] IE2076-16 was deprotected to obtain IE2076-47 using a similar procedure to that used in the synthesis of IE2076-45. The deprotected product was purified by silica gel chromatography using EtOAc / MeOH / H2O (9:2:1) as the solvent system. The final deprotected product IE2076-47 was obtained in 70% yield. 1 H NMR (400 MHz, CD3OD): δ = 0.87(d, J = 6.9 Hz, 3H), 1.03 (d, J = 6.9 Hz, 3H), 2.28 (p, J = 6.9 Hz, 1H), 3.48(d, J = 9.3 Hz, 1H), 3.61-3.67 (m, 1H), 3.82 (dd, J = 11.5, 3.0 Hz, 1H), 3.89 (ddd, J = 9.2, 5.4, 2.9 Hz, 1H), 4.54-4.64 (m, 1H), 4.79 (s, 2H), 5.72 (s,1H), 7.09 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.56 (dd, J = 8.8,2.2 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ = 18.09, 18.36, 34.90, 54.00, 63.58,68.62, 70.07, 75.11, 79.09, 101.23, 110.44, 112.50, 113.89, 115.44, 127.77,137.91, 142.58, 147.93, 150.94, 168.10, 179.16; LRMS [C 21 H 23 BrN4O8] (m / z): (positive ion mode) 562.8 [M+Na] + .

[0340] IE2076-12

[0341] 2,6-Dehydr-4-(3-cyano-5-hydroxy-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-12).

[0342] Indazole N-oxide IE2076-3 was reduced with zinc powder according to a standard procedure, followed by deprotection with LiOH solution. The deprotected product was purified by silica gel chromatography using an EtOAc / MeOH / H2O (7:2:1) solvent system. The final deprotected product IE2076-12 was obtained in 61% yield. 1 H NMR (400 MHz, D2O): δ =0.90 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.63-3.72 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz, 1H), 4.03 (ddd, J = 9.4, 6.3,2.6 Hz, 1H), 4.55-4.69 (m, 2H), 5.57-5.66 (m, 1H), 5.94 (d, J = 2.2 Hz, 1H), 6.61 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 9.3, 2.3 Hz, 1H), 7.59 (d, J = 9.4Hz, 1H); 13 C NMR (101 MHz, D2O): δ = 18.25, 18.55, 35.04, 48.19, 61.61, 68.24,69.81, 75.25, 97.35, 103.01, 112.57, 118.78, 127.92, 129.34, 143.01, 150.15,158.61, 164.81, 168.91, 180.34; LRMS [C 21 H 23 [N4NaO8] (m / z): (positive ion mode) 483.1 [M+H] + .

[0343] IE2076-14

[0344] 2,6-Dehydr-4-(3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-14).

[0345] Indazole N-oxide IE1963-114 was reduced with zinc powder according to a standard procedure, followed by deprotection with LiOH solution. The deprotected product was purified by silica gel chromatography using an EtOAc / MeOH / H2O (7:2:1) solvent system. The final deprotected product IE2076-14 was obtained in 55% yield. 1 H NMR (400 MHz, D2O): δ =0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3,2.7 Hz, 1H), 4.67 (d, J = 7.8 Hz, 2H), 5.73-5.82 (m, 1H), 5.99 (d, J = 2.3Hz, 1H), 7.42-7.50 (m, 1H), 7.52-7.59 (m, 1H), 7.82–7.89 (m, 2H); 13 C NMR (101MHz, D2O): δ = 18.16, 18.54, 48.33, 62.63, 63.05, 68.22, 69.77, 75.23, 102.40,107.73, 110.87, 117.95, 118.36, 125.51, 126.30, 128.36, 147.77, 150.47,168.77, 180.30; LRMS [C 21 H 23 [N4NaO7] (m / z): (positive ion mode) 467.1 [M+H] + .

[0346] IE2076-17

[0347] 2,6-Dehydr-4-(6-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-17).

[0348] The indazole N-oxide IE2076-2 was reduced with zinc powder according to a standard procedure, followed by deprotection with LiOH solution. The deprotected product was purified by silica gel chromatography using an EtOAc / MeOH / H2O (9:2:1) solvent system. The final deprotected product IE2076-17 was obtained in 57% yield. 1 H NMR (400 MHz, D2O): δ = 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.41 (p, J = 6.9 Hz, 1H), 3.63-3.72 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz, 1H), 4.04 (ddd, J = 9.4, 6.3,2.7 Hz, 1H), 4.66 (d, J = 8.5 Hz, 2H), 5.72-5.80 (m, 1H), 5.99 (d, J = 2.2Hz, 1H), 7.53 (dd, J = 9.0, 1.6 Hz, 1H), 7.76 (dd, J = 8.9, 0.8 Hz, 1H), 8.08(dd, J = 1.5, 0.8 Hz, 1H); 13 C NMR (101 MHz, D2O): δ = 18.19, 18.53, 34.94,48.27, 62.92, 63.04, 68.21, 69.75, 75.21, 102.11, 108.40, 110.28, 119.91,120.37, 121.73, 124.09, 129.72, 148.26, 150.58, 168.69, 180.33; LRMS[C 21 H 23 BrN4O7] (m / z): (positive ion mode) 547.0 [M+H] + .

[0349] IE2076-37

[0350] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-37).

[0351] Indazole N-oxide IE2076-16 was reduced with zinc powder according to a standard procedure, followed by deprotection with LiOH solution. The deprotected product was purified by silica gel chromatography using an EtOAc / MeOH / H2O (9:2:1) solvent system. The final deprotected product IE2076-37 was obtained in 53% yield. 1 H NMR (400 MHz, DMSO-d6): δ= 0.76 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.9 Hz, 3H), 2.21 (p, J = 6.9 Hz,1H), 3.36-3.44 (m, 2H), 3.62-3.67 (m, 2H), 4.32-4.40 (m, 1H), 4.48 (d, J =11.1 Hz, 1H), 5.54 (d, J = 2.1 Hz, 1H), 5.63 (dd, J = 9.1, 2.2 Hz, 1H), 6.72(s, 1H), 7.52 (dd, J = 9.2, 1.8 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.98-8.10(m, 1H); 13 C NMR (101 MHz, DMSO-d6): δ = 19.45, 19.60, 34.75, 48.76, 63.24, 63.83, 68.62, 70.35, 75.10, 100.01, 107.12, 110.60, 119.41, 120.78, 121.50,126.44, 131.15, 146.17, 152.61, 165.71, 177.29; LRMS [C 21 H 23 BrN4O7] (m / z): (positive ion mode) 523.2 [M+H] + .

[0352] IE2076-48

[0353] 2,6-Dehydr-3,4,5-Trideoxy-5-isobutyramido-4-(5-methoxy-3-cyano-2H-indazol-2-yl)-d-glycerol-d-galacto-non-2-enoic acid (IE2076-48).

[0354] Indazole N-oxide IE2076-11 was reduced with zinc powder according to a standard procedure, followed by deprotection with LiOH solution. The deprotected product was purified by silica gel chromatography using an EtOAc / MeOH / H2O (7:2:1) solvent system. The final deprotected product IE2076-48 was obtained in 62% yield. 1 H NMR (400 MHz, D2O): δ =0.87 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.91 (s, 4H), 4.04 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.59-4.70 (m, 2H), 5.63-5.76 (m, 1H), 5.98 (d, J = 2.2 Hz, 1H), 7.11-7.25 (m, 2H),7.74 (dd, J = 9.3, 0.8 Hz, 1H); 13 C NMR (101 MHz, D2O): δ = 18.21, 18.55,34.98, 48.23, 55.63, 62.37, 63.05, 68.22, 69.77, 75.24, 95.52, 102.51,111.19, 119.48, 122.66, 126.70, 144.42, 150.40, 157.77, 168.79, 180.26; LRMS[C 22 H 25 [N4NaO8] (m / z): (positive ion mode) 497.1 [M+H] + .

[0355] RP2066-28

[0356] 2,6-Dehydr-4-(5-carboxy-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (RP2066-28).

[0357] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 3-formyl-4-nitrobenzoate (46 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to produce deprotected indazole RP2066-28 in 8% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.62-3.75 (m, 2H), 3.93 (dd, J = 12.0, 2.8Hz, 1H), 4.04 (ddd, J = 10.5, 5.2, 2.0 Hz, 1H), 4.62-4.73 (m, 2H), 5.78-5.86(m, 1H), 6.02 (d, J = 2.2 Hz, 1H), 7.87 (dd, J = 9.0, 1.0 Hz, 1H), 7.98 (dd,J = 9.1, 1.6 Hz, 1H), 8.42-8.48 (m, 1H); 13 C NMR (101 MHz, D2O): δ 18.18,18.54, 34.94, 48.38, 62.89, 63.04, 68.20, 69.77, 75.23, 102.32, 110.34,117.92, 121.14, 124.83, 128.14, 131.42, 148.75, 150.42, 168.60, 172.51,172.58, 180.34; LRMS [C 22 H 24 [N4O9] (m / z): (Negative ion mode) 487.1 [MH] - .

[0358] RP2066-29

[0359] 2,6-Dehydr-4-(3-cyano-5-fluoro-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (RP2066-29).

[0360] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole RP2066-29 in 22% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.87 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.63-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz,1H), 4.04 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.59-4.71 (m, 2H), 5.70-5.80 (m,1H), 5.98 (d, J = 2.2 Hz, 1H), 7.36 (td, J = 9.4, 2.5 Hz, 1H), 7.50 (dd, J =8.7, 2.4 Hz, 1H), 7.87 (dd, J = 9.4, 4.4 Hz, 1H); 13 C NMR (101 MHz, D2O): δ18.16, 18.55, 34.95, 48.31, 62.81, 63.04, 68.21, 69.76, 75.21, 101.69 (d, J =26.4 Hz), 102.24, 110.58, 119.71 (d, J = 29.1 Hz), 120.59 (d, J = 10.2 Hz), 125.53, 125.66, 125.60 (d, J = 12.9 Hz), 145.18, 150.52, 159.50, 161.94,168.72, 180.30; LRMS [C 21 H 23 FN4O7] (m / z): (positive ion mode) 461.1 [MH] - .

[0361] RP2066-30

[0362] 2,6-Dehydr-4-(3-cyano-4-fluoro-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (RP2066-30).

[0363] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 2-fluoro-6-nitrobenzaldehyde (37 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole RP2066-30 in 5% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.90 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 2.44 (p, J = 6.9 Hz, 1H), 3.66-3.72 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.61-4.69 (m, 3H), 5.79 (dd, J =9.5, 2.3 Hz, 1H), 5.99 (d, J = 2.2 Hz, 1H), 7.13 (dd, J = 10.5, 7.6 Hz, 1H),7.49 (ddd, J = 8.8, 7.6, 5.1 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H); 13 C NMR (101MHz, D2O): δ 18.14, 18.57, 34.97, 48.38, 62.85, 63.04, 68.21, 69.76, 75.19,102.10, 105.56, 109.15, 109.31, 114.36, 128.72, 149.82, 150.59, 152.17,168.70, 180.37; LRMS [C 21 H 23 FN4O7] (m / z): (positive ion mode) 461.1 [MH] - .

[0364] JC2040-107

[0365] 2,6-Dehydr-4-(3-cyano-6-fluoro-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2040-107).

[0366] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2040-107 in 8% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.90 (d, J = 6.9 Hz, 3H), 0.98 (d, J = 6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.68 (dd, J = 11.5,5.4 Hz, 1H), 3.84 (dd, J = 11.5, 3.1 Hz, 1H), 3.95 (ddd, J = 8.9, 5.4, 3.0Hz, 1H), 4.66 (d, J = 11.2 Hz, 1H), 4.77 (dd, J = 11.1, 9.3 Hz, 1H), 5.79(dd, J = 9.3, 2.2 Hz, 1H), 5.86 (d, J = 2.2 Hz, 1H), 7.10 (dd, J = 11.2, 7.5Hz, 1H), 7.31 (td, J = 8.0, 4.2 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H); 13C NMR (101 MHz, CD3OD): δ 18.14, 18.21, 34.94, 48.44, 63.14, 63.42, 68.57, 70.11,75.39, 100.77, 108.20, 109.99 (d, J = 16.5 Hz), LRMS [C 21 H 23 FN4O7] (m / z): (positive ion mode) 485.1 [M+Na] + .

[0367] JC2040-110

[0368] 2,6-Dehydr-4-(6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2040-110).

[0369] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-chloro-2-nitrobenzaldehyde (41 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2040-110 in 2% yield (after 4 steps). 1H NMR (400 MHz, D2O): δ 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.64-3.73 (m, 2H), 3.93 (dd, J = 12.0, 2.7 Hz,1H), 4.04 (ddd, J = 9.3, 6.2, 2.6 Hz, 1H), 4.62-4.71 (m, 2H), 5.76 (dt, J =7.5, 2.2 Hz, 1H), 5.98 (d, J = 2.3 Hz, 1H), 7.42 (dd, J = 9.0, 1.7 Hz, 1H),7.84 (dd, J = 8.9, 0.8 Hz, 1H), 7.91 (dd, J = 1.7, 0.8 Hz, 1H); 13 C NMR (101MHz, D2O): δ 18.19, 18.54, 34.94, 48.27, 62.92, 63.04, 68.21, 69.75, 75.21,102.15, 108.37, 110.32, 117.02, 119.87, 123.93, 127.43, 133.75, 147.85,150.56, 168.70, 180.33; LRMS [C 21 H 23 ClN4O7] (m / z): (positive ion mode) 501.0 [M+Na] + .

[0370] JC2040-111

[0371] 2,6-Dehydr-4-(3-cyano-7-fluoro-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2040-111).

[0372] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3-fluoro-2-nitrobenzaldehyde (37 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2040-111 in 3% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.87 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 2.43 (p, J = 6.9 Hz, 1H), 3.65-3.74 (m, 2H), 3.93 (dd, J = 11.9, 2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.68 (d, J = 7.5 Hz, 2H), 5.74-5.86 (m, 1H), 6.00 (d, J = 2.3 Hz, 1H), 7.23 (dd, J = 11.4, 7.6 Hz, 1H), 7.39(td, J = 8.1, 4.3 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H); 13 C NMR (101 MHz, D2O): δ18.16, 18.53, 34.95, 48.32, 63.04, 63.18, 68.21, 69.76, 75.24, 102.02,103.82, 110.34, 111.27 (d, J = 15.6 Hz), 114.53, 126.70, 138.83 (d, J = 17.3Hz), 150.68, 151.15, 153.69, 168.70, 180.37; LRMS [C 21 H 23 FN4O7] (m / z): (positive ion mode) 485.0 [M+Na] + .

[0373] JC2040-112

[0374] 2,6-Dehydr-4-(5-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2040-112).

[0375] According to a standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-chloro-2-nitrobenzaldehyde (41 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to a standard procedure. Purification was then performed by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2040-112 in 1% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.86 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.42 (p, J = 6.9 Hz, 1H), 3.64-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.8 Hz,1H), 4.04 (ddd, J = 9.3, 6.2, 2.7 Hz, 1H), 4.63-4.71 (m, 2H), 5.76 (d, J =8.8 Hz, 1H), 5.99 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 9.2, 1.9 Hz, 1H), 7.82(d, J = 9.2 Hz, 1H), 7.90 (d, J = 1.3 Hz, 1H); 13 C NMR (101 MHz, D2O): δ18.17, 18.55, 34.94, 48.31, 62.85, 63.04, 68.20, 69.75, 75.20, 102.16,107.50, 110.39, 117.30, 119.68, 125.87, 129.54, 131.90, 146.21, 150.55,168.70, 180.30; LRMS [C 21 H 23 ClN4O7] (m / z): (positive ion mode) 501.0 [M+Na] + .

[0376] JC2094-3

[0377] 2,6-Dehydr-4-(4-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2094-3).

[0378] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-chloro-6-nitrobenzaldehyde (41 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2094-3 in 10% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.94 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 6.8 Hz, 3H), 2.38 (p, J = 6.8 Hz, 1H), 3.61 (d, J = 9.2 Hz, 1H), 3.68 (dd, J = 11.4,5.4 Hz, 1H), 3.84 (dd, J = 11.4, 3.0 Hz, 1H), 3.95 (ddd, J = 8.7, 5.4, 2.9Hz, 1H), 4.65 (d, J = 11.1 Hz, 1H), 4.73 (t, J = 10.2 Hz, 1H), 5.79 (dd, J =9.1, 2.2 Hz, 1H), 5.85 (d, J = 2.3 Hz, 1H), 7.31-7.40 (m, 2H), 7.76 (d, J =8.0 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.15, 18.31, 34.98, 48.50, 62.70,63.43, 68.57, 70.07, 75.33, 99.99, 101.00, 107.56, 110.30, 117.64, 123.63,123.71, 125.05, 127.42, 148.71, 151.14, 178.62; LRMS [C 21 H 23 ClN4O7] (m / z): (positive ion mode) 501.0 [M+Na] + .

[0379] CB2045-38

[0380] 2,6-Dehydr-4-(6-carboxy-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-38).

[0381] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with methyl 3-formyl-4-nitrobenzoate (46 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to produce deprotected indazole CB2045-38 in 12% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.85 (d, J = 6.8 Hz, 3H), 0.95 (d, J =7.0 Hz, 3H), 2.41 (p, J = 6.9 Hz, 1H), 3.65-3.72 (m, 2H), 3.93 (dd, J = 12.0,2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.65-4.73 (m, 2H), 5.77-5.86 (m, 1H), 6.01 (d, J = 2.2 Hz, 1H), 7.87 (d, J = 1.0 Hz, 2H), 8.31 (t, J= 1.1 Hz, 1H); 13 C NMR (101 MHz, D2O): δ 20.75, 21.05, 37.49, 50.87, 65.52,65.60, 70.77, 72.32, 77.78, 104.79, 113.22, 120.72, 121.63, 128.80, 129.25,139.29, 150.05, 153.06, 171.27, 177.31, 182.90; LRMS [C 22 H 24 [N4O9] (m / z): (positive ion mode) 511.1 [M+Na] + .

[0382] CB2045-43

[0383] 2,6-Dehydr-4-(3-cyano-6-methanesulfonyl-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-43).

[0384] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 4-(methanesulfonyl)-2-nitrobenzaldehyde (50 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole CB2045-43 in 9% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.86 (d, J = 6.9 Hz, 3H), 0.93 (d, J =7.0 Hz, 3H), 2.27 (p, J = 6.7 Hz, 1H), 3.19 (s, 3H), 4.26 (dt, J = 12.6, 2.8Hz, 1H), 4.56-4.69 (m, 4H), 5.52 (d, J = 1.7 Hz, 1H), 5.70-5.80 (m, 1H), 6.08(d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.9, 1.5 Hz, 1H), 8.01 (d, J = 8.7 Hz,1H), 8.51 (d, J = 1.4 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 17.71, 18.22,34.89, 42.72, 50.59, 61.63, 63.74, 67.39, 70.27, 75.60, 103.55, 109.43,120.05, 120.45, 122.10, 127.16, 140.14, 146.38, 169.83, 170.08, 171.03,178.28; LRMS [C 22 H 26 [N4O9S] (m / z): (positive ion mode) 545.0 [M+Na] + .

[0385] CB2045-44

[0386] 2,6-Dehydr-4-(3-cyano-6-trifluoromethyl-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-44).

[0387] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-4-(trifluoromethyl)benzaldehyde (48 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole CB2045-44 in 7% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.89 (d, J = 6.8 Hz, 3H), 0.98 (d, J =6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.62 (d, J = 9.3 Hz, 1H), 3.68 (dd, J= 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J = 8.8,5.4, 3.0 Hz, 1H), 4.67 (d, J = 11.1 Hz, 1H), 4.76 (dd, J = 11.0, 9.2 Hz, 1H),5.83 (dd, J = 9.3, 2.1 Hz, 1H), 5.90 (d, J = 2.2 Hz, 1H), 7.56 (dd, J = 8.9,1.4 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 8.20 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.13, 18.23, 34.92, 48.54, 63.25, 63.38, 68.51, 70.11, 75.45, 101.24,108.42, 109.57, 114.35, 117.10, 119.82, 120.98, 126.59, 129.00, 127.79 (d, J= 242.0 Hz), 129.32, 146.47, 167.31, 178.60; LRMS [C 22 H23 F3N4O7] (m / z): (positive ion mode) 535.1 [M+Na] + .

[0388] CB2045-50

[0389] 2,6-Dehydr-4-(4,5-dichloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-50).

[0390] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2,3-dichloro-6-nitrobenzaldehyde (48 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole CB2045-50 in 18% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.95 (d, J = 6.8 Hz, 3H), 1.00 (d, J =6.9 Hz, 3H), 2.38 (p, J = 6.9 Hz, 1H), 3.60 (d, J = 9.4 Hz, 1H), 3.67 (dd, J= 11.3, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 9.0,5.4, 2.9 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 4.71 (dd, J = 11.1, 9.0 Hz, 1H),5.76 (dd, J = 9.2, 2.2 Hz, 1H), 5.84 (d, J = 2.2 Hz, 1H), 7.49 (d, J = 9.1Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H); 13C NMR (101 MHz, CD3OD): δ 18.15, 18.32,34.97, 48.48, 63.12, 63.45, 68.60, 70.01, 75.25, 100.59, 108.02, 110.00,118.98, 121.25, 124.25, 129.04, 129.41, 146.93, 151.39, 167.78, 178.57; LRMS[C 21 H 22 [Cl2N4O7] (m / z): (positive ion mode) 537.0 [M+Na] + .

[0391] CB2045-51

[0392] 2,6-Dehydr-4-(3-cyano-2H-pyrazolo[4,3-b]pyridin-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-51).

[0393] Amberlite IR-120 resin (200 mg) was added to a solution of protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) and 3-nitropyridinecarboxaldehyde (33 mg, 0.22 mmol) in EtOH (2 mL), followed by the addition of TMSCN (55 µL, 0.44 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, concentrated under vacuum, and the residue was diluted with ethyl acetate and washed with water. The organic matter was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was dissolved in anhydrous ethanol (3 mL), and triethylamine (20 drops) was added to the stirred solution. The reaction mixture was stirred at room temperature for 2 hours, and then silica gel (1 g) was added to the mixture. The reaction mixture was concentrated under vacuum and purified by silica gel chromatography using hexane:ethyl acetate (1:3) to yield pure protected indazole-N-oxide. The protected indazole N-oxide was reduced with zinc powder and then deprotected according to a standard procedure. The deprotected indazole CB2045-51 was then purified by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to produce a 16% yield (after 4 steps). 1H NMR (400 MHz, CD3OD): δ 0.90 (d, J = 6.8 Hz,3H), 0.99 (d, J = 7.2 Hz, 3H), 2.36 (p, J = 6.9 Hz, 1H), 3.61 (d, J = 9.3 Hz,1H), 3.67 (dd, J = 11.3, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J = 8.8, 5.3, 2.9 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.75 (t, J = 10.2Hz, 1H), 5.82 (d, J = 9.1 Hz, 1H), 5.87 (s, 1H), 7.48 (dd, J = 8.8, 4.3 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 8.71 (d, J = 4.2 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 19.56, 19.67, 36.34, 49.94, 58.78, 64.85, 69.99, 71.41, 76.76,102.23, 110.19, 110.54, 124.05, 129.19, 142.06, 142.64, 152.57, 152.70,169.00, 179.99; LRMS [C 20 H 23 [N5O7] (m / z): (positive ion mode) 468.1 [M+Na] + .

[0394] IE2076-69

[0395] 2,6-Dehydr-4-(4-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-69).

[0396] According to a standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-bromo-6-nitrobenzaldehyde (50 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder, followed by deprotection according to a standard procedure, and then purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-69 in 15% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.93 (d, J = 6.9 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H), 2.45 (p, J = 6.9 Hz, 1H), 3.62-3.73 (m, 2H), 3.92 (dd, J = 12.0, 2.7 Hz,1H), 4.04 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.59 (t, J = 10.2 Hz, 1H), 4.66-4.72 (m, 1H), 5.80 (dd, J = 9.3, 2.3 Hz, 1H), 6.01 (d, J = 2.1 Hz, 1H), 7.39(dd, J = 8.8, 7.3 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.18, 18.68, 35.01, 48.50, 62.66, 63.04,68.22, 69.76, 75.15, 102.07, 110.67, 111.22, 117.61, 125.02, 128.99, 129.48,148.18, 150.60, 168.72, 180.26; LRMS [C 21 H 23 BrN4O7] (m / z): (positive ion mode) 547.0 [M+Na] + .

[0397] IE2076-78

[0398] 2,6-Dehydr-4-(5-bromo-3-cyano-6-fluoro-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-78).

[0399] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-bromo-4-fluoro-2-nitrobenzaldehyde (55 mg, 0.22 mmol) according to a standard procedure to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-78 in 21% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.8 Hz, 3H), 0.99 (d, J =6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.58 (dd, J = 9.4, 1.0 Hz, 1H), 3.66(dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.93 (ddd, J =9.6, 5.5, 2.9 Hz, 1H), 4.60-4.67 (m, 1H), 4.72 (dd, J = 11.1, 9.1 Hz, 1H),5.73 (dd, J = 9.2, 2.2 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 9.0Hz, 1H), 8.13 (d, J = 6.5 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.19, 18.26,34.93, 48.42, 63.19, 63.50, 68.65, 69.96, 75.26, 100.59, 103.36 (d, J = 26.2Hz), 109.45, LRMS [C 21 H22 BrFN4O7] (m / z): (positive ion mode) 565.1 [M+Na] + .

[0400] IE2076-80

[0401] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-80).

[0402] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-bromo-4-chloro-2-nitrobenzaldehyde (58 mg, 0.22 mmol) according to a standard procedure to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-80 in 26% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.8 Hz, 3H), 0.99 (d, J =6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.59 (dd, J = 9.6, 0.9 Hz, 1H), 3.66(dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.4, 2.9 Hz, 1H), 3.90-3.97 (m,1H), 4.64 (d, J = 11.0 Hz, 1H), 4.72 (dd, J = 11.1, 9.1 Hz, 1H), 5.74 (dd, J= 9.2, 2.2 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); 13CNMR (101 MHz, CD3OD): δ 18.18, 18.25, 34.92, 48.45, 63.33, 63.50, 68.65,69.95, 75.26, 100.47, 107.40, 109.38, 119.58, 119.82, 122.82, 124.86, 133.01,146.85, 151.47, 167.76, 178.53; LRMS [C 21 H 22 BrClN4O7] (m / z): (positive ion mode) 581.0 [M+Na] + .

[0403] IE2076-92

[0404] 2,6-Dehydr-4-(3-cyano-2H-benzo[g]indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-92).

[0405] Following standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 1-nitro-2-naphthaldehyde (44 mg, 0.22 mmol) to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-92 in 22% yield (after 4 steps). 1H NMR (400 MHz, CD3OD): δ 0.87 (d, J = 6.9 Hz, 3H), 0.96 (d, J = 6.9 Hz, 3H), 2.34 (p, J = 6.9 Hz, 1H), 3.58-3.72 (m, 2H), 3.86 (dd, J = 11.5, 2.9 Hz,1H), 3.96 (ddd, J = 9.5, 5.5, 2.9 Hz, 1H), 4.68 (d, J = 11.1 Hz, 1H), 4.76-4.81 (m, 1H), 5.80 (dd, J = 9.4, 2.3 Hz, 1H), 5.91 (d, J = 2.2 Hz, 1H), 7.57-7.70 (m, 4H), 7.88-7.94 (m, 1H), 8.57 (dd, J = 7.3, 1.9 Hz, 1H); 13 C NMR (101MHz, CD3OD): δ 18.21, 34.97, 48.49, 62.18, 63.55, 68.75, 70.00, 75.45,101.34, 108.13, 110.20, 115.20, 122.05, 123.63, 125.17, 127.24, 127.30,127.65, 128.40, 132.43, 145.62, 151.20, 168.01, 178.67; LRMS [C 25 H 26 [N4O7] (m / z): (positive ion mode) 517.2 [M+Na] + .

[0406] IE2076-97

[0407] 2,6-Dehydr-4-(3-cyano-5,7-dichloro-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-97).

[0408] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3,5-dichloro-2-nitrobenzaldehyde (48 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-97 in 18% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.9 Hz, 3H), 0.98 (d, J =6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.60 (dd, J = 9.4, 1.0 Hz, 1H), 3.67(dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J =9.5, 5.4, 2.9 Hz, 1H), 4.63-4.69 (m, 1H), 4.75 (dd, J = 11.1, 9.3 Hz, 1H),5.78 (dd, J = 9.4, 2.2 Hz, 1H), 5.86 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 1.7Hz, 1H), 7.76 (d, J = 1.7 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.23, 34.94,48.39, 63.48, 63.77, 68.63, 69.99, 75.36, 100.38, 108.35, 109.17, 116.03,125.52, 126.80, 127.31, 130.95, 143.87, 151.56, 167.72, 178.64; LRMS[C 21 H 22 Cl2N4O7] (m / z): (positive ion mode) 535.1 [M+Na] + .

[0409] IE2076-98

[0410] 2,6-Dehydr-4-(3,5-dicyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-98).

[0411] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3-formyl-4-nitrobenzene (39 mg, 0.22 mmol) according to a standard procedure to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-98 in 20% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.90 (d, J = 6.9 Hz, 3H), 0.98 (d, J =6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.59 (dd, J = 9.3, 1.0 Hz, 1H), 3.66(dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J =9.5, 5.5, 2.8 Hz, 1H), 4.63 ? 4.68 (m, 2H), 4.75 (dd, J = 11.1, 9.0 Hz, 2H),5.77-5.85 (m, 2H), 7.60 (dd, J = 9.0, 1.5 Hz, 1H), 7.98 (dd, J = 9.0, 1.0 Hz, 1H), 8.36 (t, J = 1.2 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.17, 18.24,34.91, 48.51, 63.49, 63.59, 68.63, 69.97, 75.28, 100.42, 108.83, 109.16,109.46, 118.25, 120.35, 124.35, 125.71, 127.72, 147.89, 151.55, 167.75,178.57; LRMS [C 22 H 23 [N5O7] (m / z): (positive ion mode) 492.2 [M+Na] + .

[0412] IE2076-112

[0413] 2,6-Dehydr-4-(3-cyano-5-trifluoromethyl-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-112).

[0414] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-5-(trifluoromethyl)benzaldehyde (48 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-112 in 23% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.90 (d, J = 6.8 Hz, 3H), 0.98 (d, J =7.0 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.60 (dd, J = 9.5, 1.0 Hz, 1H), 3.67(dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.8 Hz, 1H), 3.94 (ddd, J =9.5, 5.5, 2.9 Hz, 1H), 4.66 (d, J = 11.0 Hz, 1H), 4.76 (dd, J = 11.1, 9.3 Hz,1H), 5.82 (dd, J = 9.3, 2.2 Hz, 1H), 5.85 (d, J = 2.2 Hz, 1H), 7.62 (dd, J =9.2, 1.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 8.13-8.18 (m, 1H); 13C NMR (101MHz, CD3OD): δ 18.15, 18.23, 34.93, 48.50, 63.37, 63.48, 68.63, 69.98, 75.35,100.73, 109.38, 116.78 (d, J = 5.2 Hz), 120.23, 122.75 (d, J = 3.4 Hz),124.11, 125.36 (d, J = 40.2 Hz), 126.77, 127.26 (q, J = 32.3 Hz), 127.74,148.27, 151.33, 167.64, 178.59; LRMS [C 22 H 23 F3N4O7] (m / z): (positive ion mode) 535.2 [M+Na] + .

[0415] IE2124-9

[0416] 2,6-Dehydr-4-(5-bromo-3-cyano-6-methoxy-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-9).

[0417] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-bromo-4-methoxy-2-nitrobenzaldehyde (60 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-9 in 22% yield (after 4 steps). 1H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.8 Hz, 3H), 0.99 (d, J =5.7 Hz, 3H), 2.34 (dd, J = 13.9, 6.5 Hz, 1H), 3.58 (d, J = 9.5 Hz, 1H), 3.63-3.73 (m, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.94 (s, 4H), 4.63 (d, J = 11.1 Hz,1H), 4.68-4.76 (m, 1H), 5.68 (d, J = 9.3 Hz, 1H), 5.82 (s, 1H), 7.22 (s, 1H),7.98 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.21, 18.26, 34.96, 48.38, 55.56,62.37, 63.51, 68.67, 69.98, 75.37, 96.96, 101.27, 106.70, 109.86, 114.90,121.19, 121.67, 148.11, 150.98, 155.40, 167.64, 178.59; LRMS [C 22 H 25 BrN4O8] (m / z): (positive ion mode) 577.1 [M+Na] + .

[0418] IE2124-14

[0419] 2,6-Dehydr-4-(3-cyano-5,7-dibromo-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-14).

[0420] According to standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3,5-dibromo-2-nitrobenzaldehyde (68 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-14 in 12% yield (after 4 steps). 1H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.9 Hz, 3H), 0.99 (d, J =7.0 Hz, 3H), 2.35 (p, J = 6.8 Hz, 1H), 3.59 (d, J = 9.5 Hz, 1H), 3.64-3.71(m, 1H), 3.84 (dd, J = 11.4, 3.0 Hz, 1H), 3.93 (ddd, J = 8.9, 5.3, 2.9 Hz,1H), 4.64 (d, J = 11.1 Hz, 1H), 4.68-4.75 (m, 1H), 5.74 (dd, J = 9.2, 2.3 Hz,1H), 5.83 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.25 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 18.19, 18.25, 34.93, 48.47, 63.27, 63.47, 68.61, 70.00, 75.33, 100.77, 105.51, 107.44, 109.37, 121.61, 122.49, 123.14, 123.32, 125.27,147.22, 151.20, 178.55; LRMS [C 21 H 22 [Br2N4O7] (m / z): (positive ion mode) 625.1 [M+Na] + .

[0421] IE2124-51

[0422] 2,6-Dehydr-4-(3-cyano-5,6-dibromo-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-51).

[0423] Following a standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3,4-dibromo-2-nitrobenzaldehyde (68 mg, 0.22 mmol) to yield protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to a standard procedure. Purification was then performed by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-51 in 12% yield (after 4 steps).1 H NMR (400 MHz, CD3OD): δ 0.91 (d, J = 6.8 Hz, 3H), 0.99 (d, J =7.0 Hz, 3H), 2.35 (p, J = 6.8 Hz, 1H), 3.59 (d, J = 9.6 Hz, 1H), 3.64-3.70(m, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.93 (ddd, J = 9.0, 5.4, 2.8 Hz, 1H), 4.64 (d, J = 11.1 Hz, 1H), 4.72 (dd, J = 11.1, 9.2 Hz, 1H), 5.73 (dd, J= 9.2, 2.2 Hz, 1H), 5.81 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 8.25 (s, 1H); 13 CNMR (101 MHz, CD3OD): δ 18.18, 18.25, 34.93, 48.45, 63.31, 63.48, 68.63,69.98, 75.27, 100.52, 107.42, 109.37, 121.59, 122.49, 123.13, 123.31, 124.09,125.27, 147.21, 151.42, 178.55; LRMS [C 21 H 22 Br2N4O7] (m / z): (positive ion mode) 625.2 [M+Na] + .

[0424] IE2076-76

[0425] 2,6-Dehydr-4-(3-cyano-7-phenyl-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-76).

[0426] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro[1,1'-biphenyl]-3-carboxaldehyde (50 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2076-76 in 18% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.83 (d, J = 6.9 Hz, 3H), 0.95 (d, J =6.9 Hz, 3H), 2.31 (p, J = 6.9 Hz, 1H), 3.61 (dd, J = 9.3, 1.1 Hz, 1H), 3.66(dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd, J =9.5, 5.5, 2.9 Hz, 1H), 4.64-4.70 (m, 1H), 4.82 (d, J = 9.8 Hz, 1H), 5.85 (dd,J = 9.5, 2.3 Hz, 1H), 5.89 (d, J = 2.3 Hz, 1H), 7.33-7.39 (m, 1H), 7.44 (dd,J = 8.3, 7.0 Hz, 3H), 7.56 (dd, J = 7.1, 1.0 Hz, 1H), 7.71 (dd, J = 8.4, 1.0Hz, 1H), 7.94-8.00 (m, 2H); 13 C NMR (101 MHz, CD3OD): δ 18.17, 18.19, 34.93,48.44, 62.58, 63.50, 68.67, 70.05, 75.60, 101.71, 107.22, 110.26, 116.76,125.39, 125.92, 126.94, 127.55, 127.96, 128.79, 132.33, 137.16, 146.21,150.66, 167.54, 178.76; 27 H 28 [N4O7] (m / z): (positive ion mode) 543.1 [M+Na] +.

[0427] IE2124-1

[0428] 2,6-Dehydr-4-(3-cyano-7-(2-fluorophenyl)-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-1).

[0429] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2'-fluoro-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (54 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-1 in 16% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.83 (d, J = 6.9 Hz, 3H), 0.95 (d, J= 6.9 Hz, 3H), 2.30 (p, J = 6.9 Hz, 1H), 3.59 (dd, J = 9.3, 1.1 Hz, 1H), 3.66(dd, J = 11.5, 5.4 Hz, 1H), 3.83 (dd, J = 11.5, 2.9 Hz, 1H), 3.92 (ddd, J =9.4, 5.4, 2.9 Hz, 1H), 4.65 (d, J = 11.0 Hz, 1H), 4.78 (dd, J = 11.1, 9.5 Hz,1H), 5.83 (dd, J = 9.6, 2.2 Hz, 1H), 5.90 (d, J = 2.2 Hz, 1H), 7.16-7.28 (m,2H), 7.37-7.47 (m, 2H), 7.49 (dt, J = 7.0, 1.4 Hz, 1H), 7.74-7.82 (m, 2H); 13CNMR (101 MHz, CD3OD): δ 18.17, 18.18, 34.92, 48.40, 62.65, 63.47, 68.61,70.02, 75.69, 101.98, 107.18, 110.12, 115.24, 115.46, 117.55, 123.67 (d, J =3.6 Hz), 124.80 (d, J = 14.2 Hz), 125.45, 126.67 (d, J = 13.5 Hz), 127.82 (d,J = 3.8 Hz), 129.45 (d, J = 8.2 Hz), 132.21 (d, J = 3.1 Hz), 146.33, 150.30,158.67, 161.13, 167.12, 178.81; LRMS [C 27 H 27 FN4O7] (m / z): (positive ion mode) 561.2 [M+Na] + .

[0430] IE2124-5

[0431] 2,6-Dehydr-4-(3-cyano-7-(2,3-difluorophenyl)-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-5).

[0432] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2',3'-difluoro-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (58 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-5 in 13% yield (after 4 steps). 11H NMR (400 MHz, CD3OD): δ 0.83 (d, J = 6.9 Hz, 3H), 0.95 (d, J = 6.9 Hz, 3H), 2.30 (p, J = 6.9 Hz, 1H), 3.59 (dd, J = 9.4, 1.1 Hz, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.83 (dd, J = 11.5, 2.9 Hz, 1H), 3.92 (ddd, J = 9.4, 5.4, 2.9 Hz, 1H), 4.65 (d, J = 11.0 Hz, 1H), 4.78 (dd, J = 11.1, 9.4 Hz, 1H), 5.82 (dd, J = 9.6, 2.3 Hz, 1H), 5.87 (d, J = 2.3 Hz, 1H), 7.19 - 7.34 (m, 2H), 7.46 (dd, J = 8.3, 7.0 Hz, 1H), 7.52 (dt, J = 7.0, 1.4 Hz, 1H), 7.57 (ddt, J = 7.8, 6.2, 1.8 Hz, 1H), 7.81 (dd, J = 8.4, 1.1 Hz, 1H); 13 13C NMR (101 MHz, CD3OD): δ 18.16, 34.91, 48.38, 62.86, 63.49, 68.64, 70.02, 75.58, 101.44, 107.39, 110.01, 116.29 (d, J = 17.5 Hz), 118.21, 123.74, 123.79 (dd, J = 7.3, 4.7 Hz), 123.85, 125.39, 125.47 (d, J = 2.9 Hz), 126.55, 127.10 (d, J = 3.9 Hz), 127.22, 127.95 (d, J = 3.7 Hz), 146.06, 146.70 (d, J = 13.2 Hz), 149.40 (dd, J = 43.3, 13.1 Hz), 150.77, 152.06 (d, J = 13.4 Hz), 167.48, 178.73; LRMS [C 27 13 26 19F2N4O7] (m / z): (positive ion mode) 579.1 [M+Na] + 。

[0433] IE2124-6

[0434] 2,6-Dehydr-4-(3-cyano-7-(3-methoxyphenyl)-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-6).

[0435] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3'-methoxy-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (56 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole IE2124-6 in 2% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.86 (d, J = 6.9 Hz, 3H), 0.97(d, J = 6.9 Hz, 3H), 2.33 (p, J = 6.9 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.67(dd, J = 11.4, 5.4 Hz, 1H), 3.85 (m, 4H), 3.94 (ddd, J = 8.9, 5.4, 2.8 Hz,1H), 4.68 (d, J = 11.1 Hz, 1H), 4.80 (d, J = 10.2 Hz, 1H), 5.85 (dd, J = 9.5,2.2 Hz, 1H), 5.96 (d, J = 2.2 Hz, 1H), 6.92 (dd, J = 8.2, 2.6 Hz, 1H), 7.34(t, J = 7.9 Hz, 1H), 7.40-7.51 (m, 2H), 7.60 (d, J = 7.0 Hz, 1H), 7.71 (d, J= 8.4 Hz, 1H), 7.74-7.79 (m, 1H); 13C NMR (101 MHz, CD3OD): δ 18.18, 18.20,34.96, 48.64, 54.54, 62.31, 63.45, 68.58, 70.01, 75.67, 102.81, 107.40,110.28, 114.03, 114.08, 116.85, 120.46, 125.25, 125.95, 126.82, 128.92,132.00, 138.28, 146.28, 149.75, 159.66, 178.76; 28 H 30 [N4O8] (m / z): (positive ion mode) 573.3 [M+Na] + .

[0436] JC2094-64

[0437] 2,6-Dehydr-4-(3-cyano-7-(3-hydroxyphenyl)-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2094-64).

[0438] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3'-hydroxy-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (53 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2094-64 in 7% yield (after 4 steps). 1H NMR (400 MHz, D2O): δ 0.74 (d, J = 6.8 Hz, 3H), 0.89 (d,J = 6.9 Hz, 3H), 2.35 (p, J = 6.9 Hz, 1H), 3.67 (dd, J = 12.2, 7.3 Hz, 2H), 3.92 (d, J = 11.4 Hz, 1H), 4.04 (dd, J = 9.0, 5.5 Hz, 1H), 4.67 (d, J = 11.0Hz, 2H), 5.75 (d, J = 9.7 Hz, 1H), 5.98 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 6.5Hz, 1H), 7.36-7.50 (m, 4H), 7.54 (d, J = 7.1 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H); 13 C NMR (101 MHz, D2O): δ 18.18, 18.43, 30.20, 34.93, 48.05, 63.05,68.24, 69.75, 75.37, 102.34, 107.44, 110.83, 115.24, LRMS [C 27 H 28 [N4O8] (m / z): (positive ion mode) 559.2 [M+Na] + .

[0439] JC2094-65

[0440] 2,6-Dehydr-4-(3-cyano-7-(2-hydroxyphenyl)-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2094-65).

[0441] According to a standard procedure, protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2'-hydroxy-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (53 mg, 0.22 mmol) to give protected indazole N-oxide. The protected indazole N-oxide was reduced using zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2094-65 in 9% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.75 (d, J = 6.9 Hz, 3H), 0.89 (d,J = 6.9 Hz, 3H), 2.32 (p, J = 6.8 Hz, 1H), 3.61-3.72 (m, 2H), 3.91 (dd, J =12.1, 2.7 Hz, 1H), 4.02 (ddd, J = 9.2, 6.2, 2.6 Hz, 1H), 4.64 (d, J = 10.9Hz, 1H), 4.69-4.75 (m, 1H), 5.69 (dd, J = 9.3, 2.2 Hz, 1H), 5.95 (d, J = 2.2Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 7.33-7.51 (m, 4H), 7.80 (d, J = 7.8 Hz, 1H); 13 C NMR (101 MHz, D2O): δ 18.34, 18.40, 34.91, 47.93, 63.05, 63.26,68.21, 69.76, 75.35, 102.24, 110.76, 116.23, 117.81, 120.72, 124.43, 126.39,126.56, 128.56, 128.72, 129.99, 131.53, 146.47, 150.40, 152.96, 168.60,180.39; 27 H 28 [N4O8] (m / z): (positive ion mode) 559.2 [M+Na] + .

[0442] CB2045-78

[0443] 2,6-Dehydr-4-(3-cyano-7-(3,5-difluorophenyl)-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-78).

[0444] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 3',5'-difluoro-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (58 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole CB2045-78 in 11% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.64-0.80 (m, 3H), 0.83-0.96(m, 3H), 2.28-2.44 (m, 1H), 3.61-3.78 (m, 2H), 3.93 (dd, J = 10.9, 1.7 Hz,1H), 4.00-4.11 (m, 1H), 4.61-4.71 (m, 2H), 5.70-5.84 (m, 1H), 5.92-6.06 (m,1H), 7.02 (t, J = 9.9 Hz, 1H), 7.43-7.56 (m, 3H), 7.57-7.68 (m, 1H), 7.80-7.93 (m, 1H); LRMS [C 27 H 26 F₂N₄O₇ (m / z): (positive ion mode) 579.2 [M+Na] + .

[0445] CB2045-83

[0446] 2,6-Dehydr-4-(3-cyano-7-(pyrimidin-5-yl)-2H-indazol-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-83).

[0447] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 2-nitro-3-(pyrimidin-5-yl)benzaldehyde (50 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with iron powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to produce deprotected indazole CB2045-83 in 9% yield (after 4 steps). 1 H NMR (400 MHz, D2O): δ 0.74 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.9Hz, 3H), 2.36 (p, J = 6.9 Hz, 1H), 3.65-3.73 (m, 2H), 3.92 (dd, J = 11.9, 2.7Hz, 1H), 4.04 (ddd, J = 9.3, 6.3, 2.7 Hz, 1H), 4.65-4.70 (m, 1H), 4.74 (s,1H), 5.80 (dd, J = 9.5, 2.3 Hz, 1H), 6.01 (d, J = 2.3 Hz, 1H), 7.56 (dd, J =8.5, 7.1 Hz, 1H), 7.71 (dd, J = 7.2, 1.0 Hz, 1H), 7.94 (dd, J = 8.6, 1.0 Hz, 1H), 9.15 (s, 1H), 9.31 (s, 2H); 13 C NMR (101 MHz, D2O): δ 18.18, 18.41,34.91, 48.14, 63.05, 63.26, 68.22, 69.75, 75.32, 102.15, 110.54, 119.66,123.88, 126.43, 126.72, 127.58, 131.31, 145.45, 150.56, 155.63, 156.26,156.37, 168.71, 180.36; LRMS [C 25 H 26 [N6O7] (m / z): (positive ion mode) 523.2 [M+H] + .

[0448] JC2094-118

[0449] 2,6-Dehydr-4-(3-cyano-5-chloro-7-(2-difluorophenyl)-2H-indazole-2-yl)-3,4,5-trideoxy-5-isobutyramido-d-glycerol-d-galacto-non-2-enoic acid (JC2094-118).

[0450] Protected 4-amino-Neu5Ibu2en (IE889-89, 100 mg, 0.22 mmol) was reacted with 5-chloro-2'-fluoro-2-nitro-[1,1'-biphenyl]-3-carboxaldehyde (62 mg, 0.22 mmol) according to a standard procedure to yield protected indazole N-oxide. The protected indazole N-oxide was reduced with zinc powder and subsequently deprotected according to a standard procedure, followed by purification by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce deprotected indazole JC2094-118 in 7% yield (after 4 steps). 1 H NMR (400 MHz, CD3OD): δ 0.94 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H), 2.38 (p, J = 6.7 Hz, 1H), 3.66 (dd, J = 19.7, 8.2Hz, 2H), 3.85 (d, J = 11.0 Hz, 1H), 3.96 (d, J = 8.9 Hz, 1H), 4.68 (t, J =14.5 Hz, 2H), 5.81 (d, J = 8.9 Hz, 1H), 5.90 (s, 1H), 7.20 (t, J = 9.0 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.47 (q, J = 6.8 Hz, 1H), 7.79 (s, 1H), 7.94 (s, 1H); 13C NMR (101 MHz, CD3OD): δ 18.21, 18.29,34.98, 48.54, 62.96, 63.40, 68.53, 70.14, 75.47, 101.45, 107.25, 109.73,114.95, 115.17, 117.77, 121.30, 123.88, 123.92, 125.43, 126.64, 126.80,130.19, 130.27, 131.34, 131.37, 131.88, 135.17, 146.42, 158.57, 161.02,178.72; LRMS [C 27 H 26 [ClFN4O7] (m / z): (positive ion mode) 595.1 [M+Na] + .

[0451] Procedure for forming methyl 7,8,9-tri-O-acetyl-5-amino-2,6-dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoate (IE2124-20).

[0452]

[0453] Zinc powder (0.38 g, 3 equivalents, 5.85 mmol) and ammonium chloride (0.52 g, 5 equivalents, 9.75 mmol) were added to a solution of protected 4-azido-5-NHBoc-Neu2en (1.0 g, 1.95 mmol) in MeOH / H2O (4:1, 20 mL). The mixture was stirred at room temperature for 1 hour and then filtered through diatomaceous earth. The combined filtrate and washings were concentrated under vacuum and purified by silica gel chromatography using hexane:ethyl acetate (1:1) to yield pure 4-amino-5-NHBoc-Neu2en (IE927-82, 840 mg, 88% yield).

[0454] TMSCN (225 µL, 1.8 mmol) was added to a solution of IE927-82 (800 mg, 1.64 mmol) and 5-bromo-4-chloro-2-nitrobenzaldehyde (430 mg, 1.64 mmol) in glacial acetic acid (10 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was dissolved in anhydrous ethanol (20 mL), and triethylamine (0.5 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 2 hours, and 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 pure protected indazole-N-oxide.

[0455] Zinc powder (3 equivalents) and ammonium chloride (5 equivalents) were added to a solution of protected indazole-N-oxide in MeOH / H2O (4:1, 10 mL). The mixture was stirred at room temperature for 1 hour, then silica gel (2 g) was added, and the mixture was concentrated under vacuum and purified by silica gel chromatography using hexane:acetone (3:2) to produce reduced protected indazole IE2124-19 in 58% yield (after 3 steps).

[0456] While stirring, TFA (0.4 mL, 5.6 mmol) was added dropwise to a solution of indazole IE2124-19 (100 mg, 0.14 mmol) in anhydrous DCM (3 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 1:30 h, then diluted with DCM (20 mL) and washed with a saturated aqueous solution of NaHCO3 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to yield the 5-amino derivative IE2124-20 (92% yield), which was pure enough for subsequent 5-N-functionalization steps without further purification. 1H NMR (400 MHz, CD3OD): δ 2.04 (s, 3H), 2.09 (s, 3H), 2.14 (s, 3H), 3.78-3.83 (s, 3H), 4.31 (dd, J = 12.6, 5.3 Hz, 1H), 4.37 (dd, J= 10.5, 1.3 Hz, 1H), 4.61 (dd, J = 12.6, 2.4 Hz, 1H), 5.48-5.58 (m, 2H), 5.68(dd, J = 7.5, 1.3 Hz, 1H), 6.07 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 8.23 ​​(s,1H); 13 C NMR (101 MHz, CD3OD): δ 20.54, 20.61, 20.78, 51.21, 53.00, 63.12,65.36, 69.24, 71.16, 79.93, 108.68, 110.79, 120.70, 121.28, 124.55, 125.92,134.76, 146.81, 148.48, 163.12, 171.48, 172.34, 172.42; LRMS [C 24 H 24 BrClN4O9](m / z): (positive ion mode) 651.1 [M+Na] + .

[0457] Procedure for forming methyl 7,8,9-tri-O-acetyl-5-amino-2,6-dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoate (JC2094-88)

[0458]

[0459] TMSCN (225 µL, 1.8 mmol) was added to a solution of 4-amino-5-NHBoc-Neu2en (IE927-82; 800 mg, 1.64 mmol) and 5-bromo-2-nitrobenzaldehyde (380 mg, 1.64 mmol) in glacial acetic acid (10 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was separated, washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was dissolved in anhydrous ethanol (20 mL), and triethylamine (0.5 mL) was added to the stirred solution. The reaction mixture was stirred at room temperature for 2 hours, and 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 pure protected indazole-N-oxide.

[0460] Zinc powder (3 equivalents) and ammonium chloride (5 equivalents) were added to a solution of the protected indazole-N-oxide in MeOH / H2O (4:1, 10 mL). The mixture was stirred at room temperature for 1 hour, then silica gel (2 g) was added, and the mixture was concentrated under vacuum and purified by silica gel chromatography using hexane:acetone (3:2) to produce reduced protected indazole JC2094-86 in 46% yield (after 3 steps).

[0461] While stirring, TFA (0.41 mL, 5.76 mmol) was added dropwise to a solution of reduced indazole (100 mg, 0.144 mmol) in anhydrous DCM (3 mL) under argon atmosphere. The reaction mixture was stirred at room temperature for 1:30 h, then diluted with DCM (20 mL) and washed with a saturated aqueous solution of NaHCO3 (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to produce the 5-amino derivative JC2094-88 (quantitative yield) with sufficient purity for subsequent 5-N-functionalization steps without further purification. 1H NMR (400 MHz, CDCl3): δ 2.07 (s, 3H), 2.13 (s, 3H), 2.17 (s, 3H), 3.45 (s, 1H), 3.81 (s, 4H), 4.24 (dt, J = 12.7, 6.4 Hz, 1H), 4.32 (dd, J = 12.7, 4.6 Hz, 1H), 4.60 (dd, J = 12.8, 2.1 Hz, 1H), 5.38-5.54(m, 2H), 5.59 (d, J = 7.2 Hz, 1H), 6.04 (d, J = 2.3 Hz, 1H), 7.48 (dd, J =9.2, 1.8 Hz, 1H), 7.68-7.72 (m, 1H), 7.94 (dd, J = 1.8, 0.8 Hz, 1H); LRMS[C 24 H 25 BrN4O9] (m / z): (positive ion mode) 616.9 [M+Na] + .

[0462] General procedure for 5-N-acylation of protected 5-amino-4-indazole:

[0463] Diisopropylethylamine (70 µL, 0.4 mmol) was added to a solution of the protected 5-amino-4-indazole-Neu2en derivative (0.08 mmol) in anhydrous DCM (3 mL), followed by the addition of an appropriate acyl chloride (0.24 mmol). The reaction mixture was stirred overnight at room temperature under argon atmosphere, then silica gel (1 g) was added to the mixture, and the mixture was concentrated under vacuum and purified by silica gel chromatography using a suitable solvent system.

[0464] CB2045-102

[0465] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-cyclopentanecarbamate-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2045-102).

[0466] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclopentaneformyl chloride (29 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2045-102 in 42% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 1.32 (dd, J= 14.4, 8.6 Hz, 1H), 1.45-1.62 (m, 5H), 1.74 (tdd, J = 21.1, 14.9, 8.3 Hz, 2H), 2.54 (p, J = 7.8 Hz, 1H), 3.61 (d, J = 9.3 Hz, 1H), 3.68 (dd, J = 11.4,5.4 Hz, 1H), 3.84 (dd, J = 11.7, 3.0 Hz, 1H), 3.94 (dt, J = 8.8, 3.9 Hz, 1H), 4.63 (d, J = 11.0 Hz, 2H), 5.74 (t, J = 7.9 Hz, 1H), 5.83 (s, 1H), 8.05 (s, 1H), 8.19 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 26.82, 31.51, 46.50, 49.98,64.28, 64.81, 69.94, 71.45, 76.73, 102.11, 110.77, 111.10, 120.87, 121.26,125.23, 126.22, 128.10, 134.47, 148.25, 169.08, 179.18; LRMS [C 23 H 24 BrClN4O7](m / z): (positive ion mode) 607.1 [M+Na] + .

[0467] CB2045-103

[0468] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-cyclobutanecarbamate-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2045-103).

[0469] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclobutaneformyl chloride (28 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2045-103 in 38% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 1.70 (dddt,J = 10.3, 8.2, 5.3, 2.9 Hz, 1H), 1.86-1.94 (m, 2H), 1.97-2.04 (m, 1H), 2.04-2.11 (m, 2H), 2.95-3.06 (m, 1H), 3.57 (d, J = 9.3 Hz, 1H), 3.67 (dd, J =11.5, 5.4 Hz, 1H), 3.83 (dd, J = 11.5, 2.9 Hz, 1H), 3.93 (ddd, J = 9.5, 5.4,2.9 Hz, 1H), 4.60-4.73 (m, 2H), 5.71 (dd, J = 9.1, 2.3 Hz, 1H), 5.82 (d, J =2.1 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 17.48,24.34, 24.95, 39.30, 48.65, 63.29, 63.43, 68.54, 69.99, 75.27, 100.56,107.48, 109.33, 119.58, 119.84, 122.84, 124.83, 133.04, 146.89, 151.43,167.76, 176.21; LRMS [C 22 H 22 BrClN4O7] (m / z): (positive ion mode) 593.3 [M+Na] + .

[0470] CB2045-104

[0471] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazole-2-yl)-3,4,5-trideoxy-5-(2-hydroxyacetamido)-d-glycerol-d-galacto-non-2-enoic acid (CB2045-104).

[0472] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with acetoxyacetyl chloride (26 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to produce the deprotected indazole CB2045-104 in 34% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.20 (q,J = 7.3 Hz, 1H), 3.62 (d, J = 9.4 Hz, 1H), 3.68 (dd, J = 11.5, 5.5 Hz, 1H), 3.82 (q, J = 2.3, 1.7 Hz, 1H), 3.85-3.89 (m, 1H), 3.92-3.96 (m, 1H), 4.75 (d,J = 6.1 Hz, 2H), 5.84 (d, J = 2.2 Hz, 1H), 5.87-5.93 (m, 1H), 8.05 (s, 1H),8.20 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.98, 62.45, 64.10, 64.88, 69.92,71.40, 76.62, 102.42, 108.89, 110.56, 120.93, 121.18, 124.41, 126.29, 134.45,148.30, 152.58, 175.50, 177.66; LRMS [C 19 H 18 BrClN4O8] (m / z): (positive ion mode) 567.2 [M+Na] + .

[0473] CB2045-110

[0474] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-cyclopropanecarbamate-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2045-110).

[0475] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with cyclopropaneformyl chloride (22 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2045-110 in 39% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 0.36-0.46(m, 1H), 0.62-0.77 (m, 3H), 1.50 (tt, J = 8.2, 3.8 Hz, 1H), 3.60-3.73 (m,2H), 3.84 (dd, J = 11.5, 3.0 Hz, 1H), 3.94 (ddd, J = 9.8, 5.4, 2.8 Hz, 1H), 4.62-4.72 (m, 2H), 5.70-5.78 (m, 1H), 5.82 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H),8.19 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 7.40, 7.77, 14.91, 50.45, 64.77,64.90, 70.01, 71.39, 76.67, 101.92, 110.68, 121.04, 121.17, 124.16, 126.23,134.38, 148.33, 152.84, 176.39; LRMS [C 21 H 20 BrClN4O7] (m / z): (positive ion mode) 579.0 [M+Na] + .

[0476] CB2045-111

[0477] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-propamido-d-glycerol-d-galacto-non-2-enoic acid (CB2045-111).

[0478] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with propionyl chloride (21 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2045-111 in 50% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 0.96 (t, J = 7.6Hz, 3H), 2.12 (q, J = 7.7 Hz, 2H), 3.60 (d, J = 9.3 Hz, 1H), 3.67 (dd, J =11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.4, 2.9 Hz, 1H), 3.94 (ddd, J = 9.3, 5.6,2.9 Hz, 1H), 4.66 (dd, J = 7.9, 2.0 Hz, 2H), 5.73 (dt, J = 7.9, 1.9 Hz, 1H), 5.82 (d, J = 2.3 Hz, 1H), 8.06 (s, 1H), 8.19 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 10.08, 30.15, 50.12, 64.65, 64.86, 69.97, 71.36, 76.63, 101.99,108.86, 110.76, 120.95, 121.23, 124.32, 126.26, 134.46, 148.29, 152.84,169.15, 176.89; LRMS [C 20 H 20 BrClN4O7] (m / z): (positive ion mode) 567.0 [M+Na] + .

[0479] CB2045-112

[0480] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-(2-phenylacetamido)-d-glycerol-d-galacto-non-2-enoic acid (CB2045-112).

[0481] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with phenylacetyl chloride (32 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2045-112 in 37% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.36 (s, 2H), 3.57 (d, J = 9.4 Hz, 1H), 3.63 (dd, J = 11.2, 5.4 Hz, 1H), 3.83 (dd, J =11.6, 3.1 Hz, 1H), 3.93 (ddd, J = 9.0, 5.5, 2.9 Hz, 1H), 4.62 (d, J = 11.1Hz, 1H), 4.77 (dd, J = 11.1, 9.5 Hz, 1H), 5.71 (dd, J = 9.5, 2.3 Hz, 1H), 5.78 (d, J = 2.3 Hz, 1H), 7.00-7.06 (m, 2H), 7.09-7.17 (m, 3H), 7.94 (s, 1H),8.02 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 43.88, 49.94, 64.25, 65.00, 70.10,71.37, 76.78, 97.46, 101.95, 108.90, 110.66, 120.98, 124.55, 125.99, 127.77,129.40, 129.92, 134.27, 136.25, 148.15, 152.66, 169.05, 173.93; LRMS[C 25 H 22 BrClN4O7] (m / z): (positive ion mode) 629.0 [M+Na] + .

[0482] IE2076-107

[0483] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-trifluoroacetamido-d-glycerol-d-galacto-non-2-enoic acid (IE2076-107).

[0484] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trifluoroacetic anhydride (33 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2076-107 in 42% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.55 (dd, J =9.6, 1.2 Hz, 1H), 3.68 (dd, J = 11.6, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.8Hz, 1H), 3.95 (ddd, J = 9.6, 5.4, ​​2.8 Hz, 1H), 4.72 (dd, J = 11.0, 1.2 Hz, 1H), 4.79 (d, J = 9.3 Hz, 1H), 5.78 (dd, J = 9.2, 2.2 Hz, 1H), 5.84 (d, J =2.2 Hz, 1H), 8.07 (s, 1H), 8.20 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.33,62.69, 63.36, 68.58, 69.83, 74.79, 100.28, 107.29, 108.94, 115.62 (d, J =287.2 Hz), 119.53, 120.08, 122.87, 124.89, 133.28, 147.00, 151.60, 157.13,167.41; LRMS [C 19 H 15 BrClF3N4O7] (m / z): (positive ion mode) 607.0 [M+Na] + .

[0485] IE2124-27

[0486] 2,6-Dehydr-5-acetamido-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-27).

[0487] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with acetic anhydride (23 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-27 in 51% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 1.85 (s, 3H), 3.61 (d, J = 9.5 Hz, 1H), 3.68 (dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9Hz, 1H), 3.94 (ddd, J = 9.7, 5.4, 2.8 Hz, 1H), 4.63 (d, J = 6.5 Hz, 2H), 5.73(dt, J = 5.7, 2.4 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 8.06 (s, 1H), 8.20 (s,1H); 13 C NMR (101 MHz, CD3OD): δ 21.19, 48.96, 63.16, 63.48, 68.59, 69.96,75.18, 100.67, 107.48, 109.29, 119.55, 119.79, 122.95, 124.87, 133.04,146.93, 151.37, 167.73, 171.75; LRMS [C 19 H 18 BrClN4O7] (m / z): (positive ion mode) 552.9 [M+Na] + .

[0488] IE2124-28

[0489] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-(thiophen-2-carboxamido)-d-glycerol-d-galacto-non-2-enoic acid (IE2124-28).

[0490] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with thiophene-2-carbonyl chloride (26 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-28 in 49% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.61-3.74(m, 2H), 3.82 (dd, J = 11.6, 2.9 Hz, 1H), 3.97 (ddd, J = 9.4, 5.1, 2.8 Hz,1H), 4.79 (d, J = 11.2 Hz, 2H), 5.87 (h, J = 2.3 Hz, 2H), 7.08 (dd, J = 5.0, 3.8 Hz, 1H), 7.61 (dd, J = 5.0, 1.1 Hz, 1H), 7.65 (dd, J = 3.9, 1.1 Hz, 1H), 8.04 (s, 1H), 8.11 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.35, 63.02, 63.31,68.53, 69.97, 75.39, 100.72, 107.61, 109.16, 119.50, 119.85, 122.86, 124.72,127.36, 128.87, 130.94, 133.12, 137.76, 146.96, 151.47, 162.70, 167.63; LRMS[C 22 H 18 BrClN4O7S] (m / z): (positive ion mode) 620.7 [M+Na] + .

[0491] IE2124-30

[0492] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazole-2-yl)-3,4,5-trideoxy-5-(isoxazol-5-carboxamido)-d-glycerol-d-galacto-non-2-enoic acid (IE2124-30).

[0493] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with isoxazol-5-carbonyl chloride (23 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-30 in 44% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.61-3.73(m, 2H), 3.82 (dd, J = 11.5, 2.9 Hz, 1H), 3.96 (ddd, J = 9.5, 5.2, 2.8 Hz,1H), 4.81 (dd, J = 11.1, 1.1 Hz, 2H), 5.84-5.97 (m, 2H), 6.84 (d, J = 1.9 Hz,1H), 8.05 (s, 1H), 8.15 (s, 1H), 8.46 (d, J = 1.9 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.11, 62.88, 63.33, 68.53, 69.94, 75.21, 101.01, 106.27, 107.40,109.07, 119.52, 119.93, 122.92, 124.89, 133.16, 146.96, 150.90, 151.16,156.43, 161.87, 167.21; LRMS [C 21 H 17 BrClN5O8] (m / z): (positive ion mode) 606.1 [M+Na] + .

[0494] IE2124-31

[0495] 2,6-Dehydr-5-benzamido-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-31).

[0496] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with benzoyl chloride (28 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-31 in 38% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.69 (ddd, J =9.7, 5.6, 3.1 Hz, 2H), 3.83 (dd, J = 11.6, 2.9 Hz, 1H), 3.97 (ddd, J = 9.4,5.1, 2.9 Hz, 1H), 4.79-4.83 (m, 1H), 4.93 (dd, J = 11.2, 8.9 Hz, 1H), 5.87-5.94 (m, 2H), 7.37-7.43 (m, 2H), 7.47-7.54 (m, 1H), 7.65-7.71 (m, 2H), 8.04(s, 1H), 8.13(s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.42, 63.06, 63.32, 68.56,69.98, 75.40, 100.87, 107.53, 109.25, 119.50, 119.86, 122.87, 124.77, 127.02,128.06, 128.09, 131.57, 133.12, 133.37, 146.95, 151.38, 167.59, 168.68; LRMS[C 24 H 20 BrClN4O7] (m / z): (positive ion mode) 615.2 [M+Na] + .

[0497] IE2124-34

[0498] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-pentaamino-d-glycerol-d-galacto-non-2-enoic acid (IE2124-34).

[0499] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with pentanoyl chloride (30 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-34 in 45% yield (after 2 steps). 1 H NMR (400 MHz, D2O): δ 1.04 (s, 9H), 3.57 (d, J = 9.3 Hz, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9Hz, 1H), 3.94 (ddd, J = 8.9, 5.4, 2.9 Hz, 1H), 4.70 (d, J = 11.1 Hz, 1H), 4.77 (ddd, J = 11.3, 6.7, 2.3 Hz, 1H), 5.82 (dt, J = 9.4, 1.6 Hz, 1H), 5.88(d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 8.19 (s, 1H); 13 C NMR (101 MHz, D2O): δ26.24, 38.34, 48.79, 62.84, 63.44, 68.55, 70.02, 75.54, 101.62, 107.42,109.44, 119.55, 119.89, 122.83, 124.79, 133.09, 146.85, 150.63, 167.01,179.98; LRMS [C 22 H 24 BrClN4O7] (m / z): (positive ion mode) 595.1 [M+Na] + .

[0500] IE2124-36

[0501] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-pentafluoropropamido-d-glycerol-d-galacto-non-2-enoic acid (IE2124-36).

[0502] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with pentafluoropropionyl chloride (44 mg, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-36 in 37% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.51-3.56 (m,1H), 3.66 (dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.95 (ddd, J = 9.5, 5.5, 2.8 Hz, 1H), 4.72 (dd, J = 11.0, 1.2 Hz, 1H), 4.92 (dd, J= 11.0, 9.4 Hz, 1H), 5.79 (dd, J = 9.5, 2.2 Hz, 1H), 5.82 (d, J = 2.2 Hz, 1H), 8.05 (s, 1H), 8.20 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.19, 62.72,63.41, 68.66, 69.90, 74.83, 100.26, 107.23, 108.91, 118.50 (d, J = 193.7 Hz), 119.53, 120.07, 122.82, 124.91, 126.17 (d, J = 133.1 Hz), 133.25, 146.93,151.52, 153.73 (d, J = 39.9 Hz), 157.76; 20 H 15 [BrClF5N4O7] (m / z): (positive ion mode) 657.0 [M+Na] + .

[0503] IE2124-39

[0504] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(2,2,2-trichloroacetamide)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-39).

[0505] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trichloroacetyl chloride (27 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-39 in 53% yield (after 2 steps). 1 H NMR (400 MHz, D2O): δ 3.62-3.75 (m,2H), 3.92 (dd, J = 12.1, 2.7 Hz, 1H), 4.05 (ddd, J = 9.3, 6.3, 2.6 Hz, 1H), 4.60-4.68 (m, 1H), 4.73-4.76 (m, 1H), 5.88 (dd, J = 9.6, 2.3 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 8.17 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ50.58, 61.79, 63.32, 68.48, 70.02, 76.06, 105.43, 107.81, 109.12, 119.55,120.26, 122.94, 124.75, 133.49, 147.06, 147.11, 162.51, 163.72; LRMS[C 19 H 15 BrCl4N4O7] (m / z): (positive ion mode) 656.8 [M+Na] + .

[0506] IE2124-43

[0507] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-(furan-2-carboxamido)-d-glycerol-d-galacto-non-2-enoic acid (IE2124-43).

[0508] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with trichloroacetyl chloride (30 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-43 in 40% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.67 (dd, J =10.9, 5.6 Hz, 2H), 3.82 (dd, J = 11.6, 2.8 Hz, 1H), 3.96 (ddd, J = 9.0, 5.3,2.9 Hz, 1H), 4.78 (d, J = 11.0 Hz, 2H), 5.82-5.93 (m, 2H), 6.53 (dd, J = 3.4,1.8 Hz, 1H), 6.92-7.02 (m, 1H), 7.63 (d, J = 1.8 Hz, 1H), 8.04 (s, 1H), 8.13(s, 1H); 13 C NMR (101 MHz, CD3OD): δ 48.67, 63.08, 63.36, 68.56, 70.01, 75.37,100.78, 107.49, 109.05, 111.60, 114.63, 119.51, 119.81, 122.90, 124.81,133.03, 133.07, 145.26, 146.73, 146.92, 159.05; LRMS [C 22 H 18 BrClN4O8] (m / z): (positive ion mode) 605.2 [M+Na] + .

[0509] IE2124-46

[0510] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(2,2-dichloroacetamide)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-46).

[0511] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with dichloroacetyl chloride (23 µL, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-46 in 34% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.58-3.70 (m,2H), 3.85 (dd, J = 11.5, 3.0 Hz, 1H), 3.95 (ddd, J = 9.0, 5.6, 2.9 Hz, 1H), 4.72 (d, J = 11.1 Hz, 1H), 4.76-4.82 (m, 1H), 5.77-5.88 (m, 1H), 6.08 (s,1H), 8.05 (s, 1H), 8.18 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 49.35, 62.59,63.47, 65.78, 68.69, 70.06, 75.07, 100.68, 107.68, 109.23, 119.59, 119.94,122.90, 124.79, 133.15, 146.98, 151.17, 165.13, 167.44; LRMS [C 19 H 16 BrCl3N4O7](m / z): (positive ion mode) 621.3 [M+Na] + .

[0512] IE2124-82

[0513] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(2-bromo-2,2-difluoroacetamide)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-82).

[0514] The protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (50 mg, 0.08 mmol) was reacted with 2-bromo-2,2-difluoroacetyl chloride (45 mg, 0.24 mmol) according to the general procedure for N-acylation to produce the protected amide. Deprotection was performed according to the general procedure, and the product was purified by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-82 in 36% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.59(dd, J = 9.4, 1.2 Hz, 1H), 3.67 (dd, J = 11.5, 5.5 Hz, 1H), 3.84 (dd, J =11.5, 2.9 Hz, 1H), 3.95 (ddd, J = 9.5, 5.4, ​​2.8 Hz, 1H), 4.72 (dd, J = 11.0,1.2 Hz, 1H), 4.81 (s, 1H), 5.77-5.87 (m, 2H), 8.07 (s, 1H), 8.21 (s, 1H); 13 CNMR (101 MHz, CD3OD): δ 49.28, 62.58, 63.40, 68.67, 69.96, 74.96, 100.41,109.10, 109.15 (d, J = 330.7 Hz), 113.93, 119.59, 120.06, 122.92, 124.86,133.26, 147.00, 148.20, 160.48 (t, J = 28.0 Hz), 167.41; LRMS[C 19 H 15 Br₂ClF₂N₄O₇] (m / z): (positive ion mode) 666.9 [M+Na] + .

[0515] CB2160-3

[0516] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(2-ethylbutamido)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2160-3).

[0517] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (40 mg, 0.064 mmol) was reacted with 2-ethylbutyryl chloride (18 µL, 0.13 mmol) in anhydrous DCM (2 mL) containing triethylamine (45 µL, 0.32 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2160-3 in 48% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 0.42 (m, 3H), 0.71 - 0.81 (m, 3H), 1.18 - 1.48 (m, 5H), 3.54 - 3.68 (m, 2H), 3.82 (dd, J = 11.4, 2.9 Hz, 1H),3.89-3.93 (m, 1H), 4.11-4.17 (m, 1H), 4.29 - 4.39 (m, 1H), 4.51 (d, J = 11.1Hz, 1H), 5.73 (s, 1H), 8.01 (s, 1H), 8.15 (s, 1H); 13 C NMR (101 MHz, CD3OD) δ12.02, 12.45, 12.59, 20.84, 26.22, 26.76, 51.77, 64.66, 65.03, 67.48, 70.16,71.31, 77.02, 102.12, 110.66, 120.93, 121.33, 124.21, 126.28, 134.51, 148.17,152.62, 178.90; LRMS [C 23 H 26 BrClN4O7] (ESI): m / z 609.1 [M+Na] + .

[0518] CB2160-4

[0519] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(2,2-dimethylbutyramido)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2160-4).

[0520] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (40 mg, 0.064 mmol) was reacted with 2,2-dimethylbutyryl chloride (18 µL, 0.13 mmol) in anhydrous DCM (2 mL) containing triethylamine (45 µL, 0.32 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole CB2160-4 in 42% yield (after 2 steps). 1 ¹H NMR (400 MHz, CD3OD): δ 0.47 (t, J = 7.4 Hz, 3H), 0.96 (s, 3H), 1.00 (s, 3H), 1.31–1.37 (m, 2H), 3.54 (d, J = 9.5 Hz, 1H), 3.62 (dd, J = 11.4, 5.5 Hz, 1H), 3.80 (dd, J = 11.5, 2.9 Hz, 1H), 3.91 (m, 1H), 4.58 (d, J = 11.1 Hz, 1H), 5.77 (m, 1H), 8.01 (s, 1H), 8.15 (s, 1H). Two protons are masked by the solvent peak at 4.86 ppm. 13 C NMR (101 MHz, CD3OD) δ 8.01, 23.76, 33.10,42.27, 48.40, 57.07, 62.98, 63.49, 68.59, 69.98, 75.49, 100.80, 107.42,109.40, 117.51, 119.53, 119.92, 122.80, 124.80, 133.10, 146.80, 151.32,167.76, 179.36; LRMS [C 23 H 26 BrClN4O7] (ESI): m / z 609.1 [M+Na] + .

[0521] IE2124-57

[0522] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-5-(2,2,2-trichloroacetamide)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-57).

[0523] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) was reacted with 2,2,2-trichloroacetyl chloride (28 µL, 0.25 mmol) in anhydrous DCM (3 mL) containing diisopropylethylamine (74 µL, 0.42 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-57 in 56% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 3.60-3.71 (m, 2H), 3.85 (dd, J = 11.5, 2.9 Hz, 1H), 3.96 (ddd, J = 9.4, 5.6, 2.9 Hz, 1H), 4.80 (dd, J = 11.1, 1.1 Hz, 2H), 5.90 (d, J = 8.6 Hz, 2H), 7.52 (dd, J = 9.2, 1.8Hz, 1H), 7.75 (d, J = 9.2 Hz, 1H), 7.96 (d, J = 1.6 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 50.52, 61.99, 63.46, 68.80, 70.04, 75.22, 101.56, 107.10, 109.50,119.55, 120.25, 120.50, 126.49, 130.94, 146.56, 150.58, 162.35, 166.89; LRMS[C 19 H 16 BrCl3N4O7] (m / z): (positive ion mode) 622.9 [M+Na] + .

[0524] IE2124-75

[0525] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-5-terpentamido-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-75).

[0526] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) was reacted with pentanoyl chloride (32 µL, 0.25 mmol) in anhydrous DCM (3 mL) containing diisopropylethylamine (74 µL, 0.42 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-75 in 44% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 1.03 (s, 9H), 3.54-3.60 (m, 1H), 3.66 (dd, J = 11.5, 5.4 Hz, 1H), 3.84 (dd, J = 11.5, 2.9 Hz, 1H), 3.94 (ddd,J = 8.9, 5.5, 2.9 Hz, 1H), 4.68 (dd, J = 11.0, 1.1 Hz, 1H), 4.75-4.83 (m,1H), 5.82 (h, J = 2.4 Hz, 2H), 7.51 (dd, J = 9.2, 1.8 Hz, 1H), 7.74 (dd, J =9.2, 0.8 Hz, 1H), 7.95 (dd, J = 1.8, 0.8 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ26.23, 48.74, 62.61, 63.47, 68.62, 70.04, 75.40, 100.99, 106.87, 109.80,119.38, 120.17, 120.46, 126.50, 130.76, 146.37, 151.26, 167.73, 179.96; LRMS[C 22 H 25 BrN4O7] (m / z): (positive ion mode) 561.1 [M+Na] + .

[0527] IE2124-76

[0528] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-(3-methylbutyramido)-d-glycerol-d-galacto-non-2-enoic acid (IE2124-76).

[0529] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) was reacted with isovaleryl chloride (30 mg, 0.25 mmol) in a solution of anhydrous DCM (3 mL) containing diisopropylethylamine (74 µL, 0.42 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-76 in 40% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 0.71 (d, J = 6.5 Hz, 3H), 0.75(d, J = 6.6 Hz, 3H), 1.84 (dp, J = 13.7, 6.8 Hz, 1H), 1.90-2.03 (m, 2H), 3.61(dd, J = 9.5, 1.1 Hz, 1H), 3.65 (dd, J = 11.5, 5.6 Hz, 1H), 3.84 (dd, J =11.5, 2.9 Hz, 1H), 3.94 (ddd, J = 9.5, 5.5, 2.9 Hz, 1H), 4.59 (dd, J = 11.0,1.1 Hz, 1H), 4.77-4.82 (m, 1H), 5.74 (dd, J = 9.5, 2.2 Hz, 1H), 5.82 (d, J =2.2 Hz, 1H), 7.51 (dd, J = 9.1, 1.8 Hz, 1H), 7.75 (dd, J = 9.2, 0.8 Hz, 1H),7.95 (dd, J = 1.8, 0.8 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 21.22, 25.71,44.88, 48.35, 62.86, 63.56, 68.70, 69.97, 75.53, 101.17, 106.97, 109.67,119.41, 120.21, 120.49, 126.57, 130.78, 146.42, 150.97, 167.49, 174.07; LRMS[C 22 H 25 BrN4O7] (m / z): (positive ion mode) 561.1 [M+Na] + .

[0530] IE2124-77

[0531] trans-2,6-dehydro-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-(2-methylbut-2-enamido)-d-glycerol-d-galacto-non-2-enoic acid (IE2124-77).

[0532] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) was reacted with trans-2-methylbut-2-enoyl chloride (30 mg, 0.25 mmol) in anhydrous DCM (3 mL) containing diisopropylethylamine (74 µL, 0.42 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole IE2124-77 in 35% yield (after 2 steps). 1 H NMR (400 MHz, CD3OD): δ 1.67-1.73 (m, 6H), 3.62 (d, J = 9.4 Hz, 1H), 3.66-3.72 (m, 1H), 3.83 (dd, J = 11.5, 2.9 Hz, 1H), 3.95 (ddd, J = 9.5, 5.3, 2.9 Hz, 1H), 4.70 (d, J = 11.1 Hz, 1H), 4.77 (dd, J= 11.1, 9.0 Hz, 1H), 5.82 (dd, J = 9.2, 2.3 Hz, 1H), 5.89 (d, J = 2.2 Hz, 1H), 6.29 (ddt, J = 6.9, 5.4, 3.7 Hz, 1H), 7.50 (dd, J = 9.2, 1.8 Hz, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.94 (d, J = 1.7 Hz, 1H); 13 C NMR (101 MHz, CD3OD): δ 10.92, 12.57, 49.03, 62.62, 63.41, 68.56, 69.99, 75.59, 101.66, 107.01,109.65, 119.37, 120.23, 120.46, 126.48, 130.79, 131.11, 131.50, 146.47,150.75, 167.22, 170.85; LRMS [C22 H 23 BrN4O7] (m / z): (positive ion mode) 559.1 [M+Na] + .

[0533] JC2094-91

[0534] 2,6-Dehydr-4-(5-bromo-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-5-trifluoroacetamido-d-glycerol-d-galacto-non-2-enoic acid (JC2094-91).

[0535] Following the general procedure for N-acylation, the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (50 mg, 0.084 mmol) was reacted with trifluoroacetic anhydride (33 µL, 0.25 mmol) in anhydrous DCM (3 mL) containing diisopropylethylamine (85 µL, 0.48 mmol) to produce the protected amide. Deprotection was performed according to the general procedure, and purification was carried out by silica gel chromatography using ethyl acetate:MeOH:H2O (10:2:1) to produce the deprotected indazole JC2094-91 in 14% yield (after 2 steps). 1 H NMR (400 MHz, D2O): δ 3.63-3.74 (m, 2H), 3.88-3.97(m, 1H), 4.07 (ddd, J = 9.2, 6.3, 2.7 Hz, 1H), 4.71 (q, J = 10.4, 9.2 Hz, 2H), 5.88 (dd, J = 9.3, 2.5 Hz, 1H), 6.04 (d, J = 2.2 Hz, 1H), 7.59 (dd, J =9.5, 1.7 Hz, 1H), 7.74 (d, J = 9.2 Hz, 1H), 8.05 (d, J = 1.7 Hz, 1H); 13 C NMR (101 MHz, D2O): δ 49.57, 62.14, 62.99, 68.10, 69.63, 74.81, 101.90, 107.22,109.91, 115.24 (d, J = 286.5 Hz), 119.69, 120.09, 120.72, 126.44, 132.11,146.49, 150.90, 158.49 (d, J = 38.2 Hz), 168.39; LRMS [C 19 H 16BrF3N4O7] (m / z): (positive ion mode) 571.1 [M+Na] + .

[0536] IE2124-89

[0537] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(isobutylamino)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-89).

[0538] Acetic acid (150 µL) was added to a solution of the protected 5-amino-4-indazole-Neu2en derivative IE2124-20 (60 mg, 0.096 mmol) in anhydrous DCM (3 mL), followed by the addition of isobutyraldehyde (44 µL, 0.48 mmol), and the reaction mixture was stirred at room temperature for 30 min. Sodium borohydride (36 mg, 0.96 mmol) was added in portions, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth, and the diatomaceous earth bed was washed with DCM (20 mL × 2). The combined filtrate and washings were washed with a saturated aqueous solution of NaHCO3 (20 mL), followed by a brine solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to produce a crude product. Purification was performed by silica gel chromatography using hexane:acetone (5:2) to produce the protected amine. LiOH solution (1.0 M) was added dropwise to a solution of the protected amine in acetonitrile (2 mL) at 0 °C until the pH reached 13–14. The mixture was stirred at 0 °C for 2 hours, then silica gel (1 g) was added, and the mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate:MeOH:H₂O (10:2:1) to produce deprotected indazole IE₂124-89 in 45% yield (after 2 steps). 1H NMR (400MHz, CD3OD): δ 0.59 (dd, J = 8.5, 6.7 Hz, 6H), 1.20 (dtd, J = 11.0, 6.6, 5.6,3.2 Hz, 1H), 1.95 (dd, J = 11.7, 6.5 Hz, 1H), 2.46 (dd, J = 11.6, 6.7 Hz, 1H), 3.48 (ddd, J = 10.6, 9.5, 5.1 Hz, 1H), 3.71 (dd, J = 11.5, 5.6 Hz, 1H), 3.85-3.92 (m, 2H), 3.95 (ddd, J = 8.8, 5.4, ​​2.8 Hz, 1H), 4.37 (d, J = 10.7Hz, 1H), 5.53 (dd, J = 9.5, 2.1 Hz, 1H), 5.73 (d, J = 2.1 Hz, 1H), 8.06 (s,1H), 8.22 (s, 1H); 13 C NMR (101 MHz, CD3OD): δ 19.16, 19.20, 29.08, 55.23,56.21, 63.59, 64.77, 68.80, 70.39, 77.59, 101.90, 109.63, 119.32, 119.58,122.85, 124.41, 133.01, 146.83, 148.02, 150.42, 167.90; LRMS [C 21 H 24 BrClN4O6](m / z): (positive ion mode) 545.1 [M+H] + .

[0539] IE2124-106

[0540] 2,6-Dehydr-5-(benzylamino)-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (IE2124-106).

[0541] Acetic acid (150 µL) was added to a solution of the protected 5-amino-4-indazole-Neu2en derivative JC2094-88 (60 mg, 0.102 mmol) in anhydrous DCM (3 mL), followed by benzaldehyde (51 µL, 0.51 mmol), and the reaction mixture was stirred at room temperature for 30 min. Sodium borohydride (40 mg, 1.02 mmol) was added in portions, and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through diatomaceous earth, and the diatomaceous earth bed was washed with DCM (20 mL × 2). The combined filtrate and washings were washed with a saturated aqueous solution of NaHCO3 (20 mL), followed by a brine solution (20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under vacuum to produce a crude product. Purification was performed by silica gel chromatography using hexane:ethyl acetate (5:2) to produce the protected amine. LiOH solution (1.0 M) was added dropwise to a solution of the protected amine in acetonitrile (2 mL) at 0 °C until the pH reached 13–14. The mixture was stirred at 0 °C for 2 hours, then silica gel (1 g) was added, and the mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate:MeOH:H₂O (10:2:1) to produce deprotected indazole IE₂124-106 in 33% yield (after 2 steps). 1 H NMR(400 MHz, CD3OD): δ 3.40-3.54 (m, 2H), 3.71-3.81 (m, 2H), 3.93 (dd, J = 11.5,2.2 Hz, 1H), 3.99 (s, 2H), 4.37 (d, J = 10.7 Hz, 1H), 5.40 (dd, J = 9.5, 2.1Hz, 1H), 5.67 (d, J = 2.1 Hz, 1H), 6.69-6.78 (m, 3H), 6.81 (dd, J = 7.7, 1.9Hz, 2H), 7.47 (dd, J = 9.1, 1.8 Hz, 1H), 7.57 (dd, J = 9.1, 0.8 Hz, 1H), 7.84(dd, J = 1.8, 0.8 Hz, 1H); 13C NMR (101 MHz, CD3OD): δ 51.07, 54.06, 63.61,65.08, 68.74, 70.43, 78.10, 101.64, 107.29, 109.87, 118.78, 120.29, 120.42,126.05, 126.42, 127.06, 127.89, 130.34, 140.00, 145.99, 150.79, 167.94; LRMS[C 24 H 23 BrN4O6] (m / z): (positive ion mode) 545.1 [M+H] + .

[0542] CB2160-6

[0543] 2,6-Dehydr-4-(5-bromo-6-chloro-3-cyano-2H-indazol-2-yl)-5-(1-oxoisoindoline-2-yl)-3,4,5-trideoxy-d-glycerol-d-galacto-non-2-enoic acid (CB2160-6).

[0544] TMSCN (22 μL, 0.17 mmol) was added dropwise to a solution of amine JC2094-88 (50 mg, 0.084 mmol) and o-phthalaldehyde (12 mg, 0.084 mmol) in ethanol (2 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was purified by silica gel chromatography using hexane:ethyl acetate (1:1) to yield the protected isoindolinone. LiOH solution (1.0 M) was added dropwise to a solution of the protected C-5 isoindolinone in acetonitrile (2 mL) at 0 °C until the pH reached 13–14. The mixture was stirred at 0 °C for 2 hours, and then silica gel (1 g) was added to the mixture. The mixture was concentrated under vacuum and purified by silica gel chromatography using ethyl acetate:MeOH:H2O (7:2:1) to yield the deprotected indazole CB2160-6 in 25% yield (after 2 steps). 1¹H NMR (400 MHz, CD₃OD) δ 3.40 (d, J = 9.4 Hz, 1H), 3.65 (dd, J = 11.6, 5.0 Hz, 1H), 3.78 (dd, J = 11.6, 3.0 Hz, 1H), 3.97 (ddd, J = 8.9, 5.0, 3.0 Hz, 1H), 4.59 (broad s, 1H), 5.92 (s, 1H), 7.40 - 7.55 (m, 2H), 7.54 - 7.66 (m, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.85 (s, 1H). Four protons are masked by the solvent peak at 4.86 ppm. 13 C NMR (101MHz, CD3OD) δ 48.36, 48.57, 48.79, 49.00, 49.21, 49.28, 49.42, 49.50, 49.64,49.71, 64.55, 71.27, 102.27, 110.40, 120.93, 121.68, 121.81, 124.35, 129.25,132.38, 133.37, 143.60, 147.90, 152.78, 171.09;LRMS [C 25 H 21 BrN4O7] (ESI): m / z591.1 [M+Na] +

[0545] Example 2: Biological Data

[0546] Cells and viruses

[0547] Stock amplification of hPIV3 and hPIV1 was performed using LLC-MK2 and MA104 cells, respectively. Cells were grown at 37°C in a humid environment with 5% CO2 in Eagle's minimum essential medium (EMEM) supplemented with 1% glutamine (200 mM) and 2% fetal bovine serum (FBS). The hPIV3 virus strain C243 was obtained from the American Type Culture Collection. The hPIV3 virus strain CI002 and hPIV1 strain CI002 were isolated from clinical samples (Gold Coast University Hospital). All hPIVs were multiplied at 35°C in a humid environment with 5% CO2 in cells [LLC-MK2 (hPIV3) or MA104 (hPIV1)] maintained in EMEM supplemented with 1% glutamine (200 mM) and without FBS. hPIV3 strain CI002 and all hPIV1 strains also require the addition of 1.6% (v / v) TrypLE for efficient viral replication. Virus-containing culture supernatants were collected 3–4 days post-infection, with cytopathic effects monitored, and clarified from cell debris by centrifugation (3,000 x g, 15 min). The virus was concentrated at least 10-fold using a 100 kDa Amicon ultrafiltration system (Millipore, Billerica, MA) for HI assays. NI assays used polyethylene glycol (PEG)-precipitated virus, which was then purified as described below. The clarified hPIV supernatant was mixed with PEG6000 (8% final concentration) and NaCl (0.4 M final concentration) and then incubated overnight at 4°C with gentle agitation. The PEG6000 / hPIV complex was granulated by centrifugation at 3,000 x g, 30 min at 4°C. Discard the supernatant and resuspend the aggregates overnight at 4°C using a volume of GNTE buffer (200 mM glycine, 200 mM NaCl, 20 mM Tris-HCl, 2 mM EDTA, pH 7.4) corresponding to at least a 1:40 ratio of the initial viral suspension volume. Homogenize the viral suspension by pipetting and then mechanically breaking up any remaining viral aggregates using a douncer with a "tight" pestle. Load the hPIV homogenate onto a 30%–60% nonlinear sucrose gradient prepared in GNTE buffer and centrifuge at 100,000 x g for 2 hours and 30 minutes at 4°C without braking. Concentrate the virus at the 40%–50% sucrose interface and then collect and store at -80°C for NI assays.

[0548] hPIV inhibitors

[0549] Each compound is provided as a lyophilized powder, which is then dissolved in sterile water or DMSO to prepare a 10 mM stock solution. The solution is sonicated for 15 minutes to ensure complete dissolution. The stock solution is stored in amber glass vials at -20°C and freshly diluted with an appropriate buffer before use.

[0550] Blood coagulation inhibition assay (HIA) using concentrated hPIV:

[0551] hPIV HN inhibitors were evaluated in duplicate in U-bottom 96-well plates. For each test concentration, the compound was diluted in PBS to a 4X solution (25 μL / well, 1X final concentration). Each dilution (25 μL) was first mixed with 50 μL of 1% human erythrocytes (hRBCs), then mixed with 25 μL of hPIV3 or hPIV1 dilution (1 HAU final concentration) at 4 hemagglutination units. The plates were then incubated at room temperature for 1 hour, and hemagglutination levels were read. Hemagglutination inhibition assay (HIA) IC 50 The value is considered to be the concentration of an inhibitor that reduces hemagglutinin binding activity (hemagglutination) by 50% compared to a simulated viral suspension, and is equivalent to the hemagglutination observed when 0.5 HAU of virus is used in the assay.

[0552] Neuraminidase inhibition assay (NIA) using purified hPIV:

[0553] Viral neuraminidase inhibition (NIA) assays were performed using purified hPIV3 in hPIV3 NIA reaction buffer (NaOAc 50 mM, CaCl2 5 mM, pH 4.6) and purified hPIV1 in hPIV1 NIA reaction buffer (NaOAc 50 mM, CaCl2 5 mM, pH 5.0). To account for statistical correlation, the amount of purified virus used in each assay was calculated so that the maximum fluorescence signal (positive control) was at least 4 to 5 times the fluorescence background (negative control). Purified hPIV3, the inhibitor, and MUNANA were prepared and diluted in NIA reaction buffer. For each test concentration, 2 μL of purified hPIV and 4 μL of 2.5X inhibitor solution (1X final concentration) were added to each well. The plate was incubated at room temperature for 20 minutes, and then 4 μL of 5 mM MUNANA (2 mM final concentration) was added to each well. The plate was then incubated at 37°C with stirring (1,000 rpm) for 30 minutes. The enzymatic reaction was stopped by adding 50 μL of glycine buffer (glycine, 0.25 M, pH 10.4) to each well. A negative control was included by adding MUNANA to the virus and then stopping the enzymatic reaction at t = 0. Relative fluorescence (RF) was measured for each well using a Tecan M200 reader. Data were processed by background subtraction (negative control RF) and then analyzed using a GraphPad Prism 4 (GraphPad Software Inc., La Jolla, CA) to calculate IC50. 50 Values ​​[Nonlinear regression (curve fitting), dose-response-inhibition, 4-parameter logic]. The concentration of the inhibitor that reduces neuraminidase activity by 50% compared to untreated viral suspension is considered the NIA IC. 50 value.

[0554] Virus growth inhibition assay - in situ ELISA

[0555] Viral Growth Inhibition Assay - In situ ELISA is a technique used to assess viral growth inhibition by measuring the expression level of hPIV HN at the cell surface of infected cell monolayers. The expression level is directly related to the ability of non-immobilized virus to infect new target cells. In 96-well plates, confluent cell monolayers [LLC-MK2 (hPIV3), MA104 (hPIV1)] were inoculated with 100 FFU / well of hPIV for 1 hour at 37°C, gently agitated every 15 minutes. The assay was performed in triplicate. The inoculum was removed and replaced with the appropriate compound dilution. For hPIV3 strain CI002 and hPIV1 strain CI002, 1.6% (v / v) TrypLE was added for efficient viral proliferation. Infected cell monolayers were incubated at 35.5°C and 5% CO2 for 36–40 hours for viral proliferation. The virus was inactivated and cells were fixed by treatment with PBS containing 3.7% formaldehyde for 20 minutes. Next, endogenous peroxidase was inactivated by treatment with 0.3% H2O2 / PBS at 37°C for 30 min. Cell monolayers were then incubated with mouse monoclonal IgG anti-hPIV3 HN or anti-hPIV1 HN in 5% milk / PBS at 37°C for 1 h. Goat anti-mouse IgG (H+L)-HRP conjugate in 5% milk / PBS was added at 37°C for 1 h. BD OptEIA TMB substrate (100 μL) was added, and the reaction was stopped by adding 1 M H2SO4 (50 μL) after 3–5 min. Raw data were obtained by reading the absorbance of each well at 450 nm using a Biorad xMark plate reader. The final values ​​were adjusted by subtracting the absorbance of the negative control to obtain the absorbance of each other well, and the data were analyzed using GraphPad Prism4 to calculate IC50. 50 Value. Virus growth IC 50 The value is considered to be the concentration of an inhibitor that reduces absorbance at 450 nm by 50% compared to an untreated monolayer of infected cells.

[0556] result

[0557] Table 1: Biological evaluation of example compounds used to inhibit hPIV neuraminidase activity and viral growth.

[0558]

[0559]

[0560]

[0561]

[0562]

[0563] Example 3: Structural Biology

[0564] Expression and purification of recombinant HN

[0565] Based on a substantially modified literature procedure, the HN protein was expressed using the Bac-to-Bac® baculovirus expression system (Invitrogen, Carlsbad, CA). The nucleotide sequence of the honeybee venom signal peptide (HBM) was thus added downstream of a sequence encoding the HN extracellular domain (amino acids 125 to 572). This sequence (HBM+HN) was codon-optimized for expression in fall armyworm (Sf9) cells and directly sequenced to the name HBM-HNhPIV-3opt using DNA2.0 Gene Synthesis Service (DNA2.0, Menlo Park, CA). HBM-HNhPIV-3opt was amplified by PCR and ligated into the pFastBac⁄CT-TOPO® vector, which provides an additional C-terminal 6-histidine tag (His-Tag) for purification and detection purposes.

[0566] The generation and amplification of recombinant baculovirus containing HBM-HNhPIV-3opt were performed according to the manufacturer's instructions. Sf9 cells cultured in insect cell culture medium (Lonza) without insect-XPRESS protein were infected with HBM-HNhPIV-3opt baculovirus at a high MOI. Four days post-infection, supernatants containing recombinant HN were collected to produce the highest protein expression. The supernatants were clarified by centrifugation (3,000 RCF, 15 min) to remove cell debris and then purified on a HisTrap excel 5 mL column (GE Healthcare life sciences, Buckinghamshire, England) according to the manufacturer's protocol. The recombinant HN was eluted with 500 mM imidazole solution, and the collected fractions were evaluated by neuraminidase activity (NA) assay (see below). The fractions with the highest activity were combined and concentrated to a final volume of 800 μL using a 10 kDa Amicon ultrafiltration device (Millipore). Further purification steps were performed using rapid protein liquid chromatography (Amersham Biosciences) on a Superdex 75 gel filter column (GE Healthcare) at 4°C, with 1 mL fractions collected using a Frac-920. The protein-containing fractions, as determined by monitoring fraction collection at 280 nm, were evaluated in a NA assay and subjected to SDS-PAGE. The purified and concentrated recombinant HN protein was stored at 4°C.

[0567] Crystallization, data collection and structure determination

[0568] All hPIV-3 HN complexes were prepared by co-crystallization (using 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), wherein a 4 mg / mL hPIV3 HN protein stock solution was pre-incubated for 30 min in 0.1 M pH 4.6 citrate buffer, 0.2 M (NH4)2SO4, and 10% PEG 3000 with a final concentration of 1.5 mM inhibitor. Crystallization assays were performed using a hanging drop vapor diffusion method with 2 μL of pre-incubated stock solution. The droplets were equilibrated relative to a 500 μL reservoir (0.1 M pH 4.6 citrate buffer, 0.2 M (NH4)2SO4, and 10% or 15% PEG3000). The crystals were placed in nylon rings (Hampton Research) and rapidly frozen at 100 K in a cryoprotectant solution containing 20% ​​glycerol in addition to the precipitant solution.

[0569] X-ray diffraction data were collected using Blu-Ice software on the MX2 beamline at the Australian Synchrotron. The dataset was processed using XDS and scaled using Aimless within the CCP4 suite. The structure was resolved by molecular substitution using the Phaser and apo hPIV3-HN model (PDB ID: 4XJQ) as templates. The model was refined using Phenix.Refine, and structural verification was performed using MolProbity. Coot was used. 6 We used PyMOL (http: / / www.pymol.org / ; DeLano Scientific LLC) to perform structural analysis.

Claims

1. A compound of formula I or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer: Formula I in R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups; R3 is Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle; R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted; R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 Where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein any R 19 All groups are optionally substituted.

2. The compound according to claim 1, wherein the compound of formula (II) is a compound of formula (II) or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer: Formula II R1, R3, R4, R6, R7 and R8 are as defined in claim 1.

3. The compound according to claim 1 or claim 2, wherein the compound of formula I or the compound of formula II is a compound of formula III or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer: Formula III R1, R3, R4, R6, R7 and R8 are as defined in claim 1.

4. The compound according to any one of the preceding claims, wherein R1 is selected from the group consisting of: COOH or a salt thereof, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic; wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, and heterocyclic groups are optionally separated by one or more R 50 Replace; where R 50 Choose from the following groups: R 53 -OR 53 -SR 53 -C(O)-R 53 -C(S)-R 53 -C(O)-OR 53 -OC(O)-R 53 -OC(S)-R 53 -C(S)-OR 53 CN, OH, oxo, NR 51 R 51 ', Cl, F, Br, I, optionally by at least one R 52 Substituted aryl group and optionally with at least one R 52 Substituted heterocyclic groups; wherein R 51 and R 51 'Independently selected from hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 52 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 51 R 51 ', Cl, F, Br and I; where R 53 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

5. The compound according to any one of the preceding claims, wherein R1 is selected from COOH or a salt thereof and C(O)OR 11 , where R 11 Selected from methyl, ethyl, and propyl.

6. The compound according to any one of the preceding claims, wherein R4 is selected from the group consisting of: sulfonamides; ureas; NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 The same group; wherein the R 17 The group can optionally be surrounded by one or more R 75 Replace; where R 75 Choose from the following groups: R 78 -OR 78 -SR 78 -C(O)-R 78 -C(S)-R 78 -C(O)-OR 78 -OC(O)-R 78 -OC(S)-R 78 -C(S)-OR 78 CN, OH, oxo, NR 76 R 76 ', Cl, F, Br, I, optionally by at least one R 77 Substituted aryl group and optionally with at least one R 77 Substituted heterocyclic groups; wherein R 76 and R 76 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, C=O-C1-C9 alkyl, SO2-C1-C9 alkyl and C=O-NH-C1-C9 alkyl; wherein R 77 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 76 R 76 ', Cl, F, Br and I; where R 78 Selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, and C2-C6 haloynyl; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with carbon atoms of N and C(O) groups, they form 5- or 6-membered rings, which may optionally be substituted and / or fused with other rings.

7. The compound according to any one of the preceding claims, wherein R4 is selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 8. The compound according to any one of the preceding claims, wherein R6, R7 and R8 are independently selected from the group consisting of: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 Where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein each R 19 It can be replaced independently and arbitrarily.

9. The compound according to any one of the preceding claims, wherein R6, R7 and R8 are independently selected from OH and OAc.

10. The compound according to any one of the preceding claims, wherein ring A together with the carbon to which it is attached forms an optionally substituted 5- to 6-membered aryl ring, an optionally substituted 5- to 6-membered heteroaryl ring, or an optionally substituted 5- to 6-membered heterocycle.

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

12. The compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of: Wherein ring A and ring B are as defined in any one of claims 1 to 11, optionally wherein ring A is selected from the group consisting of: benzene ring, piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, tetrahydrothiophene ring and thiophene ring, and wherein ring B is selected from the group consisting of: piperidine ring, pyridine ring, pyrrolidine ring, pyrrole ring, tetrahydrofuran ring, furan ring, dioxane ring, tetrahydrothiophene ring and thiophene ring, all said rings optionally being substituted; Y is a heteroatom selected from N, O, and S; and R 12 and R 13 Independently selected from the group consisting of: hydrogen, azide, alkylthio, haloalkylthio, C1-C6 alkylamino, haloalkylamino, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -OC(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', C1-C6 alkylsulfonyl, C1-C6 haloalkylsulfonyl, arylsulfonyl, -CH(COOR) 63 NH2、-(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, halogenated, optionally by at least one R 62 Substituted aryl group and optionally with at least one R 62 Substituted heterocyclic groups, each of which may optionally be substituted, wherein R 61 and R 61 'Independently selected from the group consisting of: hydrogen, C1-C9 alkyl, C1-C9 haloalkyl, C2-C9 alkenyl, C2-C9 haloalkenyl, C2-C9 ynyl, C2-C9 haloynyl, 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 R 62 Choose from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, CN, OH, oxo, NR 61 R 61 ', Cl, F, Br and I, each of the groups may optionally be substituted as appropriate; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -(CH2) n -CH(COOH)NH2, where n is an integer from 0 to 2, -C(O)-C1-C9 alkyl, -C(O)-N-C1-C9 alkyl or dialkyl, -S(O)2-C1-C9 alkyl, aryl, heteroaryl, heterocyclic, cycloalkyl and cycloalkenyl, each of which may be optionally substituted as appropriate; And its N-oxide analogues.

13. The compound according to claim 12, wherein R 12 and R 13 Independently selected from the following groups: hydrogen, azide, R 63 -OR 63 -SR 63 -C(O)-R 63 -C(S)-R 63 -C(O)-OR 63 -C(O)-OH (or its salt), -C(O)-NR 61 R 61 '、-OC(O)-R 63 -OC(S)-R 63 -C(S)-OR 63 CN, OH, oxo, NR 61 R 61 ', Cl, F and Br; where R 61 and R 61 'Independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, -C(O)-C1-C6 alkyl, -C(O)-N-C1-C6 alkyl or dialkyl and -S(O)2-C1-C6 alkyl; wherein R 63 Choose from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl and C2-C6 haloynyl.

14. The compound according to any one of the preceding claims, wherein R3 is selected from the group consisting of: And its N-oxide analogues.

15. The compound according to any one of the preceding claims, wherein the compound is selected from the group consisting of: And its N-oxides, pharmaceutically acceptable salts, prodrugs, stereoisomers and protected forms, including acetyl substitution of the free hydroxyl group for hydrogen, all of its C-2 analogs, wherein the C-2 carboxyl group is in a protonated form, a sodium salt form or a prodrug form, and wherein each compound can be considered to have a publicly known close analog, wherein the R4 position is explicitly replaced by any -NHC(O)R group, wherein R is a C1-C4 alkyl group or a haloalkyl group thereof.

16. A pharmaceutical composition comprising an effective amount of the compound or its N-oxide, a pharmaceutically acceptable salt, a prodrug or stereoisomer according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier, diluent and / or excipient.

17. The pharmaceutical composition of claim 16, wherein the pharmaceutical composition is used to treat or prevent diseases, symptoms or conditions caused by viral infection.

18. A method for treating or preventing a disease, symptom, or illness in a subject caused by a viral infection, the method comprising the steps of: Administer an effective amount of a compound of formula I or its N-oxide, pharmaceutically acceptable salt, prodrug, or stereoisomer to the subject: Formula I in R1 is selected from the group consisting of: COOH or its salts, C(O)NR9R 10 and C(O)OR 11 Among them, R9 and R 10 and R 11 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 heterocyclic groups; R3 is Wherein ring A, together with the carbon atom it is attached to, 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 heterocycle; and When present, ring B together with the two ring atoms of ring A forms an optionally substituted 5- to 7-membered heteroaryl ring or an optionally substituted 5- to 7-membered heterocycle; R4 is selected from the group consisting of: sulfonamides; ureas; -NHC(O)R 17 , where R 17 Select 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)R 17' C3-C6 cycloalkyl, C3-C6 heterocyclic, C5 or C6 aryl, C5 or C6 heteroaryl, and C3-C6 cycloalkenyl, each of which may optionally be substituted, and wherein R 17' Can be selected from R 17 Same group; -NR 20 R 21 , where R 20 and R 21 Independently selected from the group consisting of: hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, and C1-C6 alkyl-aryl; and -NR 22 C(O)R 23 , where R 22 and R 23 Together with the carbon of the N and C(O) groups, they form a 5 or 6-membered ring, which may optionally be fused with another ring, and each of the aforementioned groups and rings may optionally be substituted; R6, R7, and R8 are independently selected from the following groups: H, OH, protected OH, R 19 OR 19 NR 18 R 18 '、-C(O)R 18 -C(S)R 18 -OC(O)R 18 -C(O)OR 18 -NH(C=O)R 18 -C(=O)NR 18 R 18 'and S(O)nR 18 Where n = 0-2, and each R 18 and R 18 'Selected independently from hydrogen, R, depending on the circumstances' 19 and optionally substituted C1-C9 alkyl acyl groups; wherein each R 19 Independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 haloalkenyl, C2-C6 ynyl, C2-C6 haloynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, wherein any R 19 All groups are optionally substituted; Or the pharmaceutical composition according to claim 16 or claim 17.

19. The method of claim 18, wherein the compound is as described in any one of claims 1 to 15.

20. The method of claim 18 or claim 19, wherein the disease, symptom or illness is selected from parainfluenza, influenza, croup, bronchiolitis and pneumonia.

21. The method according to any one of claims 18 to 20, wherein the infection is caused by a virus selected from the group consisting of: influenza A virus, influenza B virus, influenza C virus, influenza D virus, parainfluenza virus, respiratory syncytial virus (RSV), and human metapneumovirus (hMPV).

22. The method according to any one of claims 18 to 21, wherein the disease, symptom or illness is parainfluenza and / or influenza.

23. The method according to any one of claims 18 to 22, wherein the disease, symptom or illness is an infection caused by an influenza virus and / or a parainfluenza virus.

24. The method according to any one of claims 18 to 23, wherein when the disease, symptom or illness is influenza, then the disease, symptom or illness is selected from the group consisting of: influenza A, influenza B, influenza C or influenza D.

25. The method according to any one of claims 18 to 23, wherein when the disease, symptom or illness is a parainfluenza virus infection, the disease, symptom or illness is selected from the group consisting of hPIV-1 virus, hPIV-2 virus, hPIV-3 virus and hPIV-4 virus, including all viral subtypes.

26. The method according to any one of claims 18 to 23, wherein the subject is a domesticated or livestock animal or a human.

27. A method for regulating the function of viral hemagglutinin and / or neuraminidase, the method comprising the following steps: Viral hemagglutinin-neuraminidase is reacted with any one of the compounds according to claims 1 to 15, or their N-oxides, pharmaceutically acceptable salts, prodrugs, or stereoisomers, or with... Contact with the pharmaceutical composition according to claim 16 or claim 17.

28. The method of claim 27, wherein the regulation is the inhibition of the function of the viral hemagglutinin and / or neuraminidase or viral hemagglutinin-neuraminidase.

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