Sialic acid derivatives and methods of using the same

Abstract

Providing sialic acid derivatives that may be useful for the treatment and / or prevention of Alzheimer's disease. 【Solution means】Compounds of formula (I) to (V), compositions containing at least one compound selected from the compounds of formula (I) to (V), and methods of using the same, including use in the treatment of Alzheimer's disease. JPEG2025524377000326.jpg82149

Description

Technical Field

[0001] The present disclosure relates to sialic acid derivatives and methods of using the same.

Background Art

[0002] Alzheimer's disease (AD) is a complex neurodegenerative disease accompanied by progressive cognitive impairment commonly seen in the elderly. In 2006, the number of AD patients worldwide was 26.6 million, but the number of AD is expected to quadruple by 2050 (Ziegler-Graham K., et al. “Forecasting the global burden of Alzheimer’s disease,” Alzheimers Dement. 2007;3:186-91). AD consists of early-onset AD (EOAD) and late-onset AD (LOAD). LOAD, which accounts for the majority of AD, is the result of the interaction between environmental factors and genetic factors (Lu Zy et al., “Spreading of Pathology in Alzheimer’s Disease,” Neurotox Res 2017;32:707-22).Among these, genes play an important role, and the heritability is estimated to be as high as 80% (Gatz M.et al., “Role of genes and environments for explaining Alzheimer disease,” Arch Gen Psychiatry 2006;63:168-74; Palotas A,et al. “Candidate susceptibility genes in Alzheimer’s disease are at high risk for being forgotten--they don’t give peace of mind,” Curr Drug Metab 2006;7:273-93; Antoniades D.et al., “The role of reelin gene polymorphisms in the pathogenesis of Alzheimer’s disease in a Greek population,” J Biol Regul Homeost Agents 2011;25:351-8; Wang L.Z.et al., “Association between late-onset Alzheimer’s disease and microsatellite polymorphisms in intron II of the human toll-like receptor 2 gene,” Neurosci Lett 2011;489:164-7). So far, the apolipoprotein E (APOE) gene has been recognized as the only gene that increases the risk of LOAD, but this gene accounts for only 27.3% regarding the AD onset risk (Hollingworth P. et al. “Common variants in ABCA7, MS4A6A / MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease,” Nat Genet 2011;43:429-35; Jayadev S. et al., “Alzheimer’s disease phenotypes and genotypes associated with mutations in presenilin 2,” Brain 2010;133:1143-54; Alzheimer’s Association “2015 Alzheimer’s disease facts and figures.” Alzheimers Dement 2015;11:332-84; Liu Y. et al., “Multiple Effect of APOE Genotype on Clinical and Neuroimaging Biomarkers Across Alzheimer’s Disease Spectrum,” Mol Neurobiol 2016;53:4539-47). Therefore, further efforts are needed to search for risk genes other than APOE.

[0003] Preclinical evidence reported by two research groups supports the potential role of the sialic acid-binding site of CD33 and its relationship with microglial cell activation and AD. Using CD33 ligands bound to microparticles, it was found that the uptake of amyloid-β (Aβ) by microglial cells increased (Miles L.A. et al., “Small Molecule Binding to Alzheimer Risk Factor CD33 Promotes Aβ Phagocytosis,” iScience 2019;19:110 - 118). This result was reported to have been confirmed using CD33 ligands conjugated to lipids and subsequently incorporated into liposomes (Bhattacherjee A. et al., “Increasing phagocytosis of microglia through targeting CD33 with liposomes displaying glycan ligands,” J Controlled Release 2021;338:680 - 693). These results provide good evidence that ligands that bind strongly to the sialic acid-binding site on CD33 would promote the clearance of Aβ and are thus promising therapies that could affect AD.

Summary of the Invention

Problems to be Solved by the Invention

[0004] This specification provides sialic acid derivatives that may be useful for the treatment and / or prevention of Alzheimer's disease.

Means for Solving the Problems

[0005] One aspect of the disclosure provides compounds of formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (III), (IV), and (V), their tautomers, deuterated derivatives, and pharmaceutically acceptable salts of any of the foregoing, which may be useful in the treatment of AD. For example, the compound is a compound of formula (I): [Chemical] its tautomer, a deuterated derivative of the compound of formula (I), a deuterated derivative of a tautomer of the compound of formula (I), or a pharmaceutically acceptable salt of any of the foregoing [wherein, A is selected from an alkenyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. B is hydrogen, [Chemical] selected from; wherein, V is selected from O, CH2 and NR'; wherein, R' is selected from hydrogen, a hydroxy group, a straight-chain alkyl group, a branched alkyl group, and a cyclic alkyl group; R 1 and R 2 are each independently selected from hydrogen, a hydroxy group, an amino group, a straight-chain alkyl group, a branched alkyl group, and a cyclic alkyl group, or R 1 and R 2 together form a cycloalkyl group or a heterocyclic group; each R x is independently selected from hydrogen, a hydroxy group, an amino group, a sulfonyl group, a straight-chain alkyl group, a branched alkyl group, a cyclic alkyl group, a straight-chain alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a straight-chain alkylene group, a branched alkylene group, a cyclic alkylene group, a heterocycloalkyl group, an aryl group, and a heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; C, D, E, and F are selected from hydrogen, a straight-chain alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group; L is a C 1~10 straight-chain alkylene group, a C 1~10 branched alkylene group, and a C 1~10 cyclic alkylene group, -C(O)-C 1~10 straight-chain alkylene group, a C 1~10 branched alkylene group, and a C1~10 cyclic alkylene group, C 1~10 linear alkylene-C(O)-group, C 1~10 branched alkylene-C(O)-group, and C 1~10 cyclic alkylene-C(O)-group, C 1~10 linear alkenylene group, C 1~10 branched alkenylene group, and C 1~10 cyclic alkenylene group,

Chemical formula

[0006] In one aspect of the present disclosure, the compound of formula IIa is

Chemical formula

Chemical formula

[0007] In one aspect of the present disclosure, the compounds of formulas (I), (Ia), (Ib), (Ic), (Id), (II) are further derivatized to produce the compounds of formulas (III), (IV), (V), their tautomers, deuterated derivatives of this compound or this tautomer, or the pharmaceutically acceptable salts described above. For example, the compounds of formulas (III), (IV), or (V) are

Chemical formula

Chemical formula

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), a tautomer thereof, a deuterated derivative of this compound or this tautomer, or a pharmaceutically acceptable salt as described above. These compositions may further comprise at least one additional pharmaceutically active ingredient and / or at least one carrier.

[0009] Another aspect of the present disclosure is a method of treating AD, comprising administering to a subject in need thereof a pharmaceutical composition comprising at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), a tautomer thereof, a deuterated derivative of this compound or this tautomer, or a pharmaceutically acceptable salt as described above or this at least one compound.

[0010] In some embodiments, this treatment method includes either administration of at least one additional active agent to a subject in need thereof in the same pharmaceutical composition as at least one compound of formula (I), (Ia), (Ib), (Ic), (Id), (II), (III), (IV), (V), a tautomer thereof, a deuterated derivative of this compound or this tautomer, or a pharmaceutically acceptable salt as described above, or administration as a separate composition.

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Mode for Carrying Out the Invention

[0012] Definitions The following are the definitions of the terms used in this application.

[0013] As used herein, the singular terms "a," "an," and "the" include references to the plural unless the context clearly dictates otherwise.

[0014] The phrase "and / or" as used herein means "either or both" of the elements so joined conjunctively, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, "A and / or B" when used in conjunction with open-ended language such as "comprising" may, in some embodiments, refer to only A (optionally including elements other than B); in other embodiments, it may refer to only B (optionally including elements other than A); in still other embodiments, it may refer to both A and B (optionally including other elements), and so on.

[0015] As used herein, "at least one" means one or more of the elements in a list of elements, but does not necessarily include at least one of every element specifically listed in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows that, regardless of whether or not it is related to specifically identified elements, elements other than those specifically identified in the list of elements referred to by the phrase "at least one" may optionally be present. Thus, by way of non-limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B", or, equivalently "at least one of A and / or B") may, in one embodiment, refer to at least one A, optionally including two or more, in the absence of B (and optionally including elements other than B); in another embodiment, it may refer to at least one B, optionally including two or more, in the absence of A (and optionally including elements other than A); in yet another embodiment, it may refer to at least one A, optionally including two or more, and at least one B, optionally including two or more (and optionally including other elements), and so on.

[0016] When a number is recited, whether alone or as part of a numerical range, it should be understood that the number can vary by up to 10% above and below the recited value.

[0017] As used herein, "optionally substituted" is synonymous with the phrase "substituted or unsubstituted". In general, the term "substituted", whether or not preceded by the term "optionally", refers to replacement of a hydrogen group in a given structure by a specified substituent group. Unless otherwise indicated, an "optionally substituted" group may have substituents at each position where the group is substitutable, and when two or more positions in any given structure may be substituted by two or more substituents selected from the specified groups, the substituents may be the same or different at each position. Combinations of substituents contemplated by the present disclosure result in the formation of stable or chemically realizable compounds.

[0018] The term "isotopologue" refers to species that differ only in their isotopic composition with respect to a chemical structure. In addition, unless otherwise specified, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, a compound having the present structure except that hydrogen is replaced by deuterium or tritium, or carbon is replaced by 13C or 14C, is within the scope of the present disclosure.

[0019] Unless otherwise indicated, the structures illustrated herein are also intended to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the present compounds are within the scope of the present disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the present disclosure are within the scope of the present disclosure.

[0020] The term "tautomer" as used herein refers to one of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by the migration of atoms, such as hydrogen atoms, or groups, within the molecule.

[0021] "Stereoisomer", as used herein, refers to enantiomers and diastereomers.

[0022] As used herein, "deuterated derivative" refers to a compound that has the same chemical structure as the reference compound, but in which one or more hydrogen atoms have been replaced by deuterium atoms ("D" or "2H"). It will be recognized that there may be some variation in the natural isotope abundance of synthetic compounds depending on the origin of the chemical materials used in their synthesis. The concentration of the naturally abundant stable hydrogen isotope is small and negligible compared to the degree of stable isotope substitution of the deuterated derivatives described herein, notwithstanding this variation. Thus, unless otherwise specified, when reference is made to a "deuterated derivative" of a compound of the present disclosure, at least one hydrogen has been replaced by deuterium to a level far exceeding its natural isotope abundance (which is typically about 0.015%). In some embodiments, the deuterated derivatives of the present disclosure have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation for each specified deuterium), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), or at least 6600 (99% deuterium incorporation) for each deuterium atom.

[0023] The term "isotope enrichment factor", as used herein, means the ratio of the isotope abundance of the specified isotope to its natural abundance.

[0024] As used herein, the terms "alkyl" or "aliphatic" refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or has one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is completely saturated or has one or more units of unsaturation but is not aromatic, and that is attached to the remainder of the molecule at only one point. Unless otherwise specified, an alkyl group has from 1 to 20 alkyl carbon atoms. In some embodiments, the alkyl group has from 1 to 10 aliphatic carbon atoms. In some embodiments, the alkyl group has from 1 to 8 aliphatic carbon atoms. In some embodiments, the alkyl group has from 1 to 6 alkyl carbon atoms, in some embodiments, the alkyl group has from 1 to 4 alkyl carbon atoms, and in still other embodiments, the alkyl group has from 1 to 3 alkyl carbon atoms. Non-limiting examples of alkyl groups include, but are not limited to, straight or branched, and substituted or unsubstituted alkyl. Suitable alicyclic groups include cycloalkyl, bicyclic cycloalkyl (e.g., decalin), bridged bicycloalkyl such as norbornyl or [2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl. In some embodiments, the alkyl group is substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is straight-chain. In some embodiments, the alkyl group is branched.

[0025] The terms "cycloalkyl", "carbocyclic", "alicyclic", or "cyclic alkyl" refer to a spirocyclic or monocyclic C3-8 hydrocarbon or a spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic C8-14 hydrocarbon that is completely saturated or has one or more units of unsaturation but is not aromatic, wherein any individual ring in the bicyclic ring system has from 3 to 7 members. In some embodiments, the cyclo group is substituted. In some embodiments, the cyclo group is unsubstituted.

[0026] As used herein, the term "heteroalkyl" or "heteroaliphatic" means an aliphatic group in which one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocyclic", "heterocyclyl", "heteroalicyclic", or "heterocyclic" groups.

[0027] As used herein, the term "alkenyl" means a straight-chain (i.e., unbranched), branched, substituted or unsubstituted hydrocarbon chain having one or more units of saturation, or a monocyclic or bicyclic hydrocarbon having one or more units of unsaturation but which is not aromatic (referred to herein as "cyclic alkenyl"). In some embodiments, the alkenyl group is substituted. In some embodiments, the alkenyl group is unsubstituted. In some embodiments, the alkenyl group is straight-chain. In some embodiments, the alkenyl group is branched.

[0028] As used herein, the terms "heterocyclic", "heterocyclyl", "heteroalicyclic", or "heterocyclic" mean a non-aromatic, monocyclic, bicyclic, or tricyclic ring system in which one or more ring members are heteroatoms independently selected. In some embodiments, a "heterocyclic", "heterocyclyl", "heteroalicyclic", or "heterocyclic" group has 3 to 14 ring members, and one or more ring members are heteroatoms independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, each ring of a bicyclic or tricyclic ring system has 3 to 7 ring members. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-carbon bond. In some embodiments, the heterocyclic ring has at least one unsaturated carbon-nitrogen bond. In some embodiments, the heterocyclic ring has one heteroatom independently selected from oxygen, sulfur, nitrogen, and phosphorus. In some embodiments, the heterocyclic ring has one heteroatom which is a nitrogen atom. In some embodiments, the heterocyclic ring has one heteroatom which is an oxygen atom. In some embodiments, the heterocyclic ring has two heteroatoms independently selected from nitrogen and oxygen, respectively. In some embodiments, the heterocyclic ring has three heteroatoms independently selected from nitrogen and oxygen, respectively. In some embodiments, the heterocyclic ring is substituted. In some embodiments, the heterocyclic ring is unsubstituted.

[0029] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (nitrogen, sulfur, phosphorus, or silicon in any oxidation state; any basic nitrogen in a quaternized form or; a replaceable nitrogen of a heterocyclic ring, such as that in N(3,4-dihydro-2H-pyrrolyl), NH (such as that in pyrrolidinyl) or NR+ (such as that in N-substituted pyrrolidinyl)).

[0030] As used herein, the term "unsaturated" means that a moiety has one or more unsaturation units or degrees of unsaturation. Unsaturation means that not all of the available valence bonds in a compound are satisfied by substituents, so that the compound has a double or triple bond.

[0031] As used herein, the term "alkoxy" or "thioalkyl" refers to an alkyl group as previously defined, wherein one carbon of the alkyl group is replaced by an oxygen ("alkoxy") or sulfur ("thioalkyl") atom, provided that the oxygen and sulfur atoms are linked between two carbon atoms. "Cyclic alkoxy" refers to a monocyclic, spirocyclic, bicyclic, bridged bicyclic, tricyclic, or bridged tricyclic hydrocarbon that has at least one alkoxy group and is not aromatic. Non-limiting examples of cyclic alkoxy groups include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, 8-oxabicyclo[3.2.1]octanyl, and oxepanyl. In some embodiments, the "alkoxy" and / or "thioalkyl" group is substituted. In some embodiments, the "alkoxy" and / or "thioalkyl" group is unsubstituted.

[0032] As used herein, the terms "haloalkyl" and "haloalkoxy" mean a linear or branched alkyl or alkoxy optionally with a tail, substituted with one or more halogen atoms. Non-limiting examples of haloalkyl groups include CHF2, CH2F, CF3, CF2, and perhaloalkyls such as CF2CF3. Non-limiting examples of haloalkoxy groups include -OCHF2, -OCH2F, -OCF3, and -OCF2-.

[0033] The term "halogen" includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

[0034] The term "aminoalkyl" means an alkyl group substituted with or having an amino group.

[0035] As used herein, "amino" refers to a group that is a primary, secondary, or tertiary amine.

[0036] As used herein, the term "carbonyl" group refers to C=O.

[0037] As used herein, the term "cyano" or "nitrile" group refers to C≡N.

[0038] As used herein, the term "hydroxy" or "hydroxyl" group refers to OH.

[0039] As used herein, the term "thiol" group refers to SH.

[0040] As used herein, "tert" and "t-" each refer to tertiary.

[0041] As used herein, the term "aromatic group" or "aromatic ring" refers to a chemical group having a conjugated planar ring system in which the delocalized π electron orbitals are composed of [4n + 2] p-orbital electrons (where n is an integer in the range of 0 to 6). Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0042] The term "aryl", when used alone or as part of a larger moiety such as "arylalkyl", "arylalkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and each ring of the bicyclic or tricyclic ring system has 3 to 7 ring members. The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow. Non-limiting examples of aryl groups include phenyl rings. In some embodiments, the aryl group is substituted. In some embodiments, the aryl group is unsubstituted.

[0043] The term "heteroaryl", whether used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroarylalkoxy", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic, at least one ring in the system has one or more heteroatoms, and each ring of the bicyclic or tricyclic ring system has 3 to 7 ring members. In some embodiments, the heteroaryl group is substituted. In some embodiments, the heteroaryl group has one or more heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group has one heteroatom. In some embodiments, the heteroaryl group has two heteroatoms. In some embodiments, the heteroaryl group is a monocyclic ring system having 5 ring members. In some embodiments, the heteroaryl group is a monocyclic ring system having 6 ring members. In some embodiments, the heteroaryl group is unsubstituted.

[0044] Non-limiting examples of protecting groups useful for nitrogen-containing groups such as amine groups include, for example, tert-butyl carbamate (Boc), benzyl (Bn), tetrahydropyranyl (THP), 9-fluorenylmethyl carbamate (Fmoc), benzyl carbamate (Cbz), acetamide, trifluoroacetamide, triphenylmethylamine, benzylideneamine, and p-toluenesulfonamide. Methods for adding such amine protecting groups (the process generally referred to as "protecting") and removing them (the process generally referred to as "deprotecting") are well known in the art and are available, for example, in P.J. Kocienski, Protecting Groups, Thieme, 1994 (incorporated herein by reference in its entirety) and Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition (John Wiley & Sons, New York, 1999) and 4th Edition (John Wiley & Sons, New Jersey, 2014).

[0045] Non-limiting examples of suitable solvents that can be used in the present disclosure include, but are not limited to, water, methanol (MeOH), ethanol (EtOH), dichloromethane or "methylene chloride" (CH2Cl2), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptanes, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (Et2O), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0046] Non-limiting examples of suitable bases that can be used in the present disclosure include, but are not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (K2CO3), N-methylmorpholine (NMM), triethylamine (Et3N; TEA), diisopropyl-ethylamine (i-Pr2EtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH3).

[0047] The present disclosure includes pharmaceutically acceptable salts of the disclosed compounds. The salts of the compounds are formed between an acid and a basic group of the compound, such as an amino functional group, or between a base and an acidic group of the compound, such as a carboxyl functional group.

[0048] As used herein, the term "pharmaceutically acceptable" refers to components that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, and that have a reasonable risk-benefit ratio. "Pharmaceutically acceptable salts" means any non-toxic salts that have the ability to directly or indirectly provide the compounds of the present disclosure upon administration to a subject. Suitable pharmaceutically acceptable salts are, for example, those disclosed in S.M. Berge et al., J. Pharmaceutical Sciences, 1977, 66, 1 to 19.

[0049] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen disulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as paratoluenesulfonic acid, salicylic acid, tartaric acid, ditartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0050] Pharmaceutically acceptable salts obtained from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4(Alkyl)4 salts are included. This disclosure also contemplates the quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Suitable non-limiting examples of alkali metal salts and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include ammine cations formed using ammonium, quaternary ammonium, and counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Other suitable non-limiting examples of pharmaceutically acceptable salts include besylate salts and glucosamine salts.

[0051] The terms "patient" and "subject" are used synonymously and refer to animals including humans.

[0052] The terms "effective dose" and "effective amount" are used synonymously herein and refer to the amount of a compound that, when administered, will produce the desired effect (e.g., improvement in the symptoms of FSGS and / or NDKD, reduction in the severity of the symptoms of FSGS and NDKD or FSGS and / or NDKD, and / or reduction in the progression of the symptoms of FSGS and / or NDKD or FSGS and / or NDKD). The exact amount of the effective dose will depend on the purpose of the treatment and can be determined by those skilled in the art using known techniques (see, e.g., Lloyd (1999) The Art, Science and Technology of Pharmaceutical Compounding).

[0053] As used herein, the terms "treatment" and its cognates refer to slowing or stopping the progression of a disease. "Treatment" and its cognates, as used herein, include, but are not limited to: complete or partial remission, renal failure (e.g., ESRD), and reduction in the risk of disease-related complications (e.g., edema, susceptibility to infection, or thromboembolic events). Improvement in or reduction in the severity of any of these symptoms can be readily determined according to methods and techniques known in the art or developed later.

[0054] When used in connection with the dosage, amount, or weight percentage of a component of a composition or dosage form, the terms "about" and "approximately" include values of a specified dosage, amount, or weight percentage, or a range of dosages, amounts, or weight percentages, that are recognized by those skilled in the art to provide a pharmacological effect equivalent to that obtained from the specified dosage, amount, or weight percentage.

[0055] Non-limiting embodiments of the present disclosure: Embodiment 1. A compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0056] Embodiment 2. A compound of formula (Ia):

Chemical formula

Chemical formula

[0057] Embodiment 3. Compounds of formula (Ib):

Chemical formula

Chemical formula

[0058] Embodiment 4. A compound of formula (Ic):

Chemical formula

Chemical formula

[0059] Embodiment 5. A compound of formula (Id):

Chemical formula

Chemical formula

[0060] The compound according to any one of claims 1 to 5, wherein embodiment 6.A is an aryl group.

[0061] Embodiment 7.A is

Chemical formula

[0062] The compound according to any one of claims 1 to 5, wherein embodiment 8.A is a heteroaryl group.

[0063] The compound according to any one of claims 1 to 5, wherein embodiment 9.A is an alkenyl group.

[0064] The compound according to any one of claims 1 to 5, wherein embodiment 10.A is an alkenyl group.

[0065] Embodiment 11.B is

Chemical formula

[0066] Embodiment 12.B is

Chemical formula

[0067] The compound according to claim 12, wherein in Embodiment 13, R is selected from a linear alkyl group, a branched alkyl group, and a cyclic alkyl group.

[0068] The compound according to claim 13, wherein in Embodiment 14, R is a t-butyl group.

[0069] Embodiment 15.B is

Chemical formula

[0070] Embodiment 16.B is

Chemical formula

[0071] Embodiment 17.B is

Chemical formula

[0072] The compound according to claim 15, wherein Embodiment 18.R is selected from a linear alkyl group, a branched alkyl group, and a cyclic alkyl group.

[0073] The compound according to claim 15, wherein Embodiment 19.R is selected from an aryl group and a heteroaryl group.

[0074] Embodiment 20.B is

Chemical formula

[0075] The compound according to claim 15, wherein Embodiment 21.R is selected from a linear alkyl group, a branched alkyl group, and a cyclic alkyl group.

[0076] The compound according to claim 15, wherein Embodiment 22.R is selected from an aryl group and a heteroaryl group.

[0077] Embodiment 23.B is

Chemical formula

[0078] Embodiment 24.

Chemical formula

[0079] Embodiment 25. B is

Chemical formula

[0080] Embodiment 26. B is

Chemical formula

[0081] Embodiment 27. B is

Chemical formula

[0082] Embodiment 28.B is

Chemical formula

[0083] Embodiment 29.B is

Chemical formula

[0084] Embodiment 30.B is

Chemical formula

[0085] Embodiment 31.B is

Chemical formula

[0086] Embodiment 32. B is [Chemical formula] and is the compound according to claim 29.

[0087] Embodiment 33. B is [Chemical formula] and; each R x is independently selected from hydrogen, a hydroxy group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a linear alkylene group, a branched alkylene group, a cyclic alkylene group, a heterocycloalkyl group, an aryl group, and a heteroaryl group; p and q are independently selected from 0, 1, 2, 3, and 4; C, D, and E are independently selected from hydrogen, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group, the compound according to any one of claims 1 to 10.

[0088] Embodiment 34. B is [Chemical formula] The compound according to claim 33, selected from

[0089] Embodiment 35.B is

Chemical formula

[0090] Embodiment 36.B is

Chemical formula

[0091] Embodiment 37.X 7 and X 8 One of them is selected from hydrogen, an amino group, -NHC(O)alkyl group, -NHC(O)arylalkyl group, and -NHC(O)heteroarylalkyl group, the compound according to any one of claims 1 to 36.

[0092] Embodiment 38. -NH2, -NHC(O)CH3, and

Chemical formula

[0093] Embodiment 39. Z is hydrogen, the compound according to any one of claims 1 to 29.

[0094] Compound according to any one of claims 1 to 29, wherein Z is -CN.

[0095] Compound according to any one of claims 1 to 29, wherein Z is -CO2H.

[0096] Embodiment 42. Z is -C(O)R z , -CO2R z , or -C(O)NHSO2R z ; wherein R z is selected from hydrogen, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, an amino group, a heterocyclic group, an aryl group, and a heteroaryl group, Compound according to any one of claims 1 to 29.

[0097] Compound according to any one of claims 1 to 29, wherein Z is -C(O)NHCN.

[0098] Embodiment 44.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0099] Embodiment 45. A compound of formula (II):

Chem.

Chemical formula

[0100] Embodiment 46. A compound of formula (IIa):

Chemical formula

Chemical formula

[0101] Embodiment 47. The compound according to claim 45 or 46, wherein G is selected from aryl groups.

[0102] Embodiment 48. G is

Chemical formula

[0103] Embodiment 49. G is

Chemical formula

[0104] Embodiment 50.

Chemical formula

Chemical formula

[0105] Embodiment 51. A compound of formula (III), (IV), or (V): [Chemistry] Its tautomer, the deuterated derivative of the compound of formula (III), (IV), or (V), the deuterated derivative of the tautomer of the compound of formula (III), (IV), or (V), or any pharmaceutically acceptable salt of any of the foregoing [wherein, (i) A is a compound according to any one of claims 1 to 50; (ii) J is selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; (iii) Z 1 , Z 2 , and each X is independently selected from hydrogen, a hydroxy group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) L is [Chemistry] wherein s is from 1 to 50, (v) p, q, and r are independently selected from 1, 2, 3, 4, 5, and 6].

[0106] Embodiment 52. The compound of formula (III) according to claim 51, wherein (i) A is a compound according to any one of claims 1 to 50; (ii) J is selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; (iii) Each X is independently selected from hydrogen, a hydroxy group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) L is

Chemical formula

[0107] Embodiment 53. A compound of formula (IV) [wherein, (i) A is a compound according to any one of claims 1 to 50; (ii) J is selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; (iii) Each X is independently selected from hydrogen, a hydroxy group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) L is

Chemical formula

[0108] Embodiment 54. A compound of formula (V) [wherein, (i) A is a compound according to any one of claims 1 to 50; (ii) J is selected from a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; (iii) Z 1 、Z 2 and each X are independently selected from hydrogen, a hydroxy group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) L is

Chemical formula

[0109] Compound according to any one of claims 51 to 54, wherein J is absent or is a cyclohexyl group.

[0110] Embodiment 56.

Chemical formula

[0111] Embodiment 57.

Chemical formula

[0112] Embodiment 58.

Chemical formula

[0113] List of Abbreviations In this specification, the following abbreviations are used: AcOH: acetic acid AF264: Alexa Fluor 264 anhyd: anhydrous aq.: aqueous solution Bn: benzyl Boc: tert-butoxycarbonyl (tert-butoxycabonyl) CSA: Camphorsulfonic acid CV: Column volume d: Number of days DAMP: Damage-associated molecular pattern DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene DCE: 1,2-Dichloroethane DCM: Dichloromethane DIPEA: N,N-Diisopropylethylamine DMA: N,N-Dimethylacetamide DMAP: 4-Dimethylaminopyridine DMF: N,N-Dimethylformamide DMSO: Dimethyl sulfoxide dsDNA: Double-stranded DNA DSPC: Distearoyl phosphatidylcholine DSPE: Distearoyl phosphatidylethanolamine EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ee: Enantiomeric excess EA: EtOAc: Ethyl acetate EtOH: Ethanol h: Number of hours HATU: N,N,N’,N’-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HCl: Hydrochloric acid HCQ: Hydroxychloroquine hep: n-Heptane HEPES: 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid HOBt - 1-Hydroxybenzotriazole monohydrate HPLC: High performance liquid chromatography IFN: Interferon IPA: Isopropyl alcohol or isopropanol K2CO3: Potassium carbonate LHMDS: Lithium hexamethyldisilazide MeOH: Methanol MgSO4: Magnesium sulfate (anhydrous) min: fraction MTBE: Methyl tert-butyl ether Na2CO3: Sodium carbonate Na2SO4: Sodium sulfate (anhydrous) NaBH4: Sodium borohydride NaCl: Sodium chloride NaH: 60% Dispersed sodium hydride in oil NaHCO3: Sodium bicarbonate NaOH: Sodium hydroxide NBS: N-Bromosuccinimide NH4Cl: Ammonium chloride NH4Cl: Ammonium chloride NH4OH: Ammonium hydroxide NMP: N-Methylpyrrolidone Ns: Nosyl or o-nitrobenzenesulfonyl ℃: Degree Celsius PAMP: Pathogen-associated molecular pattern PBMC: Peripheral blood mononuclear cell PBS: Phosphate-buffered saline pDC: Plasmacytoid dendritic cell PEG: Polyethylene glycol PhNTf2: N-Phenyltrifluoromethanesulfonimide qPCR: Quantitative polymerase chain reaction RT: Room temperature rt: Room temperature sat.: Saturated SOC: Standard of care T3P: Propylphosphonic anhydride tBuOK: Potassium tert-butoxide TEA: Triethylamine TEMPO: 2,2,6,6-Tetramethylpiperidine 1-oxyl Tf: Trifluoromethanesulfonate TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin layer chromatography TLDA: Taqman (registered trademark) Low Density Array TLR: Toll-like Receptor TSA: p-Toluenesulfonic Acid UPLC: Ultra Performance Liquid Chromatography

Example

[0114] General procedure for the preparation of the neuraminic acid C-glycoside bond intermediate F. Scheme 1

Chem.

[0115] General procedure for the preparation of C2-amino analogs (compounds G and H) of neuraminic acid C2-C-glycosides, Option A. Scheme 2

Chem.

[0116] General procedure for the preparation of C2 - amino analogs (compounds I - H) of neuraminic acid C2 - C - glycosides, Option B. Scheme 3

Chemical formula

[0117] General procedure for the preparation of C2 - amino analogs (compounds J, and L1 - L4) of neuraminic acid C2 - C - glycosides using the SNAP reaction 1 。 Scheme 4

Chemical formula

[0118] 1. General procedure for the preparation of C2-C-glycosides of neuraminic acid C2-C-analogs (compounds O and P) using Grubbs or modified Grubbs metathesis reaction 2,3,4 。 Scheme 5

Chemical Structure

[0119] 2. General procedure for the preparation of C2-styrene analogues (compound T) of neuraminic acid C2-C-glycosides, Option A. Scheme 6

Chemical Structure

[0120] 3. General procedure for the preparation of C2-styrene analogues (compound T) of neuraminic acid C2-C-glycosides, Option B. Scheme 7

Chemical Structure

[0121] 4. General procedure for the preparation of C2-styrene analogs (compound T) of neuraminic acid C2-C-glycosides, Option C. Scheme 8

Chem.

[0122] 5. General procedure for the preparation of C2-styrene analogs (compound T) of neuraminic acid C2-C-glycosides, Option D. Scheme 9

Chem.

[0123] 6. General preparation procedures for C2-dihydroxy and -dioxylane analogs (compounds Y, Z, AA, and BB) of neuraminic acid C2-C-glycosides. Scheme 10

Chem.

[0124] 7. General preparation procedures for C2-O-glycoside analogs (compound AE) of neuraminic acid. Scheme 11

Chem.

[0125] 8. General preparation procedure of macrocyclic analogs of neuraminic acid (Compound AN). Scheme 12 [Chemical formula] An example of the synthetic route leading to compounds in the macrocyclic series is shown in Scheme 12. Using either Boc-protected D- or L-serine methyl ester (AF) as the starting material, by Mitsunobu conditions, followed by ozonolysis of the terminal olefin, subsequent reduction to alcohol, and finally formation of an allyl ether protected with t-butyldimethylsilyl, Compound AG is obtained (where n equals 1). Reduction of the ester under standard hydride conditions, allylation using similar Mitsunobu conditions, and desilylation give primary alcohol AH (n = 1). Next, commercially available phenols such as AI can be coupled with AH under standard Mitsunobu conditions, followed by deprotection of the chiral amine, condensation with the appropriate acid AJ, and ester hydrolysis to give Compound AK. Then, after condensing amine compound AL, prepared from the reduction of the azide of Compound F (Scheme 1, R = Boc), with AK, and subsequently acylating all free hydroxyl groups, fully protected intermediate compound AM is obtained. By modified Hoyveda-Grubbs ring-closing metathesis with AM, followed by Boc removal, condensation with a selected acid, and finally hydrolysis of the terminal C-1 ester using hydroxide, the desired macrocycle AN containing an olefin is obtained. The saturated analog of AN can be obtained using simple hydrogenation conditions.

[0126] 9. Alternative preparation procedure of macrocyclic analogs of neuraminic acid (Compound AV). Scheme 13 [Chemical formula] A similar procedure for preparing the macrocyclic compound is shown in Scheme 13. Starting from 4-hydroxybenzoic acid AO, first, the formation of an ether under weakly basic conditions, hydrolysis of the undesired ester formed by the ether formation reaction, formation of a methyl ester by the addition of diazomethane, and Boc deprotection of the terminal amine allow for the easy preparation of the amino ether compound AQ. Condensation of AQ with a suitable ester AR containing a terminal olefin, followed by ester hydrolysis, gives the compound AS. Next, after condensing AS with AL, subsequent transesterification with a benzyl ester and then protection of the hydroxyl group with acetyl gives AT. Ring-closing metathesis of AT, followed by Boc removal, condensation with the acid of choice AU, and then final debenzylation using a hydroxide gives the desired macrocycle AV containing an olefin. Final debenzylation using hydrogenolysis conditions provides the saturated macrocycle AV.

[0127] 10. General procedure for preparing C1 analogs (compounds x-y) of neuraminic acid. Scheme 14

Chemical Structure

[0128]

Chemical Structure

[0129] Purification method used in this example: The following table provides a typical HPLC protocol for the purification of this example listed in Table 3.

[0130]

Table 1

[0131]

Table 2

[0132]

Table 3

[0133]

Table 4

[0134] Preparation of A-001 and A-002

Chemical formula

[0135]

Chemical formula

[0136] [Chemical Formula] A stirred solution of (1S,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-chloro-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)propane-1,2,3-triyl triacetate (3.21 g, 41.19 mmol) and p-toluenethiol (15.35 g, 123.56 mmol) in DCM (315 ml) at 0 °C was added dropwise with Hunig's base (23.74 ml, 135.91 mmol) over a period of 20 minutes while maintaining the temperature at 0 °C. The reaction was slowly warmed over a period of 16 hours to room temperature. The completed reaction was poured into saturated sodium bicarbonate (900 mL), back-extracted with ethyl acetate (600 mL), washed with 50% brine, and dried over anhydrous Na2SO4. It was concentrated. The crude product was sent to a SNAP Ultra HP 340 g silica gel column and purified with 5% ethyl acetate in n-heptane, eluting with 5% ethyl acetate in n-heptane (1 CV), 0%→100% ethyl acetate in n-heptane (10 CV), and 100% ethyl acetate (2 CV). Compound 4 (20.36 g, 24.1 mmol, 83%) was obtained (MW Calc +Na = 620.63; MW Obs = 620.20). Compound 5 was found to be the major impurity.

[0137]

Chemical formula

[0138] To a stirred solution of 5-amino-4-hydroxy-2-(p-tolylthio)-6-((1R,2R)-1,2,3-trihydroxypropyl)tetrahydro-2H-pyran-2-carboxylic acid (4S,5R,6R)-methyl (6, 40 g, 25.81 mmol) in acetonitrile (150 mL) and water (150 mL) at 0 °C was added sodium bicarbonate (10.84 g, 129.05 mmol), followed by stepwise addition of 4-nitrophenyl carbonochloridate (13.01 g, 64.53 mmol) in acetonitrile (150 mL) over a period of 30 minutes while maintaining the temperature at 0 - 5 °C. The reaction mixture was stirred at 0 °C for an additional 2.5 hours, and after that time it was diluted with ethyl acetate (500 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (100 mL each), the combined organic layers were washed with brine (100 mL), and then the organic layer was concentrated and dried in vacuo to give a yellow solid 7 (28.0 g, crude mixture). (MW Calc +H=414.44;MW Obs =414.08)

[0139] A solution of crude 2-oxo-6-(p-tolylthio)-4-((1R,2R)-1,2,3-trihydroxypropyl)hexahydro-2H-pyrano[3,4-d]oxazole-6-carboxylic acid (3aR,4R,6S,7aS)-methyl (7.27 g, 21.551 mmol) in pyridine (29.6 ml) was stirred at 5 °C under a N2 atmosphere, and acetic anhydride (30.5 ml, 323.26 mmol) was added dropwise thereto over a period of 30 minutes. The reaction mixture was warmed to room temperature and stirred for 19 hours. The completed reaction was diluted with ethyl acetate (500 mL), followed by 2N aqueous HCl solution (500 mL), and transferred to a separatory funnel together with additional ethyl acetate (200 mL). The layers were separated, and the organic layer was washed with 1N HCl (100 mL), saturated ammonium chloride (100 mL) and brine (100 mL). The combined aqueous layers were extracted with ethyl acetate (1 × 300 mL), and the resulting organic layer was washed with brine (50 mL). The combined organic layers were concentrated, and then the crude residue was applied to a SNAP 340 g silica gel cartridge and eluted with 0-100% EtOAc in heptane (10 column volumes) for purification. The desired product was recovered, concentrated and dried under vacuum to give the desired product 8 (12.2 g, 22.43 mmol, 104% w / solvent) as a foam. (MW Calc +23 = 562.55; MW Obs = 562.07)

[0140] [Chemical formula] To a stirred solution of (1S,2R)-1-((3aR,4R,6S,7aS)-6-(methoxycarbonyl)-2-oxo-6-(p-tolylthio)hexahydro-2H-pyrano[3,4-d]oxazol-4-yl)propane-1,2,3-triyl triacetate (8, 9.0 g, 16.68 mmol) in THF (315 mL) was added Boc anhydride (7.75 mL, 33.36 mmol), followed by DMAP (1.019 g, 8.34 mmol) at room temperature. The mixture was stirred for 30 minutes and after that time the completed reaction was partially concentrated to approximately 30 mL and applied to a SNAP silica gel column (100 g) and eluted with 0 - 15% ethyl acetate in heptane (5 CV), then 15 - 100% ethyl acetate in heptane (10 CV). The fractions containing the desired product were concentrated and dried under high vacuum to give 9 (8.6 g, 13.44 mmol, 81%). (MW Calc +23 = 662.67; MW Obs = 662.12)

[0141] Dibutyl phosphate (7.76 mL, 41.70 mmol) and 2-oxo-6-(p-tolylthio)-4-((1S,2R)-1,2,3-triacetoxypropyl)tetrahydro-2H-pyrano[3,4-d]oxazole-3,6(6H)-dicarboxylic acid (3aR,4R,6S,7aS)-3-tert-butyl 6-methyl (9, 8.6 g, 0.445 mmol) in dry DCM (188 mL) were stirred, and dry 4 Å molecular sieves (2 g / mmol reagent) were added, followed by stirring for 2 hours. After cooling the mixture to 0 °C, N-iodosuccinimide (6.38 g, 28.36 mmol) was added, followed by trifluoromethanesulfonic acid (0.25 mL, 2.84 mmol) in DCM (0.1 mL). The final reaction mixture was stirred at 0 °C for 4 - 5 hours, and after that time, sodium thiosulfate (10 g) in NaHCO3 (50 mL) and water (50 mL) was added to quench it. After adding EtOAc (100 mL), it was stirred for an additional 5 minutes. The quenched suspension was filtered, then the layers were separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL each). The combined organic layers were washed with saturated NaHCO3 (5 mL), followed by brine (5 mL), dried over anhydrous Na2SO4, filtered, and dried by concentration. The crude product was sent to a Biotage SNAP silica gel column (100 g) and eluted with a gradient of 0 - 100% ethyl acetate in heptane (total 10 CV) for purification. After recovery, concentration, and drying under high vacuum of the desired fractions, the desired product 10 (9.20 g, 12.68 mmol, 76%) was obtained. (MW Calc +H = 726.68; MW Obs = 726.30)

[0142]

Chem.

[0143] [Chemical formula] To a stirred solution of (3aR,4R,6R,7aS)-3-tert-butyl 6-methyl 6-allyl-2-oxo-4-((1S,2R)-1,2,3-triacetoxypropyl)tetrahydro-2H-pyrano[3,4-d]oxazole-3,6(6H)-dicarboxylate (11, 0.64 g, 1.15 mmol) in pure methanol (26 mL) was slowly added 25% sodium methoxide in methanol (0.67 mL, 2.96 mmol) over a period of 2 - 3 minutes. The reaction mixture was stirred at room temperature for 30 minutes and after this time Amberlyst 15 resin (2 g) was added followed by stirring for a further 5 minutes. The completed reaction was filtered through celite, rinsed with methanol (2 x 20 mL), concentrated and dried in vacuo to afford the crude compound 12 (0.45 g, 1.11 mmol, 97%). (MW Calc +Na = 428.44; MW Obs = 428.22)

[0144]

Chemical formula

[0145] [Chemical formula] To a stirred solution of (2R,4S,5R,6R)-methyl 2-allyl-6-((1R,2R)-3-azido-1,2-dihydroxypropyl)-5-((tert-butoxycarbonyl)amino)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (13, 0.68 g, 1.57 mmol) in THF (17 mL) and water (1.1 mL) at 0 °C was added 1N trimethylphosphine (4.71 mL, 4.71 mmol). Subsequently, the reaction was warmed to room temperature and stirred for 16 h. The completed reaction was concentrated and dried by azeotroping with toluene (2 × 40 mL each) to obtain crude 14. (MW Calc +H = 405.46; MW Obs = 405.28)

[0146] Under an N2 atmosphere at room temperature, to a stirred solution of (2R,4S,5R,6R)-methyl 2-allyl-6-((1R,2R)-3-amino-1,2-dihydroxypropyl)-5-((tert-butoxycarbonyl)amino)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (14, 0.68 g, 1.57 mmol) in acetonitrile (6.76 ml) were added 4-hydroxy-3,5-dimethylbenzoic acid (0.326 g, 1.96 mmol), and TEA (0.44 ml, 3.14 mmol), followed by N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (0.488 g, 3.141 mmol). The reaction mixture was stirred for 16 h, after which time ethyl acetate (50 mL) was added and the mixture was washed successively with water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4, concentrated, and purified by passage through a Biotage SNAP silica gel column (25 g) eluting with 40→100% ethyl acetate in heptane (10 CV), 0%→20% MeOH in DCM (5 CV), and 20% MeOH in DCM (2 CV). The desired fractions were concentrated and dried under high vacuum to give compound 15 (0.444 g, 0.803 mmol, 51.2%) as a white solid. (MW Calc +Na = 575.62; MW Obs = 575.20)

[0147]

Chem.

[0148] To a stirred solution of 16 in pyridine at 0 °C, acetic anhydride (14.75 mL, 156.35 mmol) was slowly added while maintaining the temperature below 5 °C. After the final addition, the reaction was warmed to room temperature and stirred for an additional 14 hours. The completed reaction was diluted with ethyl acetate (200 mL) and washed with 0.5 N HCl (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, concentrated, and purified by eluting through a Biotage SNAP silica gel column (200 g) with 0 - 100% EtOAc in heptane. After concentration of the desired fraction and drying under vacuum, the desired amide 17 (12.0 g, 18.11 mmol, 70%) was obtained. (MW Calc +H = 663.69; MW Obs = 663.14)

[0149]

Chemical Structure

[0150] To a stirred slurry of (S)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (S)-2-hydroxy-2-phenylacetate (19.2, 1.58 g, 4.005 mmol) in dichloromethane (100 mL) was added saturated aqueous sodium bicarbonate solution (100 mL). The mixture was shaken for 5 minutes and then the layers were separated. The organic layer was washed a second time with saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with DCM (2 × 25 mL). The combined organic phases were concentrated under reduced pressure and dried by azeotroping with dichloroethane (3 × 50 mL each) to give Compound 19 (0.97 g, 4.01 mmol, 100%), which was used in the next step without further purification.

[0151] A stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-allyl-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (17, 1.30 g, 1.96 mmol) in 1,4-dioxane (23.4 mL) and water (7.80 mL) was treated with 2,6-lutidine (0.46 mL, 3.923 mmol), osmium tetroxide (0.25 mL, 0.039 mmol), and sodium periodate (1.678 g, 7.847 mmol) at room temperature. The completed reaction was diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate (50 mL), and washed with brine (50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford crude aldehyde 18.

[0152] To a stirred solution of 18 in dichloroethane (19.5 mL) and MeOH (3.90 mL, 96.398 mmol) was added (S)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19, 0.523 g, 2.158 mmol), acetic acid (0.786 mL, 13.73 mmol), and 4 Å MS (3 g) at room temperature. The suspension was stirred for 1 h, followed by addition of sodium triacetoxyborohydride (0.832 g, 3.923 mmol), and stirring continued for 16 h. The completed reaction was quenched with saturated NaHCO3 (10 mL) and extracted with EtOAc (3 × 15 mL each). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford crude amine 20. (MW Calc +H = 891.42; MW Obs = 891.55)

[0153] A stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-(2-((S)-2-(tert-butoxycarbonyl)-9-oxa-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (20, 20.3 mg, 0.023 mmol) in 7N ammonia in methanol (2 mL, 14.00 mmol) was placed in a sealed microwave apparatus at 120 °C for 1 hour. The completed reaction was cooled to room temperature and purified directly by HPLC. After recovery, concentration, and drying under vacuum of the desired fractions, A-002 (8.5 mg, 0.012 mmol, 51%) was obtained. (MW Calc +H = 723.37; MW Obs = 723.54)

[0154] To a stirred solution of 20 in methanol (3.9 ml) and THF (15.6 ml) at room temperature was added 1N sodium hydroxide in water (19.62 ml, 19.62 mmol). The reaction was stirred for 48 hours. After completion of the reaction over that time, the reaction was diluted with methanol (25 mL) and directly injected in 0.05 mL aliquots onto a Waters Sunfire Prep C18 column (5 μm, 10×250 mm) and eluted with a gradient of water (containing 0.1% formic acid) to acetonitrile from 90:10 to 60:40 over 8 minutes, from 60:40 to 1:99 over 1 minute, and 1:99 water (containing 0.1% formic acid) to acetonitrile for 1 minute, followed by re-equilibrating the solvent conditions on the column to the initial 90:10 water (containing 0.1% formic acid) to acetonitrile for 4.5 minutes before injecting the next aliquot. After concentration to dryness of the desired fractions, followed by azeotroping with toluene (3×5 mL each) and drying under high vacuum, compound A-001 (0.60 g, 0.846 mmol, 43.2%) was obtained. (MW Calc +H = 709.81; MW Obs = 709.62)

[0155] Preparation of A-003 to A-026 A-003 was prepared in the same manner as A-001, starting from compound 18 (137.0 mg, 0.206 mmol) and commercially available (R)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (82 mg, 0.340 mmol; obtained by separating each enantiomer from the commercially available racemic mixture using chiral HPLC method X) to give A-003 (37.7 mg, 0.053 mmol, 26% overall yield). (MW Calc +H = 709.36; MW Obs = 709.49)

[0156] A-004 was prepared in the same manner as A-001, starting from compound 18 (30.0 mg, 0.045 mmol) and commercially available tert-butyl (5S,8R)-8-methyl-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (18.5 mg, 0.072 mmol) to give A-004 (11.8 mg, 0.016 mmol, 36% overall yield). (MS Calc +H = 723.37; MW Obs = 723.24)

[0157] A-005 was prepared in the same manner as A-001, starting from compound 18 (30.0 mg, 0.045 mmol) and commercially available tert-butyl (5S,8S)-8-methyl-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (18.5 mg, 0.072 mmol) to give A-005 (6.0 mg, 0.008 mmol, 18% overall yield). (MS Calc +H = 723.37; MW Obs = 723.25)

[0158] A-006 was prepared in the same manner as A-001, starting from compound 18 (50.0 mg, 0.075 mmol) and commercially available tert-butyl 1,8-diazaspiro[5.5]undecane-8-carboxylate (31.6 mg, 0.124 mmol) to give A-006 (4.2 mg, 0.006 mmol, 8% overall yield). (MW Calc +H = 723.38; MW Obs=723.60)

[0159] A-007 was prepared in the same manner as A-001, starting from compound 18 (50.0 mg, 0.075 mmol) and commercially available tert-butyl 4-oxa-1,9-diazaspiro[5.5]undecane-9-carboxylate (31.8 mg, 0.124 mmol) to obtain A-007 (8.2 mg, 0.011 mmol, 15% overall yield). (MW Calc +H=723.38;MW Obs =723.60)

[0160] A-008 was prepared in the same manner as A-001, starting from compound 18 (50.0 mg, 0.075 mmol) and commercially available tert-butyl 8-oxa-2,5-diazaspiro[3.5]nonane-2-carboxylate (28.3 mg, 0.124 mmol) to obtain A-008 (28.3 mg, 0.040 mmol, 53% overall yield) (MW Calc +H=695.35;MW Obs =695.60).

[0161] A-009 was prepared in the same manner as A-001, starting from compound 18 (10.0 mg, 0.015 mmol) and commercially available tert-butyl methyl(morpholin-3-ylmethyl)carbamate (5.2 mg, 0.0.23 mmol) to obtain A-009 (0.4 mg, 0.005 mmol, 4% overall yield) (MW Calc +H=697.4;MW Obs =697.7).

[0162] A-010 and A-011 were prepared in the same manner as A-001, starting from compound 18 (335 mg, 0.504 mmol) and commercially available tert-butyl 9-methyl-2,6,9-triazaspiro[4.5]decane-2-carboxylate (193 mg, 0.756 mmol). After purification using a chiral reverse-phase HPLC column, collection of the desired fractions, and concentration to dryness under vacuum, A-010 (60 mg, 0.083 mmol, 27% overall yield) (MW Calc +H=722.39;MW Obs=(722.51) and A-011 (65.2 mg, 0.092 mmol, 30% overall yield) were obtained (MW Calc +H = 722.39; MW Obs = 722.23). (330 mg, 0.365 mmol, protected intermediate as a 72.4% diastereomeric mixture) (MW Calc +H = 722.39; MW Obs = 722.23).

[0163] A-012 and A-013 were prepared in the same manner as A-001, starting from compound 18 (230 mg, 0.346 mmol) and commercially available 2,6,9-triazaspiro[4.5]decane-2,9-dicarboxylic acid 9-((9H-fluoren-9-yl)methyl) 2-(tert-butyl) (241 mg, 0.519 mmol). After purification, A-012 (24.9 mg, 0.035 mmol, 62% overall yield) (MW Calc +H = 708.38; MW Obs = 708.5) and A-013 (25 mg, 0.036 mmol, 54% overall yield) were obtained (MW Calc +H = 708.38; MW Obs = 708.5).

[0164] A-014 and A-015 were prepared in the same manner as A-001, starting from compound 18 (60 mg, 0.0.90 mmol) and commercially available tert-butyl 9-acetyl-2,6,9-triazaspiro[4.5]decane-2-carboxylate (38 mg, 0.135 mmol). After purification using a chiral reverse-phase HPLC column, recovery of the desired fractions, and concentration to dryness under vacuum, A-014 (60 mg, 0.083 mmol, 27% overall yield) (FW = 721.85; MW Calc +H = 722.39; MW Obs = 722.51] and A-014 (6.57 mg, 0.0087 mmol, 32.7% overall yield) (MW Calc +H = 750.39; MW Obs = 750.5) and A-015 (7.19 mg, 0.0095 mmol, 35.5%) (MW Calc +H = 723.39; MW ObsA mixture with (MW = 723.4) was obtained. DL 2804.095.

[0165] A-016 was prepared in the same manner as A-001. Starting from compound 18 (20.0 mg, 0.03 mmol) and commercially available tert-butyl 9-methyl-8-oxo-2,6,9-triazaspiro[4.5]decane-2-carboxylate (10 mg, 0.036 mmol), A-016 (4.7 mg, 0.006 mmol, 21% total yield) was obtained (MW Calc +H = 736.37; MW Obs = 736.5).

[0166] A-017 was prepared in the same manner as A-001. Starting from compound 18 (24.0 mg, 0.036 mmol) and commercially available tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate (11.5 mg, 0.054 mmol), A-017 (10.4 mg, 0.027 mmol, 42% total yield) was obtained (MW Calc +H = 679.35; MW Obs = 679.35). The compound was purified by a gradient of water / acetonitrile containing 0.1% formic acid on a reverse-phase C18 Xselect.

[0167] A-018 was prepared in the same manner as A-001. Starting from compound 18 (25.0 mg, 0.038 mmol) and commercially available tert-butyl 1,6-diazaspiro[3.4]octane-6-carboxylate (20 mg, 0.094 mmol), A-018 (17.8 mg, 0.026 mmol, 69% total yield) was obtained (MW Calc +H = 679.35; MW Obs = 679.39).

[0168] A-019 and A-020 were prepared in the same manner as A-001, starting from Compound 18 (25.0 mg, 0.038 mmol) and commercially available tert-butyl 1,7-diazaspiro[4.4]nonane-7-carboxylate (21.3 mg, 0.094 mmol), followed by purification using a chiral reverse-phase HPLC column, collection of the desired fractions, and concentration to dryness under vacuum to afford A-019 (9.7 mg, 0.014 mmol, 37% overall yield), and A-020 (9.7 mg, 0.014 mmol, 37% overall yield). (MW Calc +H = 693.37; MW Obs = 693.39).

[0169] A-021 was prepared in the same manner as A-001, starting from Compound 18 (28.0 mg, 0.042 mmol) and commercially available tert-butyl 1,6-diazaspiro[3.3]heptane-6-carboxylate (21 mg, 0.105 mmol) to afford A-021 (16.5 mg, 0.0248 mmol, 59% overall yield) (MW Calc +H = 665.34; MW Obs = 665.33).

[0170] A-022 was prepared in the same manner as A-001, starting from Compound 18 (28.0 mg, 0.042 mmol) and commercially available tert-butyl 2,6-diazaspiro[4.5]decane-2-carboxylate (25.3 mg, 0.105 mmol) to afford A-022 (4.2 mg, 0.0059 mmol, 14% overall yield) (MW Calc +H = 707.38; MW Obs = 707.6)

[0171] A-023 was prepared in the same manner as A-001, starting from Compound 18 (30.0 mg, 0.042 mmol) and commercially available tert-butyl 1,7-diazaspiro[3.5]nonane-7-carboxylate (25.3 mg, 0.105 mmol) to afford A-023 (21.9 mg, 0.032 mmol, 70% overall yield) (MW Calc +H = 693.37; MW Obs = 693.36).

[0172] A-024 was prepared in the same manner as A-001, starting from compound 18 (20.0 mg, 0.03 mmol) and commercially available 3-(pyridin-3-yl)morpholine (7.4 mg, 0.045 mmol) to obtain A-024 (11 mg, 0.017 mmol, 58% total yield) (MW Calc +H = 631.29; MW Obs = 631.37).

[0173] A-025 was prepared in the same manner as A-001, starting from compound 18 (44.1 mg, 0.066 mmol) and commercially available tert-butyl 2-methyl-1,7-diazaspiro[4.4]nonane-7-carboxylate (24 mg, 0.10 mmol) to obtain A-025 (14.1 mg, 0.02 mmol, 56% total yield) (MW Calc +H = 707.38; MW Obs = 707.38).

[0174] A-026 was prepared in the same manner as A-001, starting from compound 18 (30 mg, 0.045 mmol) and commercially available tert-butyl 3-amino-3-methyl-pyrrolidine-1-carboxylate (13.6 mg, 0.10 mmol) to obtain A-026 (13.9 mg, 0.020 mmol, 47% total yield) (MW Calc +H = 667.35; MW Obs = 667.37).

[0175] Preparation of A-027

Chemical formula

[0176] To a stirred solution of the crude amine from above in acetonitrile (1 mL) at room temperature were added commercially available 4-(2-(((benzyloxy)carbonyl)amino)ethoxy)-3,5-dimethylbenzoic acid (0.075 g, 0.218 mmol) and HOBt (0.013 g, 0.087 mmol), followed by triethylamine (0.061 mL, 0.436 mmol) and EDC (0.045 g, 0.235 mmol). The reaction mixture was stirred for 16 h, and after that time, water (5 mL) and EtOAc (20 mL) were added. The resulting layers were separated, the organic layer was washed with brine (5 mL), the EtOAc layer was dried over Na2SO4, filtered, and evaporated to dryness. This crude intermediate was used directly in the next reaction.

[0177] To a stirred solution of the crude intermediate in DCM (5 mL) at room temperature was added TFA (0.1 mL, 1.31 mmol). The reaction was stirred for 15 min, and after that time, it was concentrated and dried by co-evaporating with toluene (3 × 5 mL each). This crude intermediate was used directly in the next reaction.

[0178] To a stirred solution of the final crude intermediate in pyridine (0.5 mL) at room temperature was added acetic anhydride (0.3 mL, 3.17 mmol), followed by stirring for 24 h. The completed reaction was diluted with EtOAc (20 mL) and washed with 1N HCl (5 mL), saturated NH4Cl (5 mL), and brine (5 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to afford compound 21 (75 mg, 0.094 mmol, 54%) as the pure product. (MW Calc +H = 798.86; MW Obs = 799.45)

[0179] To a stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-allyl-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-(2-(((benzyloxy)carbonyl)amino)ethoxy)-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (21, 160 mg,.201 mmol) in dioxane (3 mL) and water (1 mL) at room temperature were added 2,6-lutidine (46.7 μl, 0.401 mmol) and osmium tetroxide (79 μl, 0.010 mmol), followed by sodium periodate (172 mg, 0.802 mmol). The reaction mixture was stirred for 3 h and after that time it was diluted with water (5 mL) and extracted with DCM (3 × 10 mL each). The combined organic layers were washed with water (5 × 5 mL each), dried over MgSO4, filtered, and concentrated to dryness to afford a black crude oil which was used directly in the next reaction.

[0180] To a stirred solution of the crude aldehyde from the above in 1,2-dichloroethane (3 mL) at room temperature was added tert-butyl (S)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19A, 60.7 mg, 0.251 mmol), acetic acid (86 μL, 1.50 mmol), and dry 4A MS (220 mg). The mixture was stirred for 3 h and after that time sodium triacetoxyborohydride (85 mg, 0.401 mmol) was added followed by stirring for a further 3 h. The completed reaction was diluted with NaHCO3 (3 mL) and extracted with EtOAc (3 × 5 mL each). The combined organic layers were washed with brine (3 mL) and concentrated in vacuo to give crude compound 22 which was used directly in the next reaction.

[0181] To a stirred solution of crude 22 in 1:1 EtOAc:EtOH (10 mL) at room temperature was added 10% Pd / C (50 mg) followed by placing under a H2 atmosphere (under balloon pressure) for 6 h. The completed reaction was filtered through a pad of Celite (5 g) by elution with EtOAc (2 × 5 mL each) and the resulting filtrate was concentrated and dried by azeotroping with MeOH (2 × 5 mL). The crude residue was dissolved in MeOH (0.5 mL) followed by 1N aqueous NaOH (0.7 mL, 0.070 mmol) and stirred for 36 h. The final reaction mixture was neutralized with 1N HCl (0.7 mL, 0.07 mmol) and purified directly on an HPLC column, the desired fractions were combined, concentrated and dried under high vacuum to give compound A-027 (2.9 mg, 0.004 mmol, 2% overall yield from 21). (MW Calc +H = 752.88; MW Obs = 752.60)

[0182] Preparation of A-028 and A-029

Chemical Structure

[0183] To a stirred solution of methyl N-allyl-N-(tert-butoxycarbonyl)glycinate (24, 22.61 g, 98.62 mmol) in DCM (327 mL) at -78 °C, 1 M DIBAL-H in DCM (123 mL, 123.27 mmol) was added dropwise over 20 min. The reaction was stirred at -78 °C for 3 h and after this time it was quenched by slowly adding methanol (4.99 mL, 123.27 mmol) dropwise, followed by the addition of 0.8 M NaOH (765 mL, 612.00 mmol) and DCM (180 mL). The quenched reaction was warmed to room temperature and after this time the layers were separated and the aqueous layer was extracted with DCM (100 mL). The combined organic layers were washed with water (100 mL), 1:1 water:brine (50 mL), dried over Na2SO4, filtered, concentrated, and dried by azeotroping with MeCN (50 mL) to give compound 25 (15.92 g, 79.90 mmol, 81%) as a crude oil.

[0184] To a stirred solution of tert-butyl allyl(2-oxoethyl)carbamate(25, 15.92 g, 79.90 mmol) in DCM(120 mL) and methanol(60 mL, 1483.053 mmol) was added hydroxylamine hydrochloride(15.77 g, 226.92 mmol) and sodium acetate(18.61 g, 226.92 mmol) at room temperature, and the mixture was then stirred for 72 h. The completed reaction was poured into water(300 mL), the layers were separated, and the aqueous layer was extracted with DCM(150 mL). The combined organic layers were washed with 1:1 water:brine(50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford compound 26(15.46 g, 72.2 mmol, 90%) as a crude oil.

[0185] To a stirred solution of tert-butyl allyl(2-hydroxyiminoethyl)carbamate(26, 15.46 g, 72.15 mmol) in DCM(150 mL) at room temperature was added dropwise a 5% aqueous solution of sodium hypochlorite(170 mL, 137.71 mmol) over 60 min. The reaction was stirred at room temperature for 1 h, after which time the layers were separated, the aqueous layer was extracted with DCM(200 mL), the combined organic layers were washed with 1:1 water:brine(2 × 50 mL each), dried over Na2SO4, filtered, and concentrated. The crude product was sent onto a Biotage SNAP column(100 g) and eluted with 2 CV heptane; 2 CV, 0%→5% EtOAc in heptane; 2 CV, 5% EtOAc in heptane; 6 CV, 5%→30% EtOAc in heptane; 2 CV, 30%→50% EtOAc in heptane; 2 CV, 50% EtOAc in heptane; 2 CV, 50%→80% EtOAc in heptane; and 2 CV, 80%→100% EtOAc in heptane for purification. The desired fractions were combined and concentrated in vacuo to afford compound 27(9.49 g, 44.7 mmol, 62%).(MW Calc +Na=235.12;MW Obs =235.17)

[0186] Under an N2 atmosphere at -78 °C, boron trifluoride etherate (1.5 mL, 11.837 mmol) was added to a stirred solution of tert-butyl 3a,4-dihydro-3H-pyrrolo[3,4-c]isoxazole-5(6H)-carboxylate (27, 2.2 g, 10.365 mmol) in THF (15 mL) and toluene (15 mL) while maintaining the temperature below -60 °C. Subsequently, allylmagnesium bromide (12 mL, 12.00 mmol) in THF was added dropwise. The reaction mixture was stirred at below -70 °C for 2.5 h, and after that time it was carefully quenched with saturated aqueous NH4Cl (10 mL), and the mixture was warmed to room temperature. The completed reaction was treated with saturated NaHCO3 until pH 7-8 was reached, and then extracted with ethyl acetate (2 × 75 mL each). The combined organic layers were washed with 1:1 water:brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude intermediate (2.99 g).

[0187] This crude intermediate was dissolved in THF (40 mL) and acetic acid (5 mL) and cooled to 0 °C. After that time, zinc (2.50 g, 38.24 mmol) was added and stirred for 10 min. The reaction was warmed to room temperature and stirred for 24 h. After that time, celite (11 g) was added, and then filtered through a plug of celite (11 g). The filter pad was washed with ethyl acetate (350 mL), and then saturated sodium bicarbonate (80 g) was added to the filtrate, followed by stirring for 15 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with 1:1 water:brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give compound 28 (2.67 g, 10.36 mmol, 100%) as a crude syrup as a racemic mixture. (MW Calc +H + =257.19;MW Obs =256.90).

[0188] To a stirred solution of crude (3S,4S)-3-allyl-3-amino-4-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl (28,500 mg, 1.95 mmol) in DCM (10 mL) at 0 °C was added saturated aqueous sodium bicarbonate solution (15 mL), followed by benzyl chloroformate (0.715 ml, 2.15 mmol) in toluene with stirring. The reaction mixture was stirred at 0 °C for 2 h and after that time an additional amount of benzyl chloroformate (0.130 mL, 0.39 mmol) in toluene was added and stirred for 1.5 h. The completed reaction was quenched with isopropylamine (0.2 mL, 2.335 mmol), stirred at 0 °C for 15 min and then extracted with ethyl acetate (2 × 20 mL each). The combined organic layers were washed with 1:1 water:brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. Purification by elution on a Biotage SNAP column (25 g) with 0-100% ethyl acetate in heptane (10 CV) gave compound 29 (340.0 mg, 0.87 mmol, 45% from compound 26) after collection, concentration and drying in vacuo of the desired fractions. (MW Calc +Na + =413.22;MW Obs =413.12).

[0189] To a stirred solution of tert-butyl (3S,4S)-3-allyl-3-(((benzyloxy)carbonyl)amino)-4-(hydroxymethyl)pyrrolidine-1-carboxylate (29, 340 mg, 0.87 mmol) and imidazole (237 mg, 3.48 mmol) in DMF (3.4 mL) was added tert-butyldimethylsilyl chloride (262 mg, 1.74 mmol) at room temperature. The reaction was stirred for 23 h and then diluted with while stirring after that time. Upon completion by TLC, the reaction was worked up with 1:1 water:MTBE (30 mL) and the layers were separated. The aqueous layer was extracted with MTBE (10 mL), the combined organic layers were washed with saturated NaHCO3 (10 mL), 1:1 water:brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. It was sent to a Biotage SNAP column (25 g) and eluted with 0-40% ethyl acetate in heptane (10 CV) for purification. After recovery, concentration, and drying in vacuo of the desired fractions, compound 30 (367 mg, 0.728 mmol, 84%) was obtained. (MW Calc +Na = 527.30; MW Obs = 527.30).

[0190] To a stirred solution of tert-butyl (3S,4S)-3-allyl-3-(((benzyloxy)carbonyl)amino)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (30, 367 mg,.728 mmol) and allyl bromide (189 μL, 2.184 mmol) in DMF (3.0 mL) cooled to 0 °C was slowly added NaH (87 mg, 2.184 mmol). The reaction was stirred for 2 h and then slowly quenched with saturated NH4Cl (1.5 mL) and water (1.5 mL) after that time. The mixture was extracted with MTBE (70 mL), the organic layer was washed with 1:1 water:brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. It was sent to a Biotage SNAP column (25 g) and eluted with 0-40% ethyl acetate in heptane (10 CV) for purification. After recovery, concentration, and drying in vacuo of the desired fractions, compound 31 (397 mg, 0.728 mmol, 100%) was obtained. (MW Calc +Na = 567.33; MWObs =567.28)

[0191] To a stirred solution of tert-butyl (3S,4S)-3-allyl-3-(allyl((benzyloxy)carbonyl)amino)-4-(((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine-1-carboxylate (31, 397 mg, 0.728 mmol) in toluene (20 mL, 187.756 mmol) was added Hoveyda-Grubbs 2nd generation catalyst (46.2 mg, 0.073 mmol). The reaction mixture was degassed and refilled with N2 three times, and then stirred at 80 °C for 8 h. The completed reaction was cooled to room temperature, concentrated, loaded onto a Biotage SNAP column (25 g) and eluted with 0-40% ethyl acetate in heptane (10 CV), and after collection, concentration and vacuum drying of the desired fraction, compound 32 (360 mg, 0.697 mmol, 95%) was obtained. (MW Calc +Na=539.30;MW Obs =539.24)

[0192] To a stirred solution of (4S,5S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-diazaspiro[4.5]dec-8-ene-2,6-dicarboxylic acid 6-benzyl 2-(tert-butyl) (32, 0.36 g, 0.697 mmol) in ethyl acetate (7.2 mL) was added acetic acid (0.040 mL, 0.697 mmol), followed by 5% Pd-C (0.089 g, 0.042 mmol). The reaction mixture was stirred under a low-pressure hydrogen atmosphere for 16 h, and after degassing and purging with N2 gas three times over that time, it was subsequently filtered through celite (2 g) and eluted with MeOH (10 mL). The filtrate was concentrated to dryness, then diluted with 1:1 ethyl acetate:saturated NaHCO3 (40 mL). The layers were separated, the organic layer was washed with water:brine (20 mL), dried over Na2SO4, filtered, and concentrated to dryness. It was sent to a Biotage SNAP column (25 g) and purified by elution with 0-1OO% ethyl acetate in heptane (10 CV), and after collection, concentration and vacuum drying of the desired fraction, compound 33 (207 mg, 0.538 mmol, 77%) was obtained. (MW Calc +Na=407.28;MW Obs =407.33

[0193] A stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-allyl-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (17, 51 mg, 0.077 mmol) in methanol (1.0 mL) was subjected to ozonolysis at -78 °C for 15 minutes and after that time it was quenched with dimethyl sulfide (0.5 mL). The completed reaction was warmed to room temperature and then concentrated to dryness to afford crude compound 18.

[0194] The crude compound 18 and tert-butyl (4S,5S)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-diazaspiro[4.5]decane-2-carboxylate (33, 35.4 mg, 0.092 mmol) were dried by azeotroping with acetonitrile (3 × 10 mL) and then dissolved in dichloroethane (1.5 mL). To this solution, acetic acid (26.4 μL, 0.462 mmol) was added, followed by 4 Å MS (0.5 g), and the mixture was stirred for 2.5 hours. Sodium triacetoxyborohydride (82 mg, 0.385 mmol) was added and the reaction was stirred at room temperature for 72 hours. The completed reaction was diluted 1:1 with ethyl acetate in saturated NaHCO3 (10 mL), stirred, and the layers were separated. The aqueous layer was extracted with EA (5 mL), the combined organic layers were washed with 1:1 water:brine (5 mL), dried over Na2SO4, filtered, and concentrated to dryness to afford crude compound 34 (77 mg, 0.075 mmol, 97%). (MW Calc +H = 1033.53; MW Obs = 1033.49)

[0195] A stirred solution of crude (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-(2-((4S,5S)-2-(tert-butoxycarbonyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (34, 77.2 mg, 0.075 mmol) in THF (4.0 mL) at 0 °C was treated with 1 M TBAF in THF (250 μL, 0.25 mmol). The reaction mixture was stirred at 0 °C for 3 h, after which time 1 M TBAF in THF (100 μL, 0.10 mmol) was added and the reaction was stirred at 0 °C for 15 h. The completed reaction was diluted 1:1 with ethyl acetate in saturated NaHCO3 (10 mL), stirred, and the layers were separated. The aqueous layer was extracted with EA (5 mL), the combined organic layers were washed with 1:1 water:brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by elution on a Biotage SNAP column (25 g) with 0 - 40% ethyl acetate in heptane (10 CV) afforded compound 35 (28.1 mg, 0.031 mmol, 41%) as a diastereomeric mixture of two compounds after collection, concentration, and drying in vacuo of the desired fractions. (MW Calc +H = 919.45; MW Obs = 919.45)

[0196] (1R,2R)-1-((2R,3R,4S,6R)-3-Acetamido-4-acetoxy-6-(2-((4S,5S)-2-(tert-Butoxycarbonyl)-4-(hydroxymethyl)-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)-tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (35.6 mg, 6.529 μmol) (dilution ratio 1:1) in MeOH (0.3 mL) and water (50 μL) was stirred, and 1N NaOH (102 μL, 0.102 mmol) was added at room temperature, followed by stirring for 14 h. 2N NaOH (46 μL, 0.132 mmol) was added, and the reaction mixture was stirred for an additional 24 h. The reaction was quenched to pH ~6 - 7 with 1N HCl (230 μL, 0.23 mmol) and purified directly on a chiral HPLC column to give A-028 (3.2 mg, 0.004 mmol, 64%) (MW Calc +H = 736.39; MW Obs = 736.33) and A-029 (2.2 mg, 0.003 mmol, 44%) (MW Calc +H = 736.39; MW Obs = 736.31).

[0197] Preparation of A-030 - A-035

Chemical formula

[0198] (2S,3S)-2,3-Bis((4-methylbenzoyl)oxy)succinic acid (0.268 g, 0.694 mmol) was added to a stirred solution of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (36, 0.30 g, 1.39 mmol) in 2-propanol (2.4 mL), and then the mixture was stirred at room temperature until mostly dissolved. The resulting solution was heated at 65 °C for 1 h, and after that time the resulting white mixture was cooled to room temperature. The white solid suspension was filtered, the filter pad was washed with cold 2-propanol (1 mL), and the filter cake was dried under vacuum at 45 °C for 16 h to give crude (S)-tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (247 mg, 0.603 mmol, 43%).

[0199] (S)-tert-Butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (2S,3S)-2,3-bis((4-methylbenzoyl)oxy)succinate (209 mg, 0.51 mmol) was suspended in water (1.045 mL) and EtOAc (1.045 mL), cooled to 0 - 5 °C with stirring, and after the passage of that time, 6 M HCl (85 μL, 0.51 mmol) was added dropwise, followed by stirring at 0 - 5 °C for 1 hour. The layers were separated, and the aqueous layer was extracted with EtOAc (1 mL). The aqueous layer was cooled to 0 - 5 °C, then treated with 3 M NaOH (170 μl, 0.51 mmol), followed by stirring for 1 hour. The resulting aqueous solution was lyophilized to a dry powder, which was then suspended in EtOH (4 mL) and stirred at room temperature for 4 hours. The white suspension was filtered through a Celite pad, washed with EtOH (2 mL), and the filtrate was concentrated and dried under vacuum to give Compound 37 (98.9 mg, 0.453 mmol, 89%).

[0200] To a stirred solution of tert-butyl 3-amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (37, 1.50 g, 6.94 mmol) in THF (40 mL) and aqueous sodium carbonate (0.956 g, 9.02 mmol, 40 mL) at 0 °C was added dropwise benzyl carbonochloridate (4.48 mL, 8.32 mmol). The reaction mixture was stirred at 0 °C for 12 hours, and after the passage of that time, the completed reaction was extracted with EtOAc (2 × 50 mL each). The organic layer was washed with aqueous sodium carbonate (20 mL), dried over potassium carbonate, filtered, and concentrated to dryness to give Compound 38 (2.0 g, 5.71 mmol, 82%). (MW Calc +H = 315.19; MW Obs = 351.05)

[0201] A slurry / solution of tert-butyl (S)-3-(((benzyloxy)carbonyl)amino)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (38, 0.50 g, 1.427 mmol) in DCM (15 mL) at 5 °C was stirred, and methyl iodide (0.184 mL, 0.686 mmol), tetrabutylammonium hydrogen sulfate (73 mg, 0.214 mmol), and 50% aqueous NaOH solution (0.90 mL) were added. The reaction mixture was stirred vigorously for 4 h while maintaining the temperature at 5 - 15 °C, and after that time the completed reaction was diluted with DCM (15 mL) and stirred at room temperature for 4 h. The resulting mixture was acidified to pH 6 by adding 1N HCl, the layers were separated, and the aqueous layer was extracted with DCM (2 × 10 mL each). The combined organic layers were dried over MgSO4, filtered, concentrated, and the crude residue was sent onto a Biotage SNAP column (25 g) and eluted with 10 - 100% ethyl acetate in heptane (10 CV) for purification. After recovery, concentration, and vacuum drying of the desired fractions, compound 39 (0.25 g, 0.686 mmol, 48%) was obtained. (MW Calc +H = 365.20; MW Obs = 365.14)

[0202] To a stirred solution of tert-butyl (S)-3-(((benzyloxy)carbonyl)amino)-3-(methoxymethyl)pyrrolidine-1-carboxylate (39, 100 mg, 0.274 mmol) in THF (2 mL) was added sodium hydride 60% (16.5 mg, 0.412 mmol) at room temperature and the mixture was stirred for 30 minutes. After addition of imidazole (0.2 mg, 0.003 mmol), stirring was continued for 20 minutes and after this time iodomethane (22 uL, 0.357 mmol) was added and the reaction mixture was warmed to 45 °C. The final mixture was stirred at 45 °C for 3 hours and after this time it was cooled to room temperature and quenched with saturated aqueous ammonium chloride. The resulting mixture was extracted with ethyl acetate (3 x 2 mL each), the combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was filtered through a silica gel pad (5 g) eluting with ethyl acetate (20 mL) and the filtrate was concentrated to give a mixture of compounds 39 and 40 in a 2 to 7 ratio by HPLC (90 mg, ~0.24 mmol, ~87%) which was used as a mixture in the next step.

[0203] To a degassed stirred solution of tert-butyl (S)-3-(((benzyloxy)carbonyl)amino)-3-(methoxymethyl)pyrrolidine-1-carboxylate and tert-butyl (S)-3-(((benzyloxy)carbonyl)-(methyl)amino)-3-(methoxymethyl)pyrrolidine-1-carboxylate (39 and 40, 90 mg, ~0.24 mmol) in MeOH (5 mL) was added 10% Pd / C (10 mg), the mixture was placed under a hydrogen atmosphere and stirred at room temperature for 14 hours. The completed reaction was filtered through celite (5 g) eluting with methanol (10 mL) and concentrated. The crude product was passed through a silica gel pad (5 g) eluting with ethyl acetate (20 mL) and after drying by concentration a mixture of compounds 41 and 42 was obtained. This mixture was used in the next reaction without further purification.

[0204] A-030 and A-031 were prepared in the same manner as A-001, starting from compound 18 (30 mg, 0.045 mmol) and a mixture of compounds 41 and 42 (11 mg, 0.045 mmol). After purification, two analogs A-030 (2.0 mg, 0.02 mmol, 7%) (MW Calc +H = 697.36; MW Obs = 697.19) and A-031 (5.1 mg, 0.007 mmol, 16%) (MW Calc +H = 711.38; MW Obs = 711.20) were obtained and separated.

[0205] A-032 was prepared in the same manner as A-001, starting from compound 18 (30 mg, 0.045 mmol) and commercially available (S)-3-allyl-3-aminopyrrolidine-1-carboxylic acid tert-butyl (16.3 mg, 0.072 mmol). After purification, A-032 (14.3 mg, 0.021 mmol, 46%) was obtained (MW Calc +H = 693.37; MW Obs = 693.36).

[0206] A-033 was prepared in the same manner as A-001, starting from compound 18 (30 mg, 0.045 mmol) and commercially available (R)-3-allyl-3-aminopyrrolidine-1-carboxylic acid tert-butyl (16.3 mg, 0.072 mmol). After purification, A-033 (4.7 mg, 0.07 mmol, 15%) was obtained (MW Calc +H = 693.37; MW Obs = 693.14).

[0207]

Chemical formula

[0208] To a stirred solution of N-allyl-N-(tert-butoxycarbonyl) glycinate methyl ester (43, 86 g, 375.1 mmol) in DCM (1280 mL) at -78 °C was added 1.0 M DIBAL-H in DCM (506 ml, 506.mmol) portionwise while maintaining the temperature below -70 °C. Subsequently, the mixture was stirred at -73 °C for an additional 1.5 hours. The completed reaction was slowly quenched by dropwise addition of methanol (10.32 mL, 255.1 mmol) while maintaining the temperature below -70 °C, and then stirred for an additional 10 minutes. The completed reaction was warmed to 0 °C and 2 M sodium hydroxide (1440 mL, 2880.0 mmol) was slowly added after some time, and then stirred for an additional 1 hour after some time. The layers were separated and the aqueous layer was extracted with DCM (1 L). The combined organic layers were washed with water (2 × 1500 mL each), washed with 1:1 water:brine (800 mL), dried over Na2SO4, filtered, and dried by concentration to give compound 44 (83.9 g, crude), which was used in the next step without purification.

[0209] To a stirred solution of tert-butyl allyl(2-oxoethyl)carbamate (44, 74.7 g, 374.9 mmol) in DCM (562 mL) and methanol (282 mL) at room temperature was added hydroxylamine hydrochloride (74.0 g, 1064.7 mmol) and sodium acetate (87 g, 1064.7 mmol), followed by stirring for 24 h. Water (1600 mL) was added to the completed reaction mixture, the layers were separated, and the aqueous layer was extracted with DCM (800 mL). The combined organic layers were washed with 1:1 water:brine (400 mL), dried over Na2SO4, concentrated, and dried under vacuum to afford compound 45 (80.39 g, 375 mmol, 100%) which was used without further purification.

[0210] A solution of tert-butyl allyl(2-hydroxyimino)ethylcarbamate (45, 80 g, 373.4 mmol) in DCM (776 mL) was added dropwise to a stirred solution of 0.81 M sodium hypochlorite (880 ml, 712.6 mmol) while maintaining the temperature below 25 °C. The mixture was stirred for 1 h, after which time water (960 mL) and DCM (320 mL) were added. The layers were separated and the aqueous layer was extracted with DCM (640 mL). The combined organic layers were washed with 1:1 water:brine (500 mL), dried over Na2SO4, filtered, and dried by concentration. The residue was azeotroped with acetonitrile (2 × 300 mL), then n-heptane (2 × 300 mL), and as time passed, a solid formed. This solid was suspended in a mixture of EtOAc (15 mL) in n-heptane (300 mL), heated to 90 °C, stirred at 90 °C for 15 min after the solid had dissolved in the solution. The solution was slowly cooled to 0 °C and allowed to stand for 1 h. The resulting solid was filtered, washed with n-heptane (300 mL), and dried under vacuum to afford 50 g of the crude product. This solid was recrystallized using the same method as described above to afford compound 46 (47.5 g, 224.0 mmol, 60%).

[0211] A stirred solution of tert-butyl 3a,4-dihydro-3H-pyrrolo[3,4-c]isoxazole-5(6H)-carboxylate (46, 15 g, 70.67 mmol) in THF (102 mL) and toluene (102 mL) under a nitrogen atmosphere at -78 °C was treated with boron trifluoride etherate (10.23 mL, 80.71 mmol) while maintaining the temperature below -70 °C, followed by addition of 3 M methylmagnesium bromide in Et2O (28.3 mL, 84.81 mmol). After stirring at -78 °C for 1 h, additional boron trifluoride etherate (8.96 mL, 70.67 mmol) and 3 M methylmagnesium bromide (23.56 mL, 70.67 mmol) were added sequentially, followed by stirring at -78 °C for 16 h. The completed reaction was warmed to 0 °C and quenched slowly with saturated NaHCO3 (700 mL) in EtOAc (400 mL). The resulting layers were separated and the aqueous layer was extracted with EtOAc (300 mL). The combined organic layers were washed with 1:1 water:brine (300 mL), dried over Na2SO4, filtered, and concentrated to give crude product 47 (18.2 g), which was used in the next reaction without further purification. (MW Calc +Na=241.15;MW Obs =241.36).

[0212] To a stirred solution of crude 47 (18.2 g, ~70.67 mmol) in THF (273 mL) under a N2 atmosphere was added acetic acid (34 mL, 593.9 mmol), followed by cooling to ~8 °C in an ice bath. Zinc powder (17.05 g, 260.7 mmol) was added in two portions, and the reaction was then warmed to room temperature and stirred for 16 h. The completed reaction was filtered through a Celite pad (30 g) and eluted with EtOAc (500 mL). The filtrate was diluted with water (150 mL), followed by addition of sodium bicarbonate (59.4 g, 706.7 mmol) with stirring. The mixture was stirred for 1 h and the layers were separated. The aqueous layer was extracted with EtOAc (200 mL), and the combined organic layers were washed with 1:1 water:brine (200 mL), dried over Na2SO4, filtered, and concentrated to give compound 48 (10.45 g, 45.4 mmol, 64%) as a racemic mixture without further purification. (MW Calc+Na = 253.16; MW Obs = 253.06)

[0213] To a stirred solution of (3S,4S)-3-amino-4-(hydroxymethyl)-3-methylpyrrolidine-1-carboxylic acid tert-butyl and its enantiomer (48, 1.6 g, 6.95 mmol) in DCM (22 mL) at 0 °C was added pyridine (1.686 ml, 20.84 mmol), followed by dropwise addition of trifluoroacetic anhydride (1.08 ml, 7.64 mmol) over 5 minutes. The reaction mixture was warmed to room temperature and stirred for 18 hours. The completed reaction was quenched with saturated NaHCO3 (30 mL) and stirred for 3 hours. The resulting solution was extracted with MTBE (3 × 20 mL each), the combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. This crude oil was sent onto a Biotage SNAP column (25 g) and eluted with 0→100% EtOAc in heptane (10 CV) for purification. After recovery of the desired fraction, concentration, and drying under vacuum, compound 49 (1.48 g, 4.54 mmol, 65%) was obtained as an oil.

[0214] To a stirred solution of (3S,4S)-4-(hydroxymethyl)-3-methyl-3-(2,2,2-trifluoroacetamido)-pyrrolidine-1-carboxylic acid tert-butyl (49, 2.0 g, 6.13 mmol) in DCM (30 mL) at 0 °C was added Dess-Martin periodinane (4.55 g, 10.73 mmol), and then the mixture was warmed to room temperature. The reaction was stirred for 3 hours, and after that time, a solution of sodium thiosulfate 2 - 3 g in aqueous NaHCO3 (30 mL) was added with stirring over 30 minutes. The mixture was diluted with EtOAc (50 mL), the layers were separated, and the organic layer was washed with saturated NaHCO3 (10 mL), water (10 mL), and brine (10 mL). The organic layer was filtered through a silica gel plug (20 g silica) eluting with EtOAc (20 mL), the filtrate was concentrated, and then co-evaporated to dryness with THF (2 × 20 mL each). This crude aldehyde 50 was used in the next step.

[0215] A stirred solution of methyltriphenylphosphonium bromide (4.93 g, 13.79 mmol) in THF (24 mL) was cooled to -8 °C under an N2 atmosphere, and n-BuLi (6.74 mL, 13.48 mmol) was added dropwise over 5 minutes. The mixture was then stirred for an additional 10 minutes. The resulting ylide was cooled to -78 °C, and then (3S,4S)- and (3R,4R)-tert-butyl 4-formyl-3-methyl-3-(2,2,2-trifluoroacetamido)pyrrolidine-1-carboxylate (50, ca. 1.99 g, 6.13 mmol) in THF (12 mL) was added dropwise over 5 minutes. The reaction mixture was stirred at -78 °C for an additional 5 minutes and then slowly warmed to room temperature and stirred for 3 hours. The completed reaction was diluted with MTBE (10 mL), and silica gel (5 g) was added. The suspension was filtered through a silica gel pad (5 g) and eluted with MTBE (20 mL). The filtrate was first passed through a Biotage SNAP column (25 g) and eluted with 0 - 100% EtOAc in n-heptane (10 CV) for purification. After recovery, concentration, and drying under vacuum of the desired fractions, a mixture of compounds 51 and 52 (880 mg) was obtained. The two enantiomers were separated by elution at 35 °C with 40% methylene chloride in n-heptane at a flow rate of 3 mL / min using a 10 × 250 mm ChiralPak IC column. This separation was carried out by loading the crude mixture onto the column in multiple portions of approximately 50 mg each and pooling the separated desired fractions. After concentration and drying under vacuum, compound 51 (260 mg, 0.812 mmol, 13%) (MW Calc +H = 323.15; MW Obs = 323.15) was obtained as fraction 1, and compound 52 (260 mg, 0.812 mmol, 13%) (MW Calc +H = 323.15; MW Obs = 323.18) was obtained as fraction 2.

[0216] To a stirred solution of tert-butyl (3R,4R)-3-methyl-3-(2,2,2-trifluoroacetamido)-4-vinylpyrrolidine-1-carboxylate (51, 235 mg, 0.729 mmol) in methanol (3 mL) was added 1 M sodium hydroxide (3.0 mL, 3.00 mmol), and the mixture was then placed in a sealed vial and heated at 45 °C for 24 h. The reaction was cooled to room temperature, concentrated, and extracted with DCM (3 × 2 mL each). The combined organic layers were washed with brine (2 mL), concentrated, and dried by azeotroping with toluene (2 × 2 mL) to give compound 53 (ca. 165 mg, 0.729 mmol, 100%) (MW Calc +Na = 249.17; MW Obs = 249.34).

[0217] Compound 54 (ca. 165 mg, 0.729 mmol, 100%) was obtained in a similar manner starting from 52 (235 mg, 0.729 mmol).

[0218] A-034 was prepared in a similar manner to A-001, starting from compound 18 (13 mg, 0.020 mmol) and tert-butyl (3R,4R)-3-amino-3-methyl-4-vinylpyrrolidine-1-carboxylate (53, 7.1 mg, 0.031 mmol). After purification, A-034 (8.32 mg, 0.015 mmol, 53%) was obtained (MW Calc +H = 693.37; MW Obs = 693.34).

[0219] A-035 was prepared in a similar manner to A-001, starting from compound 18 (13 mg, 0.020 mmol) and tert-butyl (3R,4R)-3-amino-3-methyl-4-vinylpyrrolidine-1-carboxylate (54, 7.1 mg, 0.031 mmol). After purification, A-035 (13.61 mg, 0.019 mmol, 86%) was obtained (MW Calc +H = 693.37; MW Obs = 693.35).

[0220] Preparation of A-036

Chem.

[0221] To a stirred solution of (S)-9-oxa-2,6-diazaspiro[4.5]decane (55, 83 mg,.584 mmol) in THF (1.0 mL) was added triethylamine (0.814 μL, 5.837 mmol) and 4-bromo-2-fluoropyridine (308 mg, 1.751 mmol) followed by heating at 120 °C for 8 hours in a microwave. After cooling, the completed reaction was purified directly by HPLC (ammonium hydroxide conditions) and after concentration of the desired fractions and drying under vacuum, compound 56 (111 mg, 0.372 mmol, 64%) was obtained (MW Calc +H = 300.55; MW Obs = 300.10).

[0222] (S)-2-(4-Bromopyridin-2-yl)-9-oxa-2,6-diazaspiro[4.5]decane (56,111 mg, 0.372 mmol) was added to a stirred suspension of cyclopropylboronic acid (48.0 mg, 0.558 mmol) and potassium carbonate (185 mg, 1.34 mmol) in 1,4-dioxane (4.8 mL) and water (0.96 mL), and the mixture was degassed for 30 minutes. After that time, Pd(PPh3)4 (43.0 mg, 0.037 mmol) was added. The mixture was degassed at room temperature for an additional 20 minutes and then stirred at 80 °C for 2 hours and at 100 °C for 16 hours in a sealed flask. After cooling the reaction to room temperature, additional Pd(PPh3)4 (43.0 mg, 0.037 mmol) was added to the reaction, degassed for 20 minutes, and heated at 100 °C for 8 hours in a sealed flask. The completed reaction was cooled to room temperature, filtered, and purified directly on an HPLC column. After concentration of the desired fractions and drying under vacuum, compound 57 (47.5 mg, 0.183 mmol, 49%) was obtained.

[0223] Acetic acid (18.5 μL, 0.323 mmol) and then (S)-2-(4-cyclopropylpyridin-2-yl)-9-oxa-2,6-diazaspiro[4.5]decane (57, 16.7 mg, 0.065 mmol) were added to a stirred solution of (1R,2R)-1-((2R,3R,4S,6S)-3-acetamido-4-acetoxy-6-(methoxycarbonyl)-6-(2-oxoethyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (18, 28.6 mg, 0.043 mmol) in DCE (0.34 mL). The reaction was stirred at room temperature for 1 hour, and after that time, dried 4 Å MS (100 mg) was added and stirring was continued for an additional 2 hours. Next, sodium triacetoxyborohydride (18.2 mg, 0.086 mmol) was added and the reaction was stirred at room temperature for 16 hours. The completed reaction was quenched with aqueous NaHCO3 (5 mL) and extracted with EtOAc (3 × 20 mL each). The combined organic layers were washed with brine and dried by concentration to give the crude compound 58, which was used directly in the next reaction. (MW Calc +H = 908.42; MW Obs=908.45)

[0224] To a stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-(2-((S)-2-(4-cyclopropylpyridin-2-yl)-9-oxa-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (58, about 39 mg, 0.043 mmol) in methanol (2.6 mL) at 0 °C was added 1 N sodium hydroxide (0.73 mL, 0.731 mmol), followed by stirring at room temperature for 16 h. The reaction mixture was purified directly on an HPLC column and after concentration of the desired fractions and drying under vacuum, A-036 (4.0 mg, 0.06 mmol, 13%) was obtained (MW Calc +H = 726.37; MW Obs = 726.36).

[0225] Preparation of A-037 to A-041 A-037 was prepared in a similar manner to A-036, starting from compound 55 (24 mg, 0.169 mmol) and commercially available 2-fluoropyridine (49.2 mg, 0.506 mmol), and after purification, A-037 (31.2 mg, 0.035 mmol, 40%) was obtained (MW Calc +H = 686.34; MW Obs = 6896.33).

[0226] A-038 was prepared in a similar manner to A-036, starting from compound 55 (60 mg, 0.422 mmol) and commercially available 2-fluoro-4-methylpyridine (141 mg, 1.266 mmol), and after purification, A-038 (10.1 mg, 0.014 mmol, 3% overall) was obtained (MW Calc +H = 700.35; MW Obs = 700.35).

[0227] A-039 was prepared in a similar manner to A-036, starting from compound 55 (135 mg, 0.949 mmol) and commercially available 2-fluoro-4-(trifluoromethyl)pyridine (470 mg, 2.848 mmol), to give A-039 (12 mg, 0.016 mmol, 2% overall) after purification (MW Calc +H=754.32;MW Obs =754.32).

[0228] A-040 was prepared in a similar manner to A-036, starting from compound 55 (24 mg, 0.169 mmol) and commercially available 2-chloropyrazine (58 mg, 0.506 mmol), to give A-040 (24.88 mg, 0.036 mmol, 39%) after purification (MW Calc +H=687.33;MW Obs =687.33).

[0229] A-041 was prepared in a similar manner to A-036, starting from compound 55 (135 mg, 0.949 mmol) and commercially available 2-fluoro-N,N-dimethylpyridin-4-amine (58 mg, 0.506 mmol), to give A-041 (18.4 mg, 0.025 mmol, 46% overall) after purification (MW Calc +H=729.38;MW Obs =729.37).

[0230] Preparation of A-042 [ka] A stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-(2-((S)-2-(tert-butoxycarbonyl)-9-oxa-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (20,862 mg, 0.967 mmol) in DCM (3735 mL) at 0 °C was treated with TFA (3.73 mL, 48.374 mmol), and then stirred for 40 minutes while maintaining the temperature at 0 °C. The completed reaction was concentrated, dried by azeotroping with acetonitrile (2 × 20 mL each), and dried under vacuum to give the crude compound 59 (approx. 765 mg, 0.967 mmol, 100%) (MW Calc +H = 790.36; MW Obs = 792.78) as an oil. This crude product was used in the next reaction without further purification.

[0231] A stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-6-(2-((S)-9-oxa-2,6-diazaspiro[4.5]dec-6-yl)ethyl)-3-acetamido-4-acetoxy-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate TFA salt (59, 20 mg, 0.025 mmol) in acetonitrile (1.0 mL) at room temperature was treated with triethylamine (0.025 mL, 0.177 mmol), followed by 2-isocyanato-2-methylpropane (5.0 mg, 0.051 mmol). The reaction was stirred for 1 h and after that time it was quenched with saturated sodium bicarbonate (3 mL). The mixture was extracted with EtOAc (2 × 5 mL each), the combined organic layers were concentrated and then dried by azeotroping with methanol (2 × 5 mL each). The residue from the above reaction was subjected to a mixture of methanol (0.6 mL) and 1 N aqueous NaOH (0.4 mL) and stirred at room temperature for 24 h. The completed reaction was directly injected onto a reverse phase HPLC column and eluted with water / acetonitrile to afford A-042 (11.3 mg, 0.016 mmol, 63%) after collection of the desired fraction and concentration to dryness under vacuum (MW Calc +H = 708.38; MW Obs = 708.37).

[0232] Preparation of A-043 to A-108 Via Isocyanates or Isothiocyanates: A-043 was prepared in a similar manner to A-042, starting from compound 59 (150 mg, 0.190 mmol) and commercially available (S)-(1-isocyanatoethyl)benzene (36.3 mg, 0.07 mmol) to afford A-043 (120 mg, 0.159 mmol, 84%) after purification (MW Calc +H = 756.38; MW Obs = 756.52).

[0233] A-044 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.190 mmol) and commercially available 1,1,1-trifluoro-2-isocyanatopropane (9.7 mg, 0.247 mmol). After purification, A-044 (8.2 mg, 0.011 mmol, 34%) was obtained (MW Calc +H = 748.33; MW Obs = 748.33).

[0234] A-045 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available isocyanatocyclohexane (5.0 mg, 0.04 mmol). After purification, A-045 (4.44 mg, 0.006 mmol, 27%) was obtained (MW Calc +H = 734.39; MW Obs = 734.39).

[0235] A-046 was prepared in the same manner as A-042, starting from compound 59 (27.5 mg, 0.035 mmol) and commercially available 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (9.1 mg, 0.045 mmol). After purification, A-046 (1.94 mg, 0.002 mmol, 6.8%) was obtained (MW Calc +H = 810.42; MW Obs = 810.42).

[0236] A-047 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available (S)-3-(1-isocyanatoethyl)benzene-1-ium (6.0 mg, 0.041 mmol). After purification, A-047 (12.9 mg, 0.017 mmol, 53%) was obtained (MW Calc +H = 756.38; MW Obs = 756.37).

[0237] A-048 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available 2-isocyanatopropane (3.0 mg, 0.035 mmol), and after purification, A-048 (12.25 mg, 0.018 mmol, 55%) was obtained (MW Calc +H = 694.36; MW Obs = 694.36).

[0238] A-049 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available (3S,5S,7S)-1-isocyanatoadamantane (7.0 mg, 0.039 mmol), and after purification, A-049 (12.14 mg, 0.015 mmol, 48%) was obtained (MW Calc +H = 786.42; MW Obs = 786.42).

[0239] A-050 was prepared in the same manner as A-042, starting from compound 59 (30 mg, 0.038 mmol) and commercially available 2-isocyanato-2,3-dimethylbutane (7.2 mg, 0.057 mmol), and after purification, A-050 (8.7 mg, 0.012 mmol, 31%) was obtained (MW Calc +H = 736.41; MW Obs = 736.41).

[0240] A-051 was prepared in the same manner as A-042, starting from compound 59 (30 mg, 0.038 mmol) and commercially available 1,1-difluoro-4-isocyanatocyclohexane (6.6 mg, 0.041 mmol), and after purification, A-051 (9 mg, 0.012 mmol, 56%) was obtained (MW Calc +H = 770.37; MW Obs = 770.37).

[0241] A-052 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available isothiocyanatocyclohexane (5.8 mg, 0.041 mmol), and after purification, A-052 (13 mg, 0.018 mmol, 83%) was obtained (MWCalc +H = 750.37; MW Obs = 750.37).

[0242] A-053 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available 1-isocyanato-4-methylbenzene (5.0 mg, 0.038 mmol), and after purification, A-053 (13 mg, 0.018 mmol, 83%) was obtained (MW Calc +H = 742.36; MW Obs = 742.6).

[0243] A-054 was prepared in the same manner as A-042, starting from compound 59 (27.5 mg, 0.035 mmol) and commercially available (1-isocyanatocyclopropyl)benzene (7.2 mg, 0.045 mmol), and after purification, A-054 (0.8 mg, 0.001 mmol, 3%) was obtained (MW Calc +H = 768.38; MW Obs = 768.37).

[0244] A-055 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available 1-fluoro-4-(1-isocyanatocyclopentyl)benzene (8.4 mg, 0.041 mmol), and after purification, A-055 (15.3 mg, 0.019 mmol, 75%) was obtained (MW Calc +H = 770.39; MW Obs = 770.5).

[0245] A-056 was prepared in the same manner as A-042, starting from compound 59 (89 mg, 0.113 mmol) and commercially available (S)-1-bromo-4-(1-isocyanatoethyl)benzene (33 mg, 0.146 mmol), and after purification, A-056 (48.2 mg, 0.058 mmol, 52%) was obtained (MW Calc +H = 836.29; MW Obs = 836.3).

[0246] A-057 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available 1-fluoro-4-(1-isocyanatocyclopentyl)benzene (8.4 mg, 0.041 mmol), and after purification, A-057 (15.3 mg, 0.019 mmol, 75%) was obtained (MW Calc +H = 814.40; MW Obs = 814.5).

[0247] A-058 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available isothiocyanatocyclopropane (4.1 mg, 0.041 mmol), and after purification, A-058 was obtained. (MW Calc +H = 708.32; MW Obs = 708.5)

[0248] Via carboxylate chloride: A-059 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available methyl(phenyl)carbamoyl chloride (7.0 mg, 0.041 mmol), and after purification, A-059 (11.6 mg, 0.016 mmol, 71%) was obtained (MW Calc +H = 742.36; MW Obs = 742.6).

[0249] A-060 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available cyclopentyl-1-carbonyl chloride (5.5 mg, 0.041 mmol), and after purification, A-060 (13 mg, 0.018 mmol, 82%) was obtained (MW Calc +H = 705.37; MW Obs = 705.6).

[0250] A-061 was prepared in the same manner as A-042, starting from compound 59 (20 mg, 0.025 mmol) and commercially available isopropyl(methyl)carbamoyl chloride (4.5 mg, 0.033 mmol), and after purification, A-061 (6.6 mg, 0.009 mmol, 33%) was obtained (MWCalc +H=708.38;MW Obs =708.6).

[0251] A-062 was prepared in a similar manner to A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available pyrrolidine-1-carbonyl chloride (5.5 mg, 0.041 mmol), to give A-062 (13.55 mg, 0.019 mmol, 83%) after purification (MW Calc +H=706.36;MW Obs =706.6).

[0252] A-063 was prepared in a similar manner to A-042, starting from compound 59 (20 mg, 0.025 mmol) and commercially available benzyl(methyl)carbamic acid chloride (6 mg, 0.033 mmol), to give A-063 (8.1 mg, 0.011 mmol, 44%) after purification (MW Calc +H=756.37;MW Obs =756.6).

[0253] A-064 was prepared in a similar manner to A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available dimethylcarbamic acid chloride (4.4 mg, 0.041 mmol), to give A-064 (9.3 mg, 0.014 mmol, 44%) after purification (MW Calc +H=680.35;MW Obs =680.6).

[0254] A-065 was prepared in a similar manner to A-042, starting from compound 59 (71 mg, 0.090 mmol) and commercially available 4,4-difluoropiperidine-1-carbonyl chloride (21.4 mg, 0.117 mmol), to give A-065 (32.1 mg, 0.042 mmol, 46%) after purification (MW Calc +H=756.38;MW Obs =756.6).

[0255] Via carboxylic acid: A-066 was prepared in the same manner as A-042, starting from compound 59 (25 mg, 0.032 mmol) and commercially available diethylcarbamyl chloride (5.6 mg, 0.041 mmol), and after purification, A-066 (5.8 mg, 0.008 mmol, 29%) was obtained (MW Calc +H = 708.38; MW Obs = 708.6).

[0256] A-067 was prepared in the same manner as A-042, starting from using compound 59 (25 mg, 0.032 mmol) and commercially available cyclohexanecarboxylic acid (5.5 mg, 0.039 mmol) together with HATU (24.0 mg, 0.063 mmol) and triethylamine (22 μL, 0.158 mmol) in DMF (0.4 mL) for the first step, and after hydrolysis and purification, A-067 (13 mg, 0.018 mmol, 83%) was obtained (MW Calc +H = 719.38; MW Obs = 719.6).

[0257] A-068 was prepared in the same manner as A-067, starting from using compound 59 (30 mg, 0.038 mmol) and commercially available 2-phenylpropanoic acid (7 mg, 0.047 mmol) together with HATU (29 mg, 0.076 mmol) and triethylamine (26 μL, 0.253 mmol) in DMF (1 mL) for the first step, and after hydrolysis and purification, A-068 (11.16 mg, 0.015 mmol, 45%) was obtained (MW Calc +H = 741.37; MW Obs = 741.7).

[0258] A-069 was prepared in the same manner as A-067. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 6,6-difluorospiro[3.3]heptane-2-carboxylic acid (7.2 mg, 0.041 mmol) together with HATU (24 mg, 0.041 mmol) and triethylamine (44 μL, 0.316 mmol) in DMF (0.49 mL) for the first step, after hydrolysis and purification, A-069 (9.9 mg, 0.013 mmol, 49%) was obtained (MW Calc +H = 767.36; MW Obs = 767.6).

[0259] A-070 was prepared in the same manner as A-067. Starting from using compound 59 (20 mg, 0.025 mmol), commercially available 2,2-difluorocyclohexane-1-carboxylic acid (5.4 mg, 0.033 mmol) together with HATU (19.2 mg, 0.051 mmol) and triethylamine (35 μL, 0.253 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-070 (5.81 mg, 0.0077 mmol, 28%) was obtained (MW Calc +H = 755.36; MW Obs = 755.6.

[0260] A-071 was prepared in the same manner as A-042. Starting from using compound 59 (20 mg, 0.025 mmol), commercially available 1-methylcyclohexane-1-carboxylic acid (4.7 mg, 0.033 mmol) together with HATU (19.2 mg, 0.051 mmol) and triethylamine (18 μL, 0.126 mmol) in DMF (0.4 mL) for the first step, after hydrolysis and purification, A-071 (7.5 mg, 0.010 mmol, 38%) was obtained (MW Calc +H = 733.40; MW Obs = 733.6).

[0261] A-072 was prepared in the same manner as A-042. Starting from using compound 59 (20 mg, 0.025 mmol), commercially available 3,3-dimethylbutanoic acid (5.9 mg, 0.051 mmol) together with HATU (19.2 mg, 0.051 mmol) and triethylamine (35 μL, 0.253 mmol) in acetonitrile (1.0 mL) for the first step, after hydrolysis and purification, A-072 (11 mg, 0.015 mmol, 61%) was obtained (MW Calc +H = 707.38; MW Obs = 707.52).

[0262] A-073 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 2-(tetrahydro-2H-pyran-4-yl)acetic acid (6.0 mg, 0.042 mmol) together with HATU (24 mg, 0.063 mmol) and triethylamine (22 μL, 0.158 mmol) in DMF (0.85 mL) for the first step, after hydrolysis and purification, A-073 (14.3 mg, 0.019 mmol, 89%) was obtained (MW Calc +H = 735.38; MW Obs = 735.6).

[0263] A-074 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 3,3-difluorocyclopentanecarboxylic acid (7.0 mg, 0.047 mmol) together with HATU (29 mg, 0.076 mmol) and triethylamine (26 μL, 0.190 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-074 (10 mg, 0.013 mmol, 42%) was obtained (MW Calc +H = 741.35; MW Obs = 741.6).

[0264] A-075 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 4,4-difluorocyclohexanecarboxylic acid (8.0 mg, 0.047 mmol) together with HATU (29 mg, 0.076 mmol) and triethylamine (26 μL, 0.190 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-075 (10 mg, 0.013 mmol, 41%) was obtained (MW Calc +H = 755.36; MW Obs = 755.6).

[0265] A-076 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-cyclohexylpropanoic acid (8.0 mg, 0.051 mmol) together with HATU (29 mg, 0.076 mmol) and triethylamine (26 μL, 0.190 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-076 (8.9 mg, 0.012 mmol, 37%) was obtained (MW Calc +H = 747.41; MW Obs = 747.7).

[0266] A-077 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-methyltetrahydrofuran-2-carboxylic acid (6.0 mg, 0.046 mmol) together with HATU (29 mg, 0.076 mmol) and triethylamine (26 μL, 0.190 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-077 (8.8 mg, 0.012 mmol, 37%) was obtained (MW Calc +H = 721.35; MW Obs = 721.6).

[0267] A-078 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 3-methylbut-2-enoic acid (4.0 mg, 0.040 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-078 (1.2 mg, 0.0016 mmol, 5%) was obtained (MW Calc +H = 691.35; MW Obs = 691.6).

[0268] A-079 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-phenylacetic acid (7.0 mg, 0.040 mmol) together with HATU (29 mg, 0.076 mmol), triethylamine (26 μL, 0.190 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-079 (10.5 mg, 0.014 mmol, 65%) was obtained (MW Calc +H = 727.35; MW Obs = 727.6).

[0269] A-080 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 3,3-dimethylcyclobutane-1-carboxylic acid (5.3 mg, 0.041 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (44 μL, 0.316 mmol) in DMF (0.49 mL) for the first step, after hydrolysis and purification, A-080 (8.0 mg, 0.011 mmol, 40%) was obtained (MW Calc +H = 719.38; MW Obs = 719.6).

[0270] A-081 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-methyl-2-phenoxypropanoic acid (9 mg, 0.050 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-081 (11.8 mg, 0.015 mmol, 49%) was obtained (MW Calc +H = 771.37; MW Obs = 771.7).

[0271] A-082 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-methoxypropanoic acid (5 mg, 0.048 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-082 (6.0 mg, 0.0085 mmol, 25%) was obtained (MW Calc +H = 695.34; MW Obs = 695.6).

[0272] A-083 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-isobutoxyacetic acid (6 mg, 0.045 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-083 (5.6 mg, 0.0078 mmol, 23%) was obtained (MW Calc +H = 723.37; MW Obs = 723.7).

[0273] A-084 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-isopropoxyacetic acid (6 mg, 0.051 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, A-084 (6.4 mg, 0.09 mmol, 27%) was obtained after hydrolysis and purification (MW Calc +H = 709.36; MW Obs = 709.7).

[0274] A-085 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2,2-dimethyl-2-methoxyacetic acid (6 mg, 0.051 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, A-085 (9.3 mg, 0.013 mmol, 39%) was obtained after hydrolysis and purification (MW Calc +H = 709.36; MW Obs = 709.6).

[0275] A-086 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2,6-dimethylbenzoic acid (7 mg, 0.047 mmol) together with HATU (28.8 mg, 0.076 mmol) and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, A-086 (8.1 mg, 0.011 mmol, 33%) was obtained after hydrolysis and purification (MW Calc +H = 741.36; MW Obs = 741.6).

[0276] A-087 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available picolinic acid (6 mg, 0.049 mmol) together with HATU (28.8 mg, 0.076 mmol), and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-087 (4.3 mg, 0.006 mmol, 18%) was obtained (MW Calc +H = 723.38; MW Obs = 723.7).

[0277] A-088 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-(2,2,2-trifluoroethoxy)acetic acid (8 mg, 0.051 mmol) together with HATU (28.8 mg, 0.076 mmol), and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-088 (1.2 mg, 0.0016 mmol, 5%) was obtained (MW Calc +H = 749.32; MW Obs = 749.6).

[0278] A-089 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 3-(carboxy(cyclohexyl)methyl)benzene-1-ium (11 mg, 0.051 mmol) together with HATU (28.8 mg, 0.076 mmol), and triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-089 (9.9 mg, 0.012 mmol, 40%) was obtained (MW Calc +H = 809.43; MW Obs = 809.7).

[0279] A-090 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-(tert-butoxy)acetic acid (6 mg, 0.045 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-090 (4.8 mg, 0.0066 mmol, 20%) was obtained (MW Calc +H = 723.38; MW Obs = 723.7).

[0280] A-091 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available tetrahydro-2H-pyran-4-carboxylic acid (6 mg, 0.046 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-091 (7.2 mg, 0.01 mmol, 30%) was obtained (MW Calc +H = 721.36; MW Obs = 721.6).

[0281] A-092 was prepared in the same manner as A-042. Starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-(cyclopentyloxy)acetic acid (7 mg, 0.049 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL) for the first step, after hydrolysis and purification, A-092 (4.3 mg, 0.0058 mmol, 18%) was obtained (MW Calc +H = 735.38; MW Obs = 735.6).

[0282] A-093 was prepared in the same manner as A-042, starting from using compound 59 (30 mg, 0.038 mmol), commercially available furan-2-carboxylic acid (5 mg, 0.045 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL). After hydrolysis and purification, A-093 (7.4 mg, 0.011 mmol, 32%) was obtained (MW Calc +H = 703.31; MW Obs = 703.6).

[0283] A-094 was prepared in the same manner as A-042, starting from using compound 59 (30 mg, 0.038 mmol), commercially available 1H-benzo[d]imidazole-5-carboxylic acid (8 mg, 0.049 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL). After hydrolysis and purification, A-094 (2.8 mg, 0.0037 mmol, 12%) was obtained (MW Calc +H = 753.34; MW Obs = 753.34).

[0284] A-095 was prepared in the same manner as A-042, starting from using compound 59 (30 mg, 0.038 mmol), commercially available 2-(1-hydroxyethyl)-1H-benzo[d]imidazole-5-carboxylic acid (f10 mg, 0.048 mmol) together with HATU (28.8 mg, 0.076 mmol), triethylamine (26 μL, 0.316 mmol) in DMF (1.03 mL). After hydrolysis and purification, A-095 (9.3 mg, 0.012 mmol, 38%) was obtained (MW Calc +H = 797.36; MW Obs = 797.6).

[0285] A-096 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available cyclopropanecarboxylic acid (4 mg, 0.046 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-096 (14.1 mg, 0.020 mmol, 90%) was obtained (MW Calc +H = 677.33; MW Obs = 677.6).

[0286] A-097 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available pivalic acid (4 mg, 0.039 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-097 (12 mg, 0.017 mmol, 75%) was obtained (MW Calc +H = 693.36; MW Obs = 693.6).

[0287] A-098 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 1-phenylcyclopropane-1-carboxylic acid (7 mg, 0.043 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-098 (14.9 mg, 0.0020 mmol, 94%) was obtained (MW Calc +H = 753.37; MW Obs = 753.6).

[0288] A-099 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 4-methylbenzoic acid (6 mg, 0.044 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-099 (14 mg, 0.019 mmol, 87%) was obtained (MW Calc +H = 727.35; MW Obs = 727.6).

[0289] A-100 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available 3-methyloxetane-3-carboxylic acid (4.8 mg, 0.041 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.86 mL) for the first step, after hydrolysis and purification, A-100 (13.5 mg, 0.019 mmol, 86%) was obtained (MW Calc +H = 707.34; MW Obs = 707.6).

[0290] A-101 was prepared in the same manner as A-042. Starting from using compound 59 (25 mg, 0.032 mmol), commercially available benzoic acid (5 mg, 0.041 mmol) together with HATU (19.2 mg, 0.051 mmol), triethylamine (22 μL, 0.158 mmol) in DMF (0.73 mL) for the first step, after hydrolysis and purification, A-101 (10.3 mg, 0.014 mmol, 66%) was obtained (MW Calc +H = 713.33; MW Obs = 713.6).

[0291] A-102 was prepared in the same manner as A-042, starting with the use of compound 59 (25 mg, 0.032 mmol), commercially available 1-(trifluoromethyl)cyclohexane-1-carboxylic acid (8.1 mg, 0.041 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (88 μL, 0.632 mmol) in DMF (0.49 mL) for the first step. After hydrolysis and purification, A-102 (7.8 mg, 0.010 mmol, 31%) was obtained (MW Calc +H = 787.37; MW Obs = 787.5).

[0292] A-103 was prepared in the same manner as A-042, starting with the use of compound 59 (25 mg, 0.032 mmol), commercially available 1-methylcyclobutane-1-carboxylic acid (4.7 mg, 0.041 mmol) together with HATU (24 mg, 0.063 mmol), triethylamine (88 μL, 0.632 mmol) in DMF (0.49 mL) for the first step. After hydrolysis and purification, A-103 (7.6 mg, 0.011 mmol, 34%) was obtained (MW Calc +H = 705.37; MW Obs = 705.5).

[0293] Via reductive amination: A-104 was prepared by a method different from that of A-042, starting with the use of compound 59 (20 mg, 0.025 mmol), commercially available 3-methylbenzaldehyde (6.1 mg, 0.051 mmol) together with sodium triacetoxyborohydride (10.7 mg, 0.051 mmol) and acetic acid (12.2 μL, 0.202 mmol) in DCM (1 mL) for 1 hour for the first step. For the first step, it was quenched with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and after hydrolysis with 1N aqueous sodium hydroxide solution and purification, A-104 (8.1 mg, 0.011 mmol, 45%) was obtained (MW Calc +H = 713.37; MW Obs = 713.6).

[0294] Other analogs: A-105 and A-106 were prepared in the same manner as A-042, starting from the fully protected intermediate (54.0 mg, 0.067 mmol) used for obtaining A010. Subsequently, after separation of the diastereomers using a chiral reverse-phase HPLC column, concentration of the desired fraction, and drying under vacuum, A-105 (16.6 mg, 0.023 mmol, 34% total yield) (MW Calc +H = 721.41; MW Obs = 721.5) and A-106 (15.7 mg, 0.022 mmol, 33% total yield) (MW Calc +H = 721.41; MW Obs = 721.5) were obtained.

[0295] A-107 and A-108 were prepared in the same manner as A-042, starting from the fully protected intermediate (54.0 mg, 0.067 mmol) used for obtaining A-012. Subsequently, after separation of the diastereomers using a chiral reverse-phase HPLC column, concentration of the desired fraction, and drying under vacuum, A-107 (6.1 mg, 0.009 mmol, 64% total yield) (MW Calc +H = 707.39; MW Obs = 707.5) and A-108 (5.7 mg, 0.0081 mmol, 62% total yield) (MW Calc +H = 707.39; MW Obs = 707.5) were obtained.

[0296] Preparation of A-109

Chemical formula

[0297] To a stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-allyl-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-azidopropane-1,2-diyl diacetate (60, 3.90 g, 7.824 mmol) in 1,4-dioxane (70.2 mL) and water (23.4 mL) was added 2,6-lutidine (1.822 ml, 15.647 mmol), osmium tetroxide (0.994 mL,.156 mmol), and sodium periodate (6.69 g, 31.295 mmol) at room temperature. The reaction mixture was stirred for 3 h and after that time it was partitioned between EtOAc (80 mL) and water (40 mL). The aqueous layer was extracted with EtOAc (3 × 60 mL each), the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was sent onto a Biotage Ultra SNAP column (50 g) and eluted with a gradient of 50% → 100% EtOAc in heptane (5 CV), then 0 → 20% MeOH in EtOAc (5 CV) to purify. After recovery of the desired fractions, concentration, and drying under vacuum, compound 61 (3.2 g, 6.39 mmol, 82% yield) was obtained (MW Calc +Na = 523.18; MW Obs = 523.32).

[0298] To a stirred solution of (1R,2R)-1-((2R,3R,4S,6S)-3-acetamido-4-acetoxy-6-(methoxycarbonyl)-6-(2-oxoethyl)tetrahydro-2H-pyran-2-yl)-3-azidopropane-1,2-diyl diacetate (61, 3.2 g, 6.394 mmol) in DCE (76 mL) was added acetic acid (2.56 mL, 44.759 mmol)) and (S)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl (19, 1.549 g, 6.394 mmol) at room temperature, followed by dry 4A MS (14 g). The reaction mixture was stirred at room temperature for 2 h and after that time sodium triacetoxyborohydride (2.71 g, 12.788 mmol) was added. The final reaction mixture was stirred at room temperature for 45 min and after that time it was diluted with EtOAc (50 mL), filtered through a celite pad (50 g) and washed with EtOAc (3 x 20 mL). The filtrate was quenched with aqueous NaHCO3 (40 mL), the layers were separated and the resulting aqueous layer was extracted with EtOAc (3 x 60 mL each). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by sending it onto a Biotage Ultra SNAP column (50 g) and eluting with a gradient of 30%→100% EtOAc in heptane (5 CV), then 0→10% MeOH in EtOAc (5 CV) to give, after collection, concentration and drying under vacuum of the desired fractions, compound 62 (4.2 g, 5.78 mmol, 90% yield).

[0299] (1R,2R)-1-((2R,3R,4S,6R)-3-Acetamido-4-acetoxy-6-(2-((S)-2-(tert-Butoxycarbonyl)-9-oxa-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-azidopropane-1,2-diyl diacetate (62, 4.2 g, 5.78 mmol) in MeOH (38.8 mL) was stirred and K2CO3 (8.84 g, 63.941 mmol) was added at room temperature. The reaction mixture was stirred for 4 h, and after that time the mixture was quenched with AcOH (5.49 mL, 95.912 mmol) and stirred for an additional 15 min. The mixture was concentrated and filtered through a pad of celite (25 g) eluting with a 10:1 EtOAc / MeOH mixture (75 mL). The resulting filtrate was concentrated and sent onto a Biotage Ultra SNAP column (50 g) and purified by eluting with a gradient of 2→30% MeOH in DCM (10 CV), and after collection, concentration, and drying under vacuum of the desired fractions, compound 63 (3.5 g, 5.83 mmol, 91% yield) was obtained (MW Calc +H = 601.31; MW Obs = 601.46).

[0300] (S)-6-(2-((2R,4S,5R,6R)-5-Acetamido-6-((1R,2R)-3-azido-1,2-dihydroxypropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl (63, 320 mg, 0.533 mmol) in degassed and N2-flushed aqueous THF (3 mL containing 45 uL H2O) was stirred at room temperature and 1 M trimethylphosphine in THF solution (0.666 mL, 0.666 mmol) was added. The reaction was stirred for 16 h and after that time it was concentrated while maintaining the temperature below 35 °C and azeotroped with acetonitrile (3 × 10 mL each) and dried under vacuum to afford the desired crude compound 64 (300 mg, 0.522 mmol, 98%) which was used in the next step without further purification.

[0301] At room temperature, to a stirred solution of (S)-6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1R,2R)-3-amino-1,2-dihydroxypropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl ((64), 19 mg, 0.033 mmol) in dimethylacetamide (1 mL), HOBT monohydrate (2.8 mg, 0.017 mmol), 7-methyl-1H-indole-5-carboxylic acid (8.7 mg, 0.05 mmol), EDC-HCl (10.5 mg, 0.055 mmol), and 1 M TEA (83 uL, 0.083 mmol in acetonitrile) were added sequentially. The reaction mixture was stirred for 15 h, and most of the fully protected desired intermediate was obtained by LCMS and treated directly with MeOH (0.3 mL) and 1 M aqueous NaOH (0.3 mL). The subsequent reaction was stirred at room temperature for a further 15 h, and after that time it was quenched with 2 M aqueous formic acid (150 uL) and stirred for 15 min. The resulting mixture was purified and eluted using a reverse phase C18 Xbridge HPLC column with a gradient containing 0.1% NH4OH in water / acetonitrile to give A-109 (6.1 mg, 0.013 mmol, 39%) after recovery, concentration, and drying under vacuum (MW Calc +H = 718.36; MW Obs = 718.5).

[0302] Preparation of A-110 to A-188 A-110 was prepared in a similar manner to A-109, starting with compound 64 (16 mg, 0.028 mmol) and commercially available benzothiazole-6-carboxylic acid (10 mg, 0.056 mmol) used in combination with HOBT (2.1 mg, 0.014 mmol), triethylamine (97 uL, 0.097 mmol), and EDC-HCl (11.7 mg, 0.061 mmol) in dimethylacetamide (2 mL). After hydrolysis and purification, A-110 (2.7 mg, 0.004 mmol, 13%) was obtained (MW Calc+H=722.30;MW Obs =722.5).

[0303] A-111 was prepared in a similar manner to A-109, starting with the use of compound 64 (16 mg, 0.028 mmol), commercially available 1H-indazole-5-carboxylic acid (6.8 mg, 0.028 mmol) together with HOBT (2.1 mg, 0.014 mmol) in dimethylacetamide (1 mL), 1 M triethylamine in THF (70 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) for the first step. After hydrolysis and purification, A-111 (4.6 mg, 0.007 mmol, 23%) was obtained (MW Calc +H=705.34;MW Obs =705.19).

[0304] A-112 was prepared in a similar manner to A-109, starting with the use of compound 64 (12 mg, 0.021 mmol), commercially available 3-methyl-1H-indole-5-carboxylic acid (7.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (1 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8.0 mg, 0.042 mmol) for the first step. After hydrolysis and purification, A-112 (4.5 mg, 0.0061 mmol, 29%) was obtained (MW Calc +H=718.36;MW Obs =718.41).

[0305] A-113 was prepared in a similar manner to A-109, starting with the use of compound 64 (12 mg, 0.021 mmol), commercially available 5-methyl-1H-pyrrole-3-carboxylic acid (2.6 mg, 0.021 mmol) together with HOBT (2.8 mg, 0.018 mmol) in dimethylacetamide (1 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8.0 mg, 0.Calc +H=668.35;MW Obs =668.36)

[0306] A-114 was prepared in the same manner as A-109, starting from using compound 64 (12 mg, 0.021 mmol), commercially available 1,5-naphthyridine-2-carboxylic acid (7.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.019 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8.0 mg, 0.042 mmol) in dimethylacetamide (0.8 mL). After hydrolysis and purification, A-114 (4.5 mg, 0.0063 mmol, 30%) was obtained (MW Calc +H=717.34;MW Obs =717.31)

[0307] A-115 was prepared in the same manner as A-109, starting from using compound 64 (12 mg, 0.021 mmol), commercially available 3,5-dibromo-4-hydroxybenzoic acid (12.4 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8.0 mg, 0.042 mmol) in dimethylacetamide (0.8 mL). After hydrolysis and purification, A-115 (3.1 mg, 0.0037 mmol, 18%) was obtained (MW Calc +H=839.15;MW Obs =839.25)

[0308] A-116 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3-bromobenzoic acid (8.4 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (0.26 mL). After hydrolysis and purification, A-116 (7.9 mg, 0.011 mmol, 40%) was obtained (MW Calc+H=745.24; MW Obs =745.3)

[0309] A-117 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-hydroxy-3-methylbenzoic acid (6.4 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (0.26 mL) for the first step, after hydrolysis and purification, A-117 (7.2 mg, 0.010 mmol, 37%) was obtained (MW Calc +H=695.35; MW Obs =695.4)

[0310] A-118 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-methoxy-3,5-dimethylbenzoic acid (7.5 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (0.26 mL) for the first step, after hydrolysis and purification, A-118 (7.5 mg, 0.010 mmol, 38%) was obtained (MW Calc +H=723.38; MW Obs =723.5)

[0311] A-119 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-amino-3,5-dimethylbenzoic acid (6.9 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (0.26 mL) for the first step, after hydrolysis and purification, A-119 (5.6 mg, 0.008 mmol, 29%) was obtained (MW Calc+H=708.38;MW Obs =708.5).

[0312] A-120 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3,4-dimethoxybenzoic acid (7.6 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (0.26 mL) for the first step, after hydrolysis and purification, A-120 (4.4 mg, 0.006 mmol, 22%) was obtained (MW Calc +H=725.35;MW Obs =725.5).

[0313] A-121 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available benzofuran-5-carboxylic acid (6.8 mg, 0.042 mmol) together with HOBT (1.9 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.0 mL) for the first step, after hydrolysis and purification, A-121 (4.4 mg, 0.006 mmol, 22%) was obtained (MW Calc +H=705.33;MW Obs =705.4).

[0314] A-122 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (6.8 mg, 0.042 mmol) together with HOBT (1.9 mg, 0.014 mmol), triethylamine (10 μL, 0.07 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.0 mL) for the first step, after hydrolysis and purification, A-122 (5.5 mg, 0.008 mmol, 28%) was obtained (MW Calc +H=706.34;MWObs = 706.4).

[0315] A-123 was prepared in the same manner as A-109, starting with the use of compound 64 (19 mg, 0.033 mmol), commercially available 4-hydroxy-3,5-dimethoxybenzoic acid (9.8 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine (83 μL, 0.083 mmol) in THF, and EDC-HCl (10.5 mg, 0.055 mmol). After hydrolysis and purification, A-123 (9.3 mg, 0.013 mmol, 38%) was obtained (MW Calc +H = 741.35; MW Obs = 741.4).

[0316] A-124 was prepared in the same manner as A-109, starting with the use of compound 64 (19 mg, 0.033 mmol), commercially available 1-methyl-1H-indazole-5-carboxylic acid (8.7 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine (83 μL, 0.083 mmol) in THF, and EDC-HCl (10.5 mg, 0.055 mmol). After hydrolysis and purification, A-124 (6.8 mg, 0.009 mmol, 29%) was obtained (MW Calc +H = 719.36; MW Obs = 719.5).

[0317] A-125 was prepared in the same manner as A-109, starting with the use of compound 64 (19 mg, 0.033 mmol), commercially available 3-methyl-1H-indazole-5-carboxylic acid (8.7 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine (83 μL, 0.083 mmol) in THF, and EDC-HCl (10.5 mg, 0.055 mmol). After hydrolysis and purification, A-125 (6.4 mg, 0.009 mmol, 27%) was obtained (MWCalc +H=719.36;MW Obs =719.5)。

[0318] A-126 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (8.1 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step, after hydrolysis and purification, A-126 (2.3 mg, 0.003 mmol, 10%) was obtained (MW Calc +H=706.34;MW Obs =706.4)。

[0319] A-127 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (8.8 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step, after hydrolysis and purification, A-127 (9.8 mg, 0.014 mmol, 41%) was obtained (MW Calc +H=720.35;MW Obs =720.5)。

[0320] A-128 was prepared in the same manner as A-109, starting with the use of compound 64 (19 mg, 0.033 mmol), commercially available 3-fluoro-1H-indazole-5-carboxylic acid (8.9 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step. After hydrolysis and purification, A-128 (4.3 mg, 0.006 mmol, 18%) was obtained (MW Calc +H = 723.33; MW Obs = 723.5).

[0321] A-129 was prepared in the same manner as A-109, starting with the use of compound 64 (19 mg, 0.033 mmol), commercially available 1H-indole-5-carboxylic acid (8.0 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step. After hydrolysis and purification, A-129 (7.3 mg, 0.010 mmol, 31%) was obtained (MW Calc +H = 704.35; MW Obs = 704.5).

[0322] A-130 was prepared in the same manner as A-109, starting with the use of compound 64 (16.4 mg, 0.029 mmol), commercially available 7-methyl-1H-indazole-5-carboxylic acid (7.5 mg, 0.043 mmol) together with HOBT (2.4 mg, 0.014 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (71 μL, 0.071 mmol), and EDC-HCl (9.0 mg, 0.047 mmol) for the first step. After hydrolysis and purification, A-130 (2.0 mg, 0.003 mmol, 10%) was obtained (MW Calc +H = 719.36; MW Obs = 719.4).

[0323] A-131 was prepared in the same manner as A-109. Starting from using compound 64 (16.4 mg, 0.029 mmol), commercially available 2-methylbenzo[d]thiazole-5-carboxylic acid (8.3 mg, 0.043 mmol) together with HOBT (2.4 mg, 0.014 mmol) in dimethylacetamide (1.5 mL), 1M triethylamine in THF (71 μL, 0.071 mmol), and EDC-HCl (9.0 mg, 0.047 mmol) for the first step, after hydrolysis and purification, A-131 (4.9 mg, 0.007 mmol, 23%) was obtained (MW Calc +H = 736.32; MW Obs = 736.4).

[0324] A-132 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 3-bromo-4-fluorobenzoic acid (9.2 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (0.5 mL), triethylamine (15 μL, 0.105 mmol), and EDC-HCl (6.0 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-132 (7.3 mg, 0.010 mmol, 46%) was obtained (MW Calc +H = 762.23; MW Obs = 763.3;).

[0325] A-133 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 5-bromo-1H-pyrazole-3-carboxylic acid (8.0 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (0.5 mL), triethylamine (15 μL, 0.105 mmol), and EDC-HCl (6.0 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-133 (7.0 mg, 0.010 mmol, 46%) was obtained (MW Calc +H = 735.23; MW Obs = 735.3).

[0326] A-134 was prepared in the same manner as A-109. Starting from using compound 64 (25 mg, 0.044 mmol), commercially available 2-(hydroxymethyl)-7-methyl-1H-indole-5-carboxylic acid (13.4 mg, 0.065 mmol) together with HATU (33.1 mg, 0.087 mmol) and triethylamine (61 μL, 0.435 mmol) in DCM (0.56 mL) for the first step, after hydrolysis and purification, A-134 (3.7 mg, 0.005 mmol, 11%) was obtained (MW Calc +H = 748.38; MW Obs = 748.5).

[0327] A-135 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 1H-benzo[d]imidazole-5-carboxylic acid (6.8 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), 1 M triethylamine in THF (70 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.0 mL) for the first step, after hydrolysis and purification, A-135 (5.5 mg, 0.008 mmol, 28%) was obtained (MW Calc +H = 705.35; MW Obs = 705.5).

[0328] A-136 was prepared in the same manner as A-109. Starting from using compound 64 (14 mg, 0.024 mmol), commercially available 1,3-dimethyl-1H-pyrazole-4-carboxylic acid (6.8 mg, 0.049 mmol) together with HOBT (3.7 mg, 0.024 mmol), 10% triethylamine in THF (102 μL, 0.073 mmol), and EDC-HCl (9.3 mg, 0.049 mmol) in dimethylacetamide (0.5 mL) for the first step, after hydrolysis and purification, A-136 (2.7 mg, 0.0039 mmol, 16%) was obtained (MW Calc +H = 683.36; MW Obs=683.47).

[0329] A-137 was prepared in the same manner as A-109. Starting from using compound 64 (14 mg, 0.024 mmol), commercially available 2,3-dihydrobenzofuran-5-carboxylic acid (8 mg, 0.049 mmol) together with HOBT (3.7 mg, 0.024 mmol) in dimethylacetamide (0.5 mL), 10% triethylamine in THF (102 μL, 0.073 mmol), and EDC-HCl (9.3 mg, 0.049 mmol) for the first step, after hydrolysis and purification, A-137 (6.0 mg, 0.0085 mmol, 35%) was obtained (MW Calc +H = 705.33; MW Obs = 707.52).

[0330] A-138 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 3-methyl-4-oxo-3,4-dihydroquinazoline-7-carboxylic acid (2.6 mg, 0.021 mmol) together with HOBT (2.6 mg, 0.021 mmol) in dimethylacetamide (0.8 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-138 (3.3 mg, 0.0043 mmol, 20%) was obtained (MW Calc +H = 747.35; MW Obs = 747.38).

[0331] A-139 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 2-methyl-1H-imidazole-4-carboxylic acid (8.5 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (0.5 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-139 (5.1 mg, 0.0076 mmol, 36%) was obtained (MW Calc+H = 669.34; MW Obs = 669.65).

[0332] A-140 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 2,5-dimethyloxazole-4-carboxylic acid (3.0 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.5 mL) for the first step, after hydrolysis and purification, A-140 (4.9 mg, 0.0071 mmol, 34%) was obtained (MW Calc +H = 684.34; MW Obs = 684.64;).

[0333] A-141 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 4-carbamoyl-3,5-dimethylbenzoic acid (8 mg, 0.041 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, after hydrolysis and purification, A-141 (5.3 mg, 0.0072 mmol, 34%) was obtained (MW Calc +H = 736.37; MW Obs = 736.42;).

[0334] A-142 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 4-(1H-1,2,4-triazol-5-yl)benzoic acid (7.9 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, after hydrolysis and purification, A-142 (5.6 mg, 0.0076 mmol, 36%) was obtained (MWCalc +H=732.35;MW Obs =732.49)。

[0335] A-143 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 4-(4-methylpiperazin-1-yl)benzoic acid (9.2 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, A-143 (7.1 mg, 0.0093 mmol, 44%) was obtained after hydrolysis and purification (MW Calc +H=763.42;MW Obs =763.68)。

[0336] A-144 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3-methyl-4-(trifluoromethyl)benzoic acid (8.5 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL) for the first step, A-144 (6.3 mg, 0.008 mmol, 32%) was obtained after hydrolysis and purification (MW Calc +H=747.34;MW Obs =747.4)。

[0337] A-145 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-methyl-3-(trifluoromethyl)benzoic acid (8.5 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL) for the first step, A-145 (8.6 mg, 0.012 mmol, 44%) was obtained after hydrolysis and purification (MW Calc +H=747.34;MW Obs =747.4)。

[0338] A-146 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3-hydroxy-4-(trifluoromethyl)benzoic acid (8.6 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL). After hydrolysis and purification, A-146 (6.6 mg, 0.009 mmol, 34%) was obtained (MW Calc +H = 749.32; MW Obs = 749.4).

[0339] A-147 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3-hydroxy-4-(trifluoromethyl)benzoic acid (8.6 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL). After hydrolysis and purification, A-147 (7.1 mg, 0.009 mmol, 36%) was obtained (MW Calc +H = 749.32; MW Obs = 749.4).

[0340] A-148 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3,4,5-trimethoxybenzoic acid (8.9 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL). After hydrolysis and purification, A-148 (5.7 mg, 0.008 mmol, 29%) was obtained (MW Calc +H = 755.37; MW Obs = 755.5).

[0341] A-149 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-fluoro-3-methylbenzoic acid (6.4 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (0.5 mL) for the first step, A-149 (7.6 mg, 0.011 mmol, 39%) was obtained after hydrolysis and purification (MW Calc +H = 697.34; MW Obs = 697.4).

[0342] A-150 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (8.7 mg, 0.042 mmol) together with HOBT (3.7 mg, 0.028 mmol), triethylamine (10 μL, 0.070 mmol) in DMA (1.0 mL) for the first step, A-150 (7.6 mg, 0.011 mmol, 39%) was obtained after hydrolysis and purification (MW Calc +H = 750.35; MW Obs = 750.5).

[0343] A-151 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available 7-methyl-1H-indole-5-carboxylic acid (8.9 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) in dimethylacetamide (1.5 mL) for the first step, A-151 (7.0 mg, 0.010 mmol, 30%) was obtained after hydrolysis and purification (MW Calc +H = 705.34; MW Obs = 705.5).

[0344] A-152 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available benzoxazole-5-carboxylic acid (8.1 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step, after hydrolysis and purification, A-152 (8.3 mg, 0.011 mmol, 35%) was obtained (MW Calc +H = 724.34; MW Obs = 724.5).

[0345] A-153 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available benzo[c][1,2,5]thiadiazole-5-carboxylic acid (8.1 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step, after hydrolysis and purification, A-153 (4.9 mg, 0.007 mmol, 21%) was obtained (MW Calc +H = 723.30; MW Obs = 723.4).

[0346] A-154 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (5.9 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (0.8 mL), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-154 (7.6 mg, 0.011 mmol, 53%) was obtained (MW Calc +H = 683.36; MW Obs = 683.5).

[0347] A-155 was prepared in the same manner as A-109, starting with the use of compound 64 (12 mg, 0.021 mmol), commercially available 3-ethylbenzoic acid (6.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL). After hydrolysis and purification, A-155 (7.2 mg, 0.010 mmol, 49%) was obtained (MW Calc +H = 693.37; MW Obs = 693.5).

[0348] A-156 was prepared in the same manner as A-109, starting with the use of compound 64 (12 mg, 0.021 mmol), commercially available 5-methyl-1H-pyrazole-3-carboxylic acid (5.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL). After hydrolysis and purification, A-156 (6.2 mg, 0.009 mmol, 44%) was obtained (MW Calc +H = 669.34; MW Obs = 669.5).

[0349] A-157 was prepared in the same manner as A-109, starting with the use of compound 64 (12 mg, 0.021 mmol), commercially available 5-chloro-1H-pyrazole-3-carboxylic acid (6.1 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL). After hydrolysis and purification, A-157 (6.4 mg, 0.009 mmol, 45%) was obtained (MW Calc +H = 689.28; MW Obs = 689.3).

[0350] A-158 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 5-methylfuran-3-carboxylic acid (5.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, after hydrolysis and purification, A-158 (7.8 mg, 0.012 mmol, 56%) was obtained (MW Calc +H = 669.33; MW Obs = 669.4).

[0351] A-159 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 3,5-dichloro-4-fluorobenzoic acid (8.7 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.104 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, after hydrolysis and purification, A-159 (4.6 mg, 0.006 mmol, 29%) was obtained (MW Calc +H = 751.24; MW Obs = 751.3).

[0352] A-160 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 5-methyl-2-(trifluoromethyl)furan-3-carboxylic acid (11.9 mg, 0.061 mmol) together with HOBT (2.1 mg, 0.014 mmol), 1 M triethylamine in THF (97 μL, 0.097 mmol), and EDC-HCl (11.7 mg, 0.055 mmol) in acetonitrile (2 mL) for the first step, after hydrolysis and purification, A-160 (4.9 mg, 0.007 mmol, 24%) was obtained (MW Calc +H = 737.32; MW Obs = 737.5).

[0353] A-161 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.028 mmol), commercially available 1H-pyrazole-4-carboxylic acid (5.6 mg, 0.061 mmol) together with HOBT (2.8 mg, 0.014 mmol) in DMA (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.4 mg, 0.055 mmol) for the first step, after hydrolysis and purification, A-161 (10.2 mg, 0.016 mmol, 56%) was obtained (MW Calc +H = 655.33; MW Obs = 655.5).

[0354] A-162 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available (E)-3-methylhex-2-enoic acid (5.4 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (1.9 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-162 (3.1 mg, 0.004 mmol, 20%) was obtained (MW Calc +H = 671.38; MW Obs = 671.48).

[0355] A-163 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available (2E,4E)-hex-2,4-dienoic acid (4.7 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol) in dimethylacetamide (1.9 mL), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-163 (3.7 mg, 0.0055 mmol, 26%) was obtained (MW Calc +H = 655.35; MW Obs = 655.39).

[0356] A-164 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 3,5-dimethyl-4-(methylcarbamoyl)benzoic acid (9.0 mg, 0.043 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, after hydrolysis and purification, A-164 (3.2 mg, 0.0042 mmol, 20%) was obtained (MW Calc +H = 750.39; MW Obs = 750.53).

[0357] A-165 was prepared in the same manner as A-109. Starting from using compound 64 (14 mg, 0.024 mmol), commercially available 4-cyano-3-fluorobenzoic acid (8.1 mg, 0.049 mmol) together with HOBT (3.7 mg, 0.024 mmol), 10% triethylamine in THF (102 μL, 0.073 mmol), and EDC-HCl (9.3 mg, 0.049 mmol) in dimethylacetamide (0.5 mL) for the first step, after hydrolysis and purification, A-165 (4.4 mg, 0.0061 mmol, 25%) was obtained (MW Calc +H = 720.34; MW Obs = 720.54).

[0358] A-166 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3,5-difluoro-4-(trifluoromethyl)benzoic acid (9.4 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL) for the first step, after hydrolysis and purification, A-166 (4.6 mg, 0.006 mmol, 23%) was obtained (MW Calc +H = 769.30; MW Obs = 769.4).

[0359] A-167 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3,4-bis(trifluoromethyl)benzoic acid (10.8 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL) for the first step, after hydrolysis and purification, A-167 (6.6 mg, 0.008 mmol, 34%) was obtained (MW Calc +H = 801.31; MW Obs = 801.4).

[0360] A-168 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3,5-bis(trifluoromethyl)benzoic acid (10.8 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL) for the first step, after hydrolysis and purification, A-168 (6.4 mg, 0.008 mmol, 33%) was obtained (MW Calc +H = 801.31; MW Obs = 801.4).

[0361] A-169 was prepared in the same manner as A-109. Starting from using compound 64 (16 mg, 0.028 mmol), commercially available 3-((trifluoromethyl)thio)benzoic acid (9.3 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL) for the first step, after hydrolysis and purification, A-169 (7.2 mg, 0.009 mmol, 37%) was obtained (MW Calc +H = 765.29; MW Obs=765.4).

[0362] A-170 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (6.4 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL). After hydrolysis and purification, A-170 (6.2 mg, 0.009 mmol, 32%) was obtained (MW Calc +H = 696.34; MW Obs = 696.4).

[0363] A-171 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 6-hydroxynicotinic acid (5.8 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL). After hydrolysis and purification, A-171 (10 mg, 0.015 mmol, 51%) was obtained (MW Calc +H = 682.33; MW Obs = 682.4).

[0364] A-172 was prepared in the same manner as A-109, starting from using compound 64 (16 mg, 0.028 mmol), commercially available 5-bromo-2-fluorobenzoic acid (9.2 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol), triethylamine (9.7 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.046 mmol) in dimethylacetamide (1.5 mL). After hydrolysis and purification, A-172 (7.4 mg, 0.010 mmol, 38%) was obtained (MW Calc +H = 763.23; MW Obs=763.3).

[0365] A-173 was prepared in the same manner as A-109, starting from using compound 64 (19 mg, 0.033 mmol), commercially available 1H-pyrazole-4-carboxylic acid (5.6 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step. After hydrolysis and purification, A-173 (10.2 mg, 0.016 mmol, 47%) was obtained (MW Calc +H = 655.33; MW Obs = 655.5).

[0366] A-174 was prepared in the same manner as A-109, starting from using compound 64 (19 mg, 0.033 mmol), commercially available 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (9.6 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step. After hydrolysis and purification, A-174 (6.9 mg, 0.009 mmol, 27%) was obtained (MW Calc +H = 737.33; MW Obs = 737.4).

[0367] A-175 was prepared in the same manner as A-109. Starting from using compound 64 (19 mg, 0.033 mmol), commercially available 3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (8.9 mg, 0.05 mmol) together with HOBT (2.8 mg, 0.017 mmol) in dimethylacetamide (1.5 mL), 1 M triethylamine in THF (83 μL, 0.083 mmol), and EDC-HCl (10.5 mg, 0.055 mmol) for the first step, A-175 (10.2 mg, 0.014 mmol, 43%) was obtained after hydrolysis and purification (MW Calc +H = 723.31; MW Obs = 723.4).

[0368] A-176 was prepared in the same manner as A-109. Starting from using compound 64 (16.0 mg, 0.028 mmol), commercially available (E)-3-(1H-pyrazol-4-yl)acrylic acid (6.8 mg, 0.042 mmol) together with HOBT (2.1 mg, 0.014 mmol) in dimethylacetamide (1.0 mL), 1 M triethylamine in THF (70 μL, 0.070 mmol), and EDC-HCl (8.8 mg, 0.047 mmol) for the first step, A-176 (8.5 mg, 0.012 mmol, 43%) was obtained after hydrolysis and purification (MW Calc +H = 681.34; MW Obs = 681.4).

[0369] A-177 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 1-methyl-1H-pyrazole-4-carboxylic acid (5.3 mg, 0.042 mmol) together with HOBT (3.2 mg, 0.021 mmol), triethylamine (15 μL, 0.105 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.5 mL) for the first step, A-177 (7.2 mg, 0.011 mmol, 51%) was obtained after hydrolysis and purification (MW Calc +H = 669.34; MW Obs = 669.5).

[0370] A-178 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 1H-benzo[d][1,2,3]triazole-5-carboxylic acid (4.4 mg, 0.021 mmol) together with HOBT (2.8 mg, 0.021 mmol), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, A-178 (5.3 mg, 0.007 mmol, 33%) was obtained after hydrolysis and purification (MW Calc +H = 706.34; MW Obs = 706.6).

[0371] A-179 was prepared in the same manner as A-109. Starting from using compound 64 (12 mg, 0.021 mmol), commercially available 5-(2-methyl-1,3-thiazol-4-yl)-3-isoxazolecarboxylic acid (4.4 mg, 0.021 mmol) together with HOBT (2.8 mg, 0.021 mmol), triethylamine (8.7 μL, 0.063 mmol), and EDC-HCl (8 mg, 0.042 mmol) in dimethylacetamide (0.8 mL) for the first step, A-179 (15.7 mg, 0.021 mmol, 100%) was obtained after hydrolysis and purification (MW Calc +H = 753.31; MW Obs = 753.52).

[0372] Via acid chloride condensation<� A-180 was prepared via acid chloride condensation in the same manner as A-109.

[0373] A stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1R,2R)-3-azido-1,2-dihydroxypropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (63, 0.2 g, 0.333 mmol) in THF (3.00 mL) and water (0.240 mL) at 0 °C was treated with 1N trimethylphosphine (0.999 mL, 0.999 mmol). The reaction mixture was warmed to room temperature and stirred for 16 h, after which time the mixture was concentrated and dried by azeotroping with toluene (2 x 20 mL each) to afford crude 64.

[0374] To a stirred solution of the concentrated amine (64) in DCM (3.21 mL) at room temperature was added triethylamine (0.464 mL, 3.33 mmol), and 3,4-dimethylbenzene-1-carbonyl chloride (0.084 g, 0.499 mmol). The reaction mixture was stirred for 2 h, after which time the reaction was quenched with saturated 1N NaOH (4 mL) and then extracted with EtOAc (3 x 6 mL each). The combined organic fractions were concentrated, diluted with methanol (5 mL), then K2CO3 (100 mg), and then stirred for an additional 2 h. The fully quenched reaction was diluted with water (5 mL) and then extracted with EtOAc (4 x 6 mL each). The combined organic layers were concentrated and purified by elution on a Biotage Ultra SNAP column (25 g) with a gradient of 30% → 100% EtOAc in heptane (10 CV) to afford, after collection, concentration, and drying under vacuum, the desired compound 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1R,2R)-3-(3,4-dimethylbenzamide)-1,2-dihydroxypropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (0.22 g, 0.311 mmol, 93% yield) (MW Calc +H = 707.38; MW Obs = 707.81).

[0375] To a stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1R,2R)-3-(3,4-dimethylbenzamide)-1,2-dihydroxypropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (10 mg, 0.014 mmol) in MeOH (400 μL) and THF (400 μL) at room temperature was added 1 N aqueous NaOH solution (495 μL, 0.495 mmol). The reaction mixture was stirred at room temperature for 16 h and, after completion of the reaction over that time, the reaction was acidified to pH 4 with concentrated HCl and sent onto a reversed-phase C18 Xbridge HPLC column eluting with a water / acetonitrile gradient containing 0.1% NH4OH for purification. After recovery, concentration, and drying under vacuum of the desired fractions, A-180 (6.0 mg, 0.009 mmol, 61%) was obtained (MW Calc +H = 715.37; MW Obs = 715.38).

[0376] A-181 was prepared in a similar manner to A-180, starting in the first step from compound 64 (12 mg, 0.021 mmol) and commercially available m-toluoyl chloride (6.5 mg, 0.042 mmol). After hydrolysis and purification, A-181 (4 mg, 0.006 mmol, 52%) was obtained (MW Calc +H = 679.35; MW Obs = 679.42).

[0377] A-182 was prepared in a similar manner to A-180, starting in the first step from compound 64 (12 mg, 0.021 mmol) and commercially available 3-chlorobenzoyl chloride (11 mg, 0.063 mmol). After hydrolysis and purification, A-182 (6.1 mg, 0.009 mmol, 42%) was obtained (MW Calc +H = 699.30; MW Obs = 699.35).

[0378] A-183 was prepared in the same way as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 3-dimethylaminobenzoyl chloride hydrochloride (13.8 mg, 0.063 mmol) for the first step, after hydrolysis and purification, A-183 (7.2 mg, 0.010 mmol, 49%) was obtained (MW Calc +H = 708.38; MW Obs = 708.36).

[0379] A-184 was prepared in the same way as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 4-acetamidobenzoyl chloride (8.1 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-184 (4.0 mg, 0.006 mmol, 27%) was obtained (MW Calc +H = 722.36; MW Obs = 722.42).

[0380] A-185 was prepared in the same way as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 3,4,5-trifluorobenzoyl chloride (8.1 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-185 (4.0 mg, 0.006 mmol, 27%) was obtained (MW Calc +H = 719.31; MW Obs = 719.51).

[0381] A-186 was prepared in the same way as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 3,4-dichlorobenzoyl chloride (8.8 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-186 (4.0 mg, 0.006 mmol, 26%) was obtained (MW Calc +H = 733.35; MW Obs = 733.36).

[0382] A-187 was prepared in the same manner as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 3,4-dichlorobenzoyl chloride (6.2 mg, 0.042 mmol) for the first step, after hydrolysis and purification, A-187 (4.0 mg, 0.006 mmol, 29%) was obtained (MW Calc +H = 665.34; MW Obs = 665.52).

[0383] A-188 was prepared in the same manner as A-180. Starting from compound 64 (12 mg, 0.021 mmol) and commercially available 5-methylisoxazole-3-carbonyl chloride (9.1 mg, 0.063 mmol) for the first step, after hydrolysis and purification, A-188 (4.5 mg, 0.007 mmol, 32%) was obtained (MW Calc +H = 670.33; MW Obs = 670.49).

[0384] Preparation of A-189

Chemical formula

[0385] To a stirred solution of methyl (2R,4S,5R,6R)-5-acetamido-2-allyl-6-((1R,2R)-3-azido-1,2-dihydroxypropyl)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (657.10 mg, 1.91 mmol) in 2,2-dimethoxypropane (4.69 mL, 38.13 mmol) and acetone (5 mL) was added p-toluenesulfonic acid monohydrate (36.3 mg, 0.191 mmol) at room temperature. After the reaction mixture was stirred for 2 h, triethylamine (1.33 mL, 9.53 mmol) was subsequently added, concentrated, and then saturated NaHCO3 (7 mL). The quenched reaction mixture was extracted with EtOAc (3 × 10 mL each), washed with brine (5 mL), dried over Na2SO4, filtered, and dried by concentration. The residue was sent onto a Biotage Ultra SNAP silica gel column (25 g) and eluted with a gradient of 5 CV of 1:1 EtOAc:heptane followed by 5 CV of 0→10% MeOH in EtOAc) to purify. After recovery of the desired fractions, concentration, and evaporation to dryness under vacuum, compound 66 (720 mg, 1.746 mmol, 92%) was obtained (MW Calc +Na = 435.20; MW Obs = 435.29).

[0386] A stirred solution of methyl (2R,4S,5R,6R)-5-acetamido-2-allyl-6-((4R,5R)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (66, 0.7 g, 1.70 mmol) in 1,4-dioxane (12.60 mL) and water (4.20 mL) at room temperature was treated with 2,6-lutidine (0.198 mL, 1.697 mmol), osmium tetroxide (0.216 mL, 0.034 mmol), and sodium periodate (1.452 g, 6.789 mmol). The reaction mixture was stirred for 3 h and, after completion of the reaction over that time, the reaction was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was separated, extracted with EtOAc (3 × 10 mL each), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by sending it onto a Biotage Ultra SNAP silica gel column (25 g) and eluting with 20% EtOAc in heptane for 3 CV, 50→100% EtOAc in heptane for 5 CV, and EtOAc for 3 CV, followed by recovery of the desired fractions, concentration, and evaporation to dryness under vacuum to afford compound 67 (0.58 g, 1.400 mmol, 82% yield) (MW Calc +Na = 437.18; MW Obs = 437.26).

[0387] A stirred solution of methyl (2S,4S,5R,6R)-5-acetamido-6-((4R,5R)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-2-(2-oxoethyl)tetrahydro-2H-pyran-2-carboxylate (67,580 mg, 1.40 mmol) in dichloroethane (13.2 mL) at room temperature was treated with acetic acid (561 μL, 9.797 mmol), (S)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19,339 mg, 1.40 mmol), and dried 4A molecular sieves (3 g, 2 g / mmol). The mixture was stirred for 2 h, and after that time sodium triacetoxyborohydride (593 mg, 2.799 mmol) was added with stirring for an additional 45 min. The completed reaction was diluted with EtOAc (15 mL) and eluted with EtOAc (2 × 10 mL each) by filtration through a Celite pad (10 g). The filtrate was quenched with aqueous NaHCO3 (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 20 mL each). The combined organic layers were dried over Na2SO4, filtered, and dried by concentration. The residue was sent onto a Biotage Ultra SNAP silica gel column (25 g) and eluted with 50→100% EtOAc in heptane for 5 CV, then 0→20% MeOH in EtOAc for 5 CV to purify. After collection, concentration, and evaporation to dryness under vacuum of the desired fractions, compound 68 (800 mg, 1.249 mmol, 89% yield) was obtained (MW Calc +Na = 663.34; MW Obs = 663.36).

[0388] At room temperature, to a stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((4R,5R)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (68,600 mg, 0.936 mmol) in THF (10 mL) and water (0.5 mL) was added trimethylphosphine (3.0 mL, 3.00 mmol) in THF. The mixture was stirred for 2 hours, and after that time the completed reaction mixture was concentrated and then dried by azeotroping with acetonitrile (3 × 10 mL each) to give crude compound 69 (MW Calc +H = 615.35; MW Obs = 615.53) (assuming 100% conversion), which was used in the next step without further purification.

[0389] To a stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((4R,5R)-5-(aminomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (69, 32 mg, 0.052 mmol) in acetonitrile (0.5 mL) at room temperature were added 6-hydroxy-5-methylnicotinic acid (8.77 mg, 0.057 mmol), triethylamine (50 μL, 0.359 mmol), HOBT (1.594 mg, 0.010 mmol), and EDC (10.98 mg, 0.057 mmol). The reaction mixture was stirred at room temperature for 16 hours, and after that time the completed reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (2 × 10 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated to dryness. The crude residue was purified, and after recovery of the desired fractions, concentration, and evaporation to dryness under vacuum, compound 70 (13.8 mg, 0.018 mmol, 35%) was obtained (MW Calc +H = 750.38; MW Obs = 750.62).

[0390] To a stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-4-hydroxy-6-((4R,5R)-5-((6-hydroxy-5-methylnicotinamide)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (70, 13.8 mg, 0.018 mmol) in methanol (1.0 mL) and water (0.5 mL) at room temperature was added p-toluenesulfonic acid (1.9 mg, 0.010 mmol) over 24 h. The nearly complete reaction mixture was cooled to room temperature, concentrated, and co-evaporated to dryness with toluene (2 x 10 mL). The crude mixture was purified and after recovery, concentration, and evaporation to dryness under vacuum of the desired fractions, compound 71 (6.9 mg, 0.010 mmol, 53%) was obtained (MW Calc +H = 710.35; MW Obs = 710.58).

[0391] To a stirred solution of 6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1R,2R)-1,2-dihydroxy-3-(6-hydroxy-5-methylnicotinamide)propyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid (S)-tert-butyl (71, 6.0 mg, 8.453 μmol) in methanol (2.0 mL) at room temperature was added 2.0 M aqueous sodium hydroxide solution (0.5 mL). The mixture was stirred for 16 h and after completion of the reaction over that time, the reaction mixture was quenched with 1 N aqueous HCl solution (1.0 mL), concentrated, and dried by azeotroping with toluene (5 x 5 mL each). The crude mixture was purified and after recovery, concentration, and evaporation to dryness under vacuum of the desired fractions, A-189 (0.9 mg, 0.001 mmol, 15%) was obtained (MW Calc +H = 696.34; MW Obs = 696.6).

[0392] Preparation of A-190 to A-192 A-190 was prepared in the same manner as A-189. Starting from compound 68 (20 mg, 0.031 mmol) and commercially available 3,5-dimethylbenzoic acid (9.4 mg, 0.062 mmol) for the first step, after hydrolysis and purification, A-190 (6.0 mg, 0.009 mmol, 29%) was obtained (MW Calc +Na = 715.36; MW Obs = 715.45).

[0393] A-191 was prepared in the same manner as A-189. Starting from compound 69 (100 mg, 0.163 mmol) and commercially available 1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (37 mg, 0.221 mmol) for the first step, after hydrolysis and purification, A-191 (2.2 mg, 0.003 mmol, 2%) was obtained (MW Calc +H = 710.36; MW Obs = 710.5).

[0394] A-192 was prepared in the same manner as A-189. Starting from compound 69 (100 mg, 0.163 mmol) and commercially available 4-fluoro-3,5-dimethylbenzoic acid (41 mg, 0.244 mmol) for the first step, after hydrolysis and purification, A-192 (5.3 mg, 0.007 mmol, 5%) was obtained (MW Calc +H = 711.36; MW Obs = 711.5).

[0395] Preparation of A-193

Chemical formula

[0396] To a stirred solution containing (1R,2R)-1-((2R,3R,4S,6S)-3-acetamido-4-acetoxy-6-(methoxycarbonyl)-6-((E)-prop-1-en-1-yl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (72, 14 mg, 0.021 mmol) in methanol (3 mL) and DCM (1 mL) at -78 °C, ozone was added over a period of 25 minutes. After that time, the reaction mixture was purged with N2 at -78 °C for 10 minutes to remove ozone. Dimethyl sulfide (0.1 ml, 1.36 mmol) was added, and the completed reaction mixture was warmed to room temperature and then diluted successively with EtOAc (5 mL) and water (2 mL). The layers were separated, and the organic layer was dried over Na2SO4, filtered, and dried by concentration to give crude compound 73 (MW Calc +H = 651.23; MW Obs = 651.43), which was used without further purification.

[0397] To a stirred solution of 73 in DCM (2 mL), tert-butyl 2,7-diazaspiro[4.5]decane-2-carboxylate (19.1, 10.16 mg, 0.042 mmol) and 4 Å MS (150 mg) were added, and the mixture was then stirred at room temperature for 2 hours. Sodium triacetoxyborohydride (8.96 mg, 0.042 mmol) was added to the resulting mixture, and the mixture was stirred for an additional 1 hour. The completed reaction was quenched slowly with NaHCO3 (3 mL), and then extracted with EtOAc (3 × 2 mL each). The combined organic layers were washed with brine (3 mL) and concentrated to dryness. The residue was purified by HPLC to give compound 74 (3 mg, 3.43 μmol, 16% yield) (MW Calc +H = 875.40; MW Obs = 875.63).

[0398] A stirred solution of (1R,2R)-1-((2R,3R,4S,6S)-3-acetamido-4-acetoxy-6-((2-(tert-butoxycarbonyl)-2,7-diazaspiro[4.5]decane-7-yl)methyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (74.9 mg, 10.286 μmol) in methanol (0.4 mL) was treated with 1 N aqueous sodium hydroxide solution (0.35 mL, 0.35 mmol), and the reaction mixture was stirred for 22 h over time. The completed reaction was purified directly on an HPLC column to afford compound A-193 (4 mg, 5.77 μmol, 56% yield) as a mixture of diastereomers (MW Calc +H = 693.37; MW Obs = 693.39).

[0399] Preparation of A-194

Chemical formula

[0400] To a stirred solution of (1R,2R)-1-((2R,3R,4S,6R)-3-acetamido-4-acetoxy-6-((E)-3-((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)allyl)-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (76, 50 mg, 0.06 mmol) in MeOH (1488 μl, 36.783 mmol) at 0 °C, NaOH (1022 μl, 1.022 mmol) was added. The mixture was stirred at room temperature for 16 h. The reaction mixture was directly subjected to HPLC purification using the analytical base to afford compound A-194 (11.9 mg, 0.018 mmol, 31%) (MWCalc +H = 650.32; MW Obs = 650.5).

[0401] Preparation of A-195 to A-199

Chem.

[0402] To a stirred solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (78, 0.5 g, 2.51 mmol) in THF (7.50 mL) at 0 °C, 1 M tBuOK in THF (5.02 mL, 5.019 mmol) was added and then stirred for 10 min and after that time methyl iodide (1.26 ml, 20.075 mmol) was added. The reaction mixture was stirred at 0 °C for 2 h and then quenched with saturated NaHCO3 (10 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL each), the combined organic layers were washed with brine (1 × 10 mL), dried over Na2SO4, filtered and concentrated to give compound 79 (0.50 g, 2.34 mmol, 93% yield).

[0403] Under an N2 atmosphere at 0 °C, 1M LHMDS (9.38 ml, 9.38 mmol) in THF was added to a stirred solution of methyltriphenylphosphonium bromide (4.19 g, 11.72 mmol) in THF (15.00 mL), and then the mixture was stirred for an additional 30 minutes. tert-Butyl 3-formyl-3-methylpyrrolidine-1-carboxylate (79, 0.5 g, 2.34 mmol) in THF (1 mL) was added at 0 °C, and then the reaction mixture was warmed to room temperature and stirred for 16 hours. The completed reaction was quenched with saturated NH4Cl (4 mL) and extracted with EtOAc (2 × 5 mL each). The combined organic layers were washed with brine (1 × 10 mL), dried over Na2SO4, filtered, concentrated, and then sent to a Biotage SNAP column (25 g) and eluted with 0-50% ethyl acetate in heptane for purification. After recovery, concentration, and vacuum drying, tert-butyl 3-methyl-3-vinylpyrrolidine-1-carboxylate 80 (0.30 g, 1.42 mmol, 61%) was obtained.

[0404] A-195 was prepared in the same manner as A-194, starting from compound 17 (0.30 g, 0.453 mmol) and tert-butyl 3-methyl-3-vinylpyrrolidine-1-carboxylate (80, 0.29 g, 1.36 mmol). After purification, A-195 (43 mg, 0.065 mmol, 14% overall yield) was obtained (MW Calc +H = 664.34; MW Obs = 664.20).

[0405] The preparation of A-196 was carried out by dissolving the fully protected intermediate of A-195 (60.0 mg, 0.071 mmol) in ethyl acetate (1.2 mL) and methanol (0.9 mL) at room temperature, followed by the addition of 10% palladium on carbon (75 mg), and then stirring the mixture under hydrogen gas at a pressure above atmospheric pressure for 16 hours. The completed reaction was filtered through celite (3 g) and eluted with 10% methanol in ethyl acetate (20 mL). The filtrate was concentrated to a syrup. This syrup was dissolved in methanol (0.9 mL) and THF (0.9 mL), 1N NaOH (0.71 mL, 0.71 mmol) was added, and the resulting mixture was stirred for 24 hours and at 35 °C for 24 hours. The completed reaction obtained was purified directly by HPLC to give A-196 (10.3 mg, 0.015 mmol, 22%) (MW Calc +Na = 688.36; MW Obs = 688.25).

[0406] [Chemical formula] To a stirred solution of commercially available tert-butyl 3-oxopyrrolidine-1-carboxylate (815.09 mg, 2.75 mmol) in Et2O (8.57 mL) at -45 °C, 1M vinylmagnesium bromide in Et2O (5.50 mL, 5.50 mmol) was added dropwise. Subsequently, the reaction was allowed to warm to room temperature and stirred for 16 hours. The completed reaction was cooled to -45 °C and then quenched with saturated NH4Cl (10 mL). The resulting mixture was warmed to room temperature and the layers were separated. The aqueous layer was extracted with EtOAc (2 × 20 mL each), the combined organic layers were washed with NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. This crude oil was purified by HPLC to give compound 82 (318 mg, 1.49 mmol, 54%).

[0407] A-197 was prepared in the same manner as A-194, starting from compound 17 (50 mg, 0.075 mmol) and tert-butyl 3-hydroxy-3-vinylpyrrolidine-1-carboxylate (82, 48.3 g, 0.226 mmol), and after purification, A-197 (1.8 mg, 0.003 mmol, 4% total yield) was obtained (MW Calc +H = 666.32; MW Obs = 666.5).

[0408] [Chemical formula] To a stirred solution of tert-butyl 3-formylpyrrolidine-1-carboxylate (78, 760 mg, 3.81 mmol) in THF (9.4 mL) was added pyrrolidine-3-carboxylic acid (329 mg, 2.86 mmol) and NFSI (4.21 g, 13.35 mmol) at room temperature. The reaction mixture was stirred for 16 hours, and after that time, the reaction was diluted with EtOAc (30 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL each), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The crude oil was sent onto a Biotage SNAP column (25 g) and eluted with 1:1 ethyl acetate to heptane and purified twice to give, after collection of the desired fractions, concentration, and drying under vacuum, compound 83 (520 mg, 2.39 mmol, 63%).

[0409] To a stirred solution of methyltriphenylphosphonium bromide (2.47 g, 6.91 mmol) in THF (8.83 mL) at 0 °C was added 1 M LHMDS (5.52 mL, 5.52 mmol), and the mixture was stirred for an additional 30 minutes. After this time, tert-butyl 3-fluoro-3-formylpyrrolidine-1-carboxylate (83, 300 mg, 1.38 mmol) in THF (1 mL) was added. The reaction mixture was warmed to room temperature and stirred for 16 hours. The completed reaction was quenched with saturated NH4Cl (4 mL) and extracted with EtOAc (2 × 5 mL each). The combined organic layers were dried over Na2SO4, filtered, concentrated, and then purified by passing through a Biotage SNAP column (25 g) eluting with a gradient of 0→50% ethyl acetate in heptane. After collection of the desired fractions, concentration, and drying under vacuum, compound 84 (26 mg, 0.121 mmol, 9%) was obtained.

[0410] A-198 was prepared in a similar manner to A-194, starting from compound 17 (44 mg, 0.05 mmol) and tert-butyl 3-fluoro-3-vinylpyrrolidine-1-carboxylate (84, 42.9 g, 0.199 mmol). After purification, A-198 (3 mg, 0.0045 mmol, 19% overall yield) was obtained (MW Calc +H = 668.31; MW Obs = 667.6).

[0411] [Chemical formula] To a stirred solution of commercially available (R)-3-vinylpyrrolidine 2,2,2-trifluoroacetate (85, 200 mg, 0.947 mmol) in THF (2 mL) at room temperature was added commercially available 2-fluoro-N,N-dimethylpyridin-4-amine (86, 206 mg, 1.468 mmol), followed by triethylamine (0.396 mL, 2.841 mmol). The reaction mixture was microwave heated at 150 watts for 5 h, and after that time the mixture was cooled to room temperature and applied directly to a Biotage SNAP Ultra silica gel column (10 g) and eluted with 0→10% MeOH in DCM (5 CV) to give, after collection, concentration and drying under vacuum, (R)-N,N-dimethyl-2-(3-vinylpyrrolidin-1-yl)pyridin-4-amine (87, 189 mg, 0.870 mmol, 92% yield) (MW Calc +H = 217.16; MW Obs = 217.89) as a pale brown solid.

[0412] A-199 was prepared in a similar manner to A-194, starting from compound 17 (24 mg, 0.036 mmol) and (R)-N,N-dimethyl-2-(3-vinylpyrrolidin-1-yl)pyridin-4-amine (87, 39.4 mg, 0.181 mmol), to give A-199 (9.37 mg, 0.014 mmol, 38%) after hydrolysis and purification (MW Calc +H = 669.34; MW Obs = 670.40).

[0413] Preparation of A-200 and A-201 [Chemical formula] To a stirred solution of (2R,4S,5R,6R)-methyl 2-allyl-6-((1R,2R)-3-azido-1,2-dihydroxypropyl)-5-((tert-butoxycarbonyl)amino)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (13, 0.20 g, 0.465 mmol) in acetone (5 mL) at room temperature was added 2,2-dimethoxypropane (1.143 mL, 9.293 mmol), followed by p-toluenesulfonic acid monohydrate (9.0 mg, 0.046 mmol). The reaction was stirred for 16 h and after that time it was quenched with saturated NaHCO3 (5 mL), extracted with EtOAc (3 × 2 mL each), the combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, concentrated and dried under vacuum to give crude compound 88a (ca. 219 mg, 0.465 mmol, 100%) without further purification (MW Calc +Na = 493.24; MW Obs = 493.21).

[0414] To a stirred solution of crude (2R,4S,5R,6R)-2-allyl-6-((4S,5S)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((tert-butoxycarbonyl)amino)-4-hydroxytetrahydro-2H-pyran-2-carboxylate methyl ester (88a, 0.4 g, 0.85 mmol) in DCM (4.80 mL) at room temperature was added sodium bicarbonate (0.357 g, 4.251 mmol), followed by Dess-Martin periodinane (0.541 g, 1.275 mmol). The reaction mixture was stirred for 2 h and after that time it was quenched with saturated Na2S2O3 (3 mL) and saturated NaHCO3 (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 6 mL each). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by sending it onto a Biotage SNAP silica gel column (25 g) and eluting with a 10 → 100% EtOAc gradient in heptane (10 CV), and after collection, concentration and drying under vacuum of the desired fractions, the 4-oxo analogue of 88b (0.25 g, 0.534 mmol, 63%) was obtained (MW Calc +Na = 491.24; MWObs = 491.22).

[0415] A stirred solution of zirconium(IV) chloride (111 ml, 1.334 mmol) in THF (27.5 mL) was heated to 60 °C for 20 minutes. After that time, it was cooled to -55 °C, and then 1.6 M methyllithium in THF (3.34 mL, 5.336 mmol) was added dropwise. The mixture was stirred at -55 °C for 10 minutes, then warmed to 0 °C and stirred for 30 minutes. The resulting yellowish solution was cooled to -78 °C, and after that time, methyl (2R,5S,6R)-2-allyl-6-((4S,5S)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((tert-butoxycarbonyl)amino)-4-oxotetrahydro-2H-pyran-2-carboxylate (88b, 0.25 g, 0.534 mmol) in THF (5 mL) was added slowly over a period of 5 minutes. The final reaction mixture was stirred at -78 °C for 20 minutes, then quenched with a 1:1 mixture of water and saturated NH4Cl (10 mL) and warmed to room temperature. The resulting mixture was diluted with EtOAc (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (3 × 30 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by sending it through a Biotage SNAP silica gel column (25 g) and eluting with a 0→100% EtOAc gradient in 10 CV of heptane. After recovery of the desired fractions, concentration, and drying under vacuum, compound 89 (0.22 g, 0.454 mmol, 85%) was obtained (MW Calc + Na = 507.25; MW Obs = 507.23).

[0416] A stirred solution of methyl (2R,5S,6R)-2-allyl-6-((4R,5R)-5-(azidomethyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-5-((tert-butoxycarbonyl)amino)-4-hydroxy-4-methyltetrahydro-2H-pyran-2-carboxylate (89, 0.22 g, 0.454 mmol) in THF (3.30 mL) and water (0.327 mL) at room temperature was treated with 1 M trimethylphosphine in THF (1.362 ml, 1.362 mmol). The reaction mixture was stirred for 16 h and after that time was concentrated and dried by azeotroping with toluene (2 x 20 mL each). The residue was dissolved in acetonitrile (3.30 mL) and then 4-hydroxy-3,5-dimethylbenzoic acid (0.121 g, 0.726 mmol), HOBt (0.035 g, 0.227 mmol), EDC (0.131 g, 0.681 mmol), and then triethylamine (0.190 mL, 1.362 mmol) were added. The final reaction was stirred at room temperature for 5 h and after that time was quenched with 1:1 saturated NaHCO3 in water (3 mL) and extracted with EtOAc (3 x 5 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by sending it onto a Biotage SNAP silica gel column (10 g) and eluting with a 20→100% EtOAc gradient in 10 CV of heptane. After recovery of the desired fractions, concentration, and drying under vacuum, compound 90 (0.180 g, 0.297 mmol, 65%) was obtained (MW Calc +Na = 629.32; MW Obs = 629.30).

[0417] (2R,5S,6R)-2-Allyl-5-((tert-butoxycarbonyl)amino)-4-hydroxy-6-((4R,5R)-5-((4-hydroxy-3,5-dimethylbenzamide)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-methyltetrahydro-2H-pyran-2-carboxylic acid methyl ester (90, 0.180 g, 0.297 mmol) was added 4N HCl (0.742 mL, 2.967 mmol) in dioxane at room temperature. The reaction mixture was stirred for 2 h and after that time it was dried by concentration. The resulting residue was diluted with DCM (2.70 mL) at room temperature, followed by addition of triethylamine (0.827 mL, 5.934 mmol), DMAP (7.3 mg, 0.059 mmol), and then acetic anhydride (0.168 ml, 1.78 mmol). The resulting reaction mixture was stirred for 2 h and after that time additional DMAP (7.3 mg, 0.059 mmol) was added and stirred for 48 h. The final reaction mixture was concentrated and then sent to a Biotage SNAP silica gel column (10 g) and eluted with a gradient of 20→100% EtOAc in heptane for 10 CV, followed by a gradient of 0-20% EtOAc in MeOH for 5 CV to purify. After collection, concentration, and drying under vacuum of the desired fractions, compound 91 (0.080 g, 0.228 mmol, 40%) (MW Calc +Na = 699.28; MW Obs = 699.20), and compound 92 (0.1 g, 0.158 mmol, 53%) (MW Calc +Na = 657.27; MW Obs = 657.21) were obtained.

[0418] A stirred solution of (1R,2R)-1-((2R,3S,6R)-3-acetamido-4-acetoxy-6-allyl-6-(methoxycarbonyl)-4-methyltetrahydro-2H-pyran-2-yl)-3-(4-acetoxy-3,5-dimethylbenzamide)propane-1,2-diyl diacetate (91.80 mg, 0.118 mmol) in 1,4-dioxane (2.40 mL) and water (0.48 mL) at room temperature was treated with 2,6-lutidine (27.5 μL, 0.236 mmol), osmium tetroxide (15.03 μL, 2.364 μmol), and sodium periodate (101 mg, 0.473 mmol). The reaction was stirred for 3 h and after this time the reaction was diluted with EtOAc (3 mL) and water (2 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 4 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude aldehyde intermediate was dissolved in dichloroethane (1.20 mL) at room temperature and then treated with acetic acid (47.4 μL, 0.828 mmol), (S)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylic acid tert-butyl (19.28 mg, 0.118 mmol), and 4 Å molecular sieves (2 g / mmol). The suspension was stirred for 2 h and after this time sodium triacetoxyborohydride (50.1 mg, 0.236 mmol) was added followed by stirring for 24 h. The reaction was quenched with saturated NaHCO3 (2 mL), extracted with EtOAc (3 × 3 mL each), dried over Na2SO4, filtered, and concentrated. The protected intermediate was purified by sending it through a Biotage SNAP silica gel column (10 g) eluting with a gradient of 30→100% EtOAc in heptane over 10 CV to give the protected intermediate. The protected intermediate was dissolved in MeOH (1.20 mL) at room temperature and then treated with 1 M aqueous NaOH (1.182 mL, 1.182 mmol). The final reaction mixture was stirred for 24 h and after this time it was neutralized with 4 N acetic acid (0.3 mL, 1.20 mmol) in water and subjected directly to HPLC purification to give A-200 (1.5 mg, 0.002 mmol, 1.8%) (MW Calc +H = 723.38; MW Obs=723.50) and A-201 (3.1 mg, 0.0043 mmol, 3.6%) (MW Calc +H=723.38; MW Obs =723.40) was obtained.

[0419] Preparation of A-202

Chemical formula

[0420] A stirred solution of (1R,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,3R,4S,6R)-4-acetoxy-6-allyl-3-amino-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate 2,2,2-trifluoroacetate (93, ca. 50 mg, 0.068 mmol) in acetonitrile (0.50 mL) and water (1.00 mL) at room temperature was treated with sodium bicarbonate (51.5 mg, 0.613 mmol), followed by the dropwise addition of a solution of O-phenyl carbonochloridothioate (19.97 mg, 0.116 mmol) in acetonitrile (0.50 mL). The reaction mixture was stirred at room temperature for 4 days, and after completion of the reaction over that time, the reaction was concentrated and the resulting residue was diluted with saturated NaHCO3 (20 mL) and EtOAc (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated. The final residue was sent onto a Biotage Ultra SNAP silica gel column (10 g) and eluted with 5% EtOAC in heptane for 2 CV, a 5-20% EtOAc gradient for 5 CV, 20% EtOAC in heptane for 3 CV, a gradient of 20→50% EtOAc in heptane for 5 CV, followed by 50% EtOAC in heptane for 3 CV to purify. After recovery, concentration, and drying under vacuum of the desired fractions, compound 94 (28.5 mg, 0.042 mmol, 62%) was obtained (MW Calc +H = 663.21; MW Obs = 663.27).

[0421] A stirred solution of (1R,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,3R,4S,6R)-4-acetoxy-6-allyl-3-isothiocyanato-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate (94.28 mg, 0.042 mmol) in toluene (1.12 mL) at room temperature was treated with 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (67.8 μL, 0.22 mmol), followed by AIBN (1.041 mg, 6.338 μmol). The reaction mixture was warmed to 90 °C, stirred for 70 minutes, cooled to room temperature and then stirred for 16 hours. The resulting mixture was purified by sending it onto a Biotage Ultra SNAP silica gel column (10 g) and eluting with a 5 CV gradient of 10→50% EtOAc and 5 CV of 50% EtOAc in heptane. After collection, concentration and drying under vacuum of the desired fractions, compound 95 (9.7 mg, 0.015 mmol, 35%) was obtained (MW Calc +Na = 628.25; MW Obs = 628.35).

[0422] To a stirred solution of (1S,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,4R,6R)-4-acetoxy-6-allyl-6-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate (95.8 mg, 0.013 mmol) in 1,4-dioxane (0.288 mL) and water (0.096 mL) at room temperature were added 2,6-lutidine (3.08 μL, 0.026 mmol), osmium tetroxide (1.68 μL, 0.264 μmol), and sodium periodate (11.3 mg, 0.053 mmol). The reaction mixture was stirred for 2 hours and, after completion of the reaction over that time, the reaction was diluted with DCM (10 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. This crude aldehyde intermediate was used in the next reaction without further purification.

[0423] A stirred solution of (1S,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,4R,6S)-4-acetoxy-6-(methoxycarbonyl)-6-(2-oxoethyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate (8.5 mg, 0.014 mmol) and (S)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19, 6.78 mg, 0.028 mmol) in DCE (0.50 mL) at room temperature was treated with acetic acid (8.0 μL, 0.14 mmol), followed by 4 Å molecular sieves (30 mg). The suspension was stirred for 2 h and after that time sodium triacetoxyborohydride (8.89 mg, 0.042 mmol) was added. The final reaction mixture was stirred for 16 h and after that time it was diluted with saturated NaHCO3 (10 mL) and EtOAc (15 mL). The layers were separated and the aqueous layer was extracted with EtOAc (15 mL). The combined organic layers were washed with saturated NaHCO3 (5 mL), then brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by sending it onto a Biotage Ultra SNAP silica gel column (10 g) and eluting with a 1→10% methanol gradient in DCM (10 CV) to afford, after collection, concentration, and drying under vacuum of the desired fractions, compound 96 (11.8 mg, 0.013 mmol, 94%) (MW Calc +H = 834.39; MW Obs = 834.58).

[0424] A stirred solution of (1S,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,4R,6R)-4-acetoxy-6-(2-((S)-2-(tert-butoxycarbonyl)-9-oxa-2,6-diazaspiro[4.5]decane-6-yl)ethyl)-6-(methoxycarbonyl)-tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate (96, 11.6 mg, 0.014 mmol) in methanol (0.464 mL) and THF (0.464 mL) at room temperature was treated with 1 N aqueous sodium hydroxide solution (0.417 mL, 0.417 mmol). The reaction mixture was stirred for 2 days and after that time it was neutralized with 2 N HCl and subjected to HPLC purification, and after recovery, concentration and drying under vacuum of the desired fractions, A-202 (4.3 mg, 0.006 mmol, 47%) was obtained (MW Calc +H = 652.34; MW Obs = 652.33).

[0425] Preparation of A-203

Chemical Structure

[0426] A-203 was prepared in a similar manner to A-202 starting from (1R,2R)-3-(4-acetoxy-3,5-dimethylbenzamide)-1-((2R,3R,4S,6S)-4-acetoxy-3-(dimethylamino)-6-(methoxycarbonyl)-6-(2-oxoethyl)tetrahydro-2H-pyran-2-yl)propane-1,2-diyl diacetate (97.47 mg, 0.072 mmol) and (S)-tert-butyl 9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19.22.8 mg, 0.094 mmol). After hydrolysis and purification, A-203 (15.0 mg, 0.022 mmol, 31%) (MW Calc +H = 695.45: MW Obs=(695.49) was obtained after recovery, concentration, and drying under vacuum of the desired fraction.

[0427] Preparation of A-204 and A-205 [Chemical formula] To a stirred solution of methyl (2R,4S,5R,6R)-2-allyl-6-((1S,2S)-3-azido-1,2-dihydroxypropyl)-5-((tert-butoxycarbonyl)amino)-4-hydroxy-tetrahydro-2H-pyran-2-carboxylate (13, 2.8 g, 6.505 mmol) in DCE (42.0 mL) at 0 °C, 2,4,6-trimethylpyridine (8.60 mL, 65.047 mmol) and benzoyl chloride (1.888 mL, 16.262 mmol) were added. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After the passage of this time, the mixture was cooled to 0 °C and subsequently benzoyl chloride (0.906 ml, 7.806 mmol) was added. The resulting mixture was warmed to room temperature and stirred for 24 h. The final reaction mixture was slowly quenched with saturated NaHCO3 (30 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (4 × 40 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was sent to a Biotage Ultra SNAP silica gel column (50 g) and eluted with a gradient of 20→100% EtOAc in heptane at 10 CV for purification. After recovery, concentration, and drying under vacuum of the desired fraction, compound 98 (2 g, 3.74 mmol, 58%) (MW Calc +Na = 557.23; MW Obs = 557.35) and 99 (1 g, 1.566 mmol, 24%) (MW Calc +Na = 661.26; MW Obs = 661.4) were obtained.

[0428] A stirred solution of methyl (2R,4S,5R,6R)-2-allyl-6-((1R,2R)-3-azido-1-(benzoyloxy)-2-hydroxypropyl)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate (99, 700 mg, 1.096 mmol) in DCM (10.5 mL) at room temperature was treated with sodium bicarbonate (460 mg, 5.48 mmol) and Dess-Martin periodinane (558 mg, 1.315 mmol). The reaction mixture was stirred for 2 h and after that time it was quenched with saturated Na2S2O3 (5 mL) and extracted with EtOAc (4 × 6 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was sent onto a Biotage Ultra SNAP silica gel column (10 g) and eluted with a gradient of 20→100% EtOAc in heptane (10 CV) to purify, and after collection, concentration, and drying under vacuum of the desired fractions, compound 100 (420 mg, 0.660 mmol, 60%) was obtained (MW Calc +Na = 659.24; MW Obs = 659.22).

[0429] A stirred suspension of zirconium(IV) chloride (65.4 mL, 0.785 mmol) in THF (22.00 mL) at room temperature was heated to 60 °C for 20 minutes. After the passage of that time, the clear solution was cooled to -55 °C and then methyl lithium (1.963 mL, 3.141 mmol) was added. The mixture was stirred for 10 minutes, warmed to 0 °C and stirred for 30 minutes. The slightly yellowish solution was cooled to -78 °C and then a solution of methyl (2R,4S,5R,6R)-2-allyl-6-((R)-3-azido-1-(benzoyloxy)-2-oxopropyl)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate (100, 0.2 g, 0.314 mmol) in THF (5 mL) was added. The reaction mixture was stirred at -78 °C for 20 minutes and after the passage of that time it was quenched with 1:1 saturated aqueous NH4Cl (25 mL) and warmed to room temperature. The mixture was diluted with EtOAc (30 mL), the layers were separated and the aqueous layer was extracted with EtOAc (3 × 30 mL each). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was sent onto a Biotage Ultra SNAP silica gel column (25 g) and eluted with a 20→100% EtOAc gradient in 10 CV of heptane for purification. After recovery of the desired fractions, concentration and drying under vacuum, compound 101 (0.1 g, 0.153 mmol, 49%) was obtained (MW Calc +Na = 675.27; MW Obs = 675.31).

[0430] At room temperature, K2CO3 (0.212 g, 1.532 mmol) was added to a stirred solution of methyl (2R,4S,5R,6R)-2-allyl-6-((1R)-3-azido-1-(benzoyloxy)-2-hydroxy-2-methylpropyl)-4-(benzoyloxy)-5-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-2-carboxylate (101, 0.1 g, 0.153 mmol) in MeOH (2.00 mL). The reaction mixture was stirred for 3 hours and after that time it was diluted with saturated NaHCO3 (3 mL) and extracted with EtOAc (3 × 5 mL each). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was sent to a Biotage Ultra SNAP silica gel column (10 g) and eluted with a gradient of 30→100% EtOAc in heptane for 5 CV, then a gradient of 0→30% MeOH for 5 CV for purification. After recovery of the desired fractions, concentration and drying under vacuum, the debenzoylated intermediate (0.1 g, 0.153 mmol, 49%) was obtained (MW Calc +Na = 467.22; MW Obs = 467.20).

[0431] At room temperature, a solution of 4N HCl (337 μl, 1.35 mmol) in dioxane was added to methyl (2R,4S,5R,6R)-2-allyl-6-((1S)-3-azido-1,2-dihydroxy-2-methylpropyl)-5-((tert-butoxycarbonyl)amino)-4-hydroxytetrahydro-2H-pyran-2-carboxylate (60 mg, 0.135 mmol). The reaction mixture was stirred for 2 hours and then concentrated and co-evaporated to dryness with toluene (2 × 10 mL each). The resulting residue was dissolved in DCM (0.90 mL) with stirring, followed by the addition of Et3N (376 μL, 2.70 mmol), DMAP (3.30 mg, 0.027 mmol), and Ac2O (76 μL, 0.81 mmol). The final reaction mixture was stirred at room temperature for 48 hours and then concentrated. The final residue was purified by sending it through a Biotage Ultra SNAP silica gel column (10 g) and eluting with a 0→20% MeOH gradient of 10 CV, followed by recovery of the desired fraction, concentration, and drying under vacuum to give compound 102 (60 mg, 0.128 mmol, 94%) (MW Calc +Na = 493.20; MW Obs = 493.15).

[0432] To a stirred solution of methyl (2R,4S,5R,6R)-5-acetamido-4-acetoxy-6-((1S)-1-acetoxy-3-azido-2-hydroxy-2-methylpropyl)-2-allyltetrahydro-2H-pyran-2-carboxylate (102, 60 mg, 0.128 mmol) in 1,4-dioxane (1.80 mL) and water (0.36 mL) at room temperature were added 2,6-lutidine (29.7 μL, 0.255 mmol), osmium tetroxide (16.21 μL, 2.551 μmol), and sodium periodate (109 mg, 0.51 mmol). The mixture was stirred for 3 h, and after that time the reaction was diluted with EtOAc (3 mL) and water (2 mL). The layers were separated, the aqueous layer was extracted with EtOAc (3 × 4 mL), the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude aldehyde was dissolved in DCE (0.90 mL) at room temperature with stirring, followed by the addition of acetic acid (51.1 μl, 0.893 mmol), tert-butyl (S)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (19, 30.9 mg, 0.128 mmol), and oven-dried 4 Å molecular sieves (256 mg). The mixture was stirred for 2 h, and after that time sodium triacetoxyborohydride (54.1 mg, 0.255 mmol) was added and the mixture was stirred for 24 h. The completed reaction was quenched with saturated NaHCO3 (2 mL) and extracted with EtOAc (3 × 3 mL each). The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by sending it onto a Biotage Ultra SNAP silica gel column (10 g) and eluting with a 30→100% EtOAc gradient in 5 CV of heptane, followed by a 0→30% MeOH gradient in 5 CV to afford tert-butyl (5R)-6-(2-((2R,4S,5R,6R)-5-acetamido-4-acetoxy-6-((1S)-1-acetoxy-3-azido-2-hydroxy-2-methylpropyl)-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (70 mg, 0.100 mmol, 79%) after collection, concentration, and drying under vacuum of the desired fractions.This semi-pure product was dissolved in MeOH (1.20 mL) at room temperature, followed by the addition of K2CO3 (176 mg, 1.275 mmol). The reaction mixture was stirred for 16 h and after that time it was diluted with saturated NaHCO3 (2 mL) and EtOAc (5 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 4 mL each). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was sent onto a Biotage Ultra SNAP silica gel column (10 g) and eluted with a 30→100% EtOAc gradient in heptane for 5 CV, then a 0→30% MeOH gradient for 5 CV to purify. After collection, concentration and drying under vacuum of the desired fractions, compound 103 (20 mg, 0.033 mmol, 26%) was obtained (MW. Calc +Na = 637.33; MW Obs = 633.21).

[0433] To a stirred solution of tert-butyl (5S)-6-(2-((2R,4S,5R,6R)-5-acetamido-6-((1S)-3-azido-1,2-dihydroxy-2-methylpropyl)-4-hydroxy-2-(methoxycarbonyl)tetrahydro-2H-pyran-2-yl)ethyl)-9-oxa-2,6-diazaspiro[4.5]decane-2-carboxylate (103, 20 mg, 0.033 mmol) in THF (0.300 mL) and water (0.23 mL) at room temperature was added 1N trimethylphosphine (98 μL, 0.098 mmol). The reaction mixture was stirred for 16 h and the completed intermediate was concentrated, concentrated and dried by azeotroping with toluene (2 x 10 mL each). The resulting amine intermediate was dissolved in dimethylacetamide (0.40 mL) at room temperature with stirring, followed by the addition of 4-hydroxy-3,5-dimethylbenzoic acid (10.81 mg, 0.065 mmol), HOBt (4.98 mg, 0.033 mmol), EDC (12.47 mg, 0.065 mmol), and finally triethylamine (22.68 μl, 0.163 mmol). The reaction mixture was stirred for 5 h to give crude 104, and after the passage of that time 1M NaOH (325 μL, 0.325 mmol) was added and the final mixture was stirred for 1 day. The completed reaction was neutralized with 1N HCl (325 μL, 0.325 mmol), filtered, and the filter pad was eluted with methanol (2 x 2 mL each) and subjected to HPLC purification to give, after recovery, concentration and drying under vacuum of the desired fractions, A-204 (0.5 mg, 0.0007 mmol, 2%) (MW Calc +H = 723.38; MW Obs = 723.33) and A-205 (0.5 mg, 0.0007 mmol, 2%) (MW Calc +H = 723.38; MW Obs = 723.28).

[0434] Preparation of A-206, A-207, and A-208

Chemical formula

[0435] To a stirred solution of (3aR,4R,7S,8aR)-7-hydroxy-2,2-dimethyltetrahydro-4,7-methano[1,3]dioxolo[4,5-c]oxepin-6(4H)-one (105, 3.54 g, 16.525 mmol) in THF (48 mL) at 0 °C was added dropwise 1 M LiAlH4 in THF (25.4 mL, 25.4 mmol). After that time, the reaction mixture was warmed to room temperature and then to reflux temperature. The mixture was stirred for 20 hours and, after that time, it was cooled to 0 °C, followed by the slow addition of water (0.956 mL, 53.055 mmol), 15% aqueous sodium hydroxide solution (0.963 ml, 3.59 mmol), and finally water (2.87 mL, 159.164 mmol). The quenched reaction was stirred for 30 minutes and, after that time, celite (14 g) was added and stirring was continued for 2 more hours. The suspension was filtered through a celite pad (10 g), the filter pad was rinsed with MeOH (3 x 20 mL), and the filtrate was concentrated. The residue was triturated with MeCN (20 mL) at 60 °C, concentrated, and dried by azeotroping with MeCN (20 mL). The resulting product was used in the next step without further purification.

[0436] To a stirred solution of crude (3aS,4R,6R,7aR)-6-(hydroxymethyl)-2,2-dimethylhexahydrobenzo-[d][1,3]dioxole-4,6-diol (2.21 g, 10.126 mmol) in DMF (37 mL) at 0 °C was added imidazole (2.76 g, 40.504 mmol) and TBDPS-Cl (2.86 mL, 11.139 mmol). The reaction mixture was stirred at 0 °C for 16 h, and after that time it was slowly warmed to 15 °C and stirred for 24 h. The reaction was quenched with water:MTBE in a 1:1 ratio and stirred at room temperature for 16 h. The layers were separated and the aqueous layer was extracted with MTBE (30 mL). The combined organic layers were washed with saturated brine (10 mL), dried over Na2SO4, filtered, and dried by concentration. The residue was sent onto a Biotage Ultra SNAP silica gel column (50 g) and eluted with 1 CV of heptane, a 0→5% EtOAc gradient in 2 CV of heptane, 5% EtOAc in 4 CV of heptane, a 5→20% EtOAc gradient in 1 CV of heptane, a 20→100% EtOAc gradient in 3 CV of heptane, and then 1 CV of EtOAc to purify. After recovery, concentration, and drying under vacuum of the desired fractions, compound 106 (3.13 g, 6.85 mmol, 68%) was obtained (MW Calc +Na = 479.23; MW Obs = 479.38).

[0437] A stirred solution of (3aS,4R,6R,7aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-2,2-dimethyl-hexahydrobenzo[d][1,3]dioxole-4,6-diol (106, 15.83 g, 34.665 mmol) in DCM (139 mL) at 0 °C was treated with pyridine (8.41 mL, 103.996 mmol), followed by dropwise addition of benzoyl chloride (4.43 mL, 38.132 mmol). The reaction was maintained below 4 °C for 1 h, after which additional benzoyl chloride (0.604 mL, 5.20 mmol) was added followed by stirring at 0 °C for 1 h. Benzoyl chloride (1.207 mL, 10.40 mmol) was added to the uncompleted reaction and the mixture was stirred at 0 °C for 16 h. The completed reaction was quenched with water (150 mL) at 0 °C and then extracted with MTBE (2 × 500 mL each). The combined organic layers were washed with 0.3 N HCl (300 mL), then carefully washed with saturated NaHCO3 (200 mL), 1:1 water:brine (100 mL), dried over Na2SO4, filtered, and concentrated. This crude 5-benzoate intermediate was used in the next step without purification.

[0438] To a stirred solution of crude benzoic acid (3aR,4R,6S,7aR)-6-(((tert-butyldiphenylsilyl)oxy)methyl)-6-hydroxy-2,2-dimethylhexahydrobenzo[d][1,3]dioxol-4-yl (19.44 g, 34.667 mmol) in water (19.43 mL) at room temperature was added acetic acid (78 mL, 1.36 mol). The reaction mixture was warmed to 70 °C and stirred for 1 h, after which it was cooled to 0 °C and after that time water (400 mL mmol), ethyl acetate (649 mL), and then sodium bicarbonate (145 g, 1.73 mol) were slowly added portionwise. The quenched reaction was stirred at 0 °C for 1 h, after which the layers were separated and the aqueous layer was extracted with EtOAc (700 mL). The combined organic layers were washed with 1:1 water:brine (100 mL), dried over Na2SO4, filtered, and concentrated. This crude triol intermediate was used in the next step without purification.

[0439] To a stirred solution of crude benzoic acid (1R,2R,3R,5S)-5-(((tert-butyldiphenylsilyl)oxy)methyl)-2,3,5-trihydroxycyclohexyl (1.35 g, 2.593 mmol) in acetone (30 mL) and water (15 mL) at room temperature was added sodium periodate (0.832 g, 3.889 mmol). The reaction mixture was stirred for 12 h and after that time sodium periodate (0.277 g, 1.296 mmol) was added and the reaction mixture was stirred for 16 h. The completed mixture was extracted with MTBE (2 x 70 mL each), the combined organic layers were washed with saturated NaHCO3 (50 mL), 1:1 water:brine (50 mL), dried over Na2SO4, filtered, and concentrated. This crude dialdehyde intermediate was used in the next step without purification.

[0440] To a stirred solution of crude benzoic acid (2R,4R)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxy-1,6-dioxohexan-2-yl (1.345 g, 2.593 mmol) in THF (19.3 mL) and methanol (2.72 mL) at 0 °C was added sodium borohydride (0.196 g, 5.186 mmol). The reaction was stirred at 0 °C for 2 h and after that time it was then diluted with EtOAc (58 mL) and quenched with saturated sodium bicarbonate (40 mL). The layers were separated and the aqueous layer was extracted with EtOAc (40 mL). The combined organic layers were washed with 1:1 water:brine (10 mL), dried over Na2SO4, filtered, and concentrated. This crude triol intermediate was used in the next step without purification.

[0441] A 20% solution of sodium methoxide (0.448 mL, 1.959 mmol) was added to a stirred solution of crude (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-1,4,6-trihydroxyhexan-2-yl benzoate (1.28 g, 2.449 mmol) in methanol (27.5 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 16 h, after which time Dowex 50WX4 hydrogen form resin (4.4 g) was added and the suspension was stirred at 0 °C for 5 - 10 min, then filtered, the filter pad was rinsed with MeOH (5 mL), and the filtrate was dried by concentration. The residue was dissolved in acetonitrile, triethylamine (0.4 mL, 2.87 mmol) was added, and the mixture was dried by concentration. The final residue was sent onto a Biotage Ultra SNAP silica gel column (25 g) and purified by eluting with 5% EtOAc in heptane for 1 CV, a gradient of 5→50% EtOAc in heptane for 2 CV, a gradient of 50→100% EtOAc in heptane for 10 CV, and then 2 CV of EtOAc. After collection, concentration, and drying under vacuum of the desired fractions, compound 107 (0.87 g, 2.078 mmol, 30% overall yield) was obtained (MW Calc +Na = 441.22; MW Obs = 441.30).

[0442] To a stirred solution of (2R,4S)-4-(((tert-butyldiphenylsilyl)oxy)methyl)hexane-1,2,4,6-tetraol (107, 2.33 g, 5.566 mmol) in DCM (15 mL) at 0 °C was added 2,2-dimethoxypropane (0.80 mL, 6.123 mmol) and p-toluenesulfonic acid monohydrate (0.053 g, 0.278 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h, after which time it was quenched with aqueous NaHCO3 (10 mL), followed by the addition of EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL each). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, concentrated, and dried in vacuo to afford the desired acetonide (2.50 g, 5.45 mmol, 98%) as a clear oil, which was used in the next step without purification.

[0443] To a stirred solution of (S)-4-((tert-butyldiphenylsilyl)oxy)-3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)butane-1,3-diol (2.1 g, 4.578 mmol) in DMSO (11 mL) at room temperature was added IBX (2.56 g, 9.157 mmol). The reaction mixture was stirred for 7 h, after which time the reaction was quenched with a solution of sodium thiosulfate (2 g) in water (10 mL) and aqueous NaHCO3 (10 mL). The resulting mixture was diluted with EtOAc (30 mL), stirred for 5 min, after which time the layers were separated. The aqueous layer was extracted with EtOAc (10 mL) and the combined organic layers were washed with aqueous NaHCO3 (10 mL), water (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The final residue was purified by sending it onto a Biotage Ultra SNAP silica gel column (25 g) and eluting with a 0→100% EtOAc gradient in heptane (10 CV) to afford the desired aldehyde intermediate (1.80 g, 3.94 mmol, 86%) after collection of the desired fractions, concentration, and drying under vacuum.

[0444] To a stirred solution of (R)-4-((tert-butyldiphenylsilyl)oxy)-3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-hydroxybutanal (1.7 g, 3.723 mmol) in dry 1,2-DCE (17 mL) at room temperature was added ethyl (triphenylphosphoranylidene)acetate (2.59 g, 7.445 mmol). The reaction mixture was warmed to 40 °C and stirred for 4 h, after which time it was cooled to room temperature and then stirred for 16 h. The completed reaction was concentrated to approximately 7 mL and sent onto a Biotage Ultra SNAP silica gel column (50 g) and eluted with a 0→65% EtOAc gradient in 10 CV of heptane for direct purification, affording compound 108 (1.80 g, 3.42 mmol, 92%) after collection, concentration, and drying under vacuum of the desired fractions.

[0445] To a stirred solution of ethyl (S,E)-6-((tert-butyldiphenylsilyl)oxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-hydroxyhex-2-enoate (108, 1.8 g, 3.417 mmol) in ethanol (6 mL) and ethyl acetate (18 mL) at room temperature was added 5% Pd-C (0.364 g, 3.417 mmol), followed by purging with H2 (3×) and placing under an H2 atmosphere for 20 h. The reaction mixture was stirred for 20 h, after which time it was purged with N2 gas (3×), filtered through a Celite pad (10 g), rinsed with ethanol (3×10 mL), the filtrate concentrated, and then co-evaporated to dryness with toluene (2×10 mL each). The residue was dissolved in DCM (10 mL) at room temperature with stirring, followed by addition of 2,2-dimethoxypropane (2 mL), then p-toluenesulfonic acid monohydrate (0.020 g, 0.105 mmol). The reaction mixture was stirred for 20 min, after which time it was quenched with aqueous NaHCO3 (10 mL), followed by addition of EtOAc (20 mL). The layers were separated,...

Claims

1. Compound of formula (I): 【Chemistry 1】 The tautomer, a deuterated derivative of the compound of formula (I), a deuterated derivative of the tautomer of the compound of formula (I), or any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is selected from alkenyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) B is hydrogen, 【Chemistry 2】 Selected from; During the ceremony, V is O, CH ２ and NR' are selected; where R' is selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; R １ and R ２ Each of these is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; Each R ｘ These are independently selected from hydrogen, hydroxyl group, amino group, sulfonyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; C, D, E, and F are selected from hydrogen, linear, branched, cyclic alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups; (iii) L is C １～１０ a straight-chain alkylene group, C １～１０ a branched alkylene group, C １～１０ a cyclic alkylene group, -C(O)-C １～１０ a straight-chain alkylene group, -C(O)-C １～１０ a branched alkylene group, -C(O)-C １～１０ a cyclic alkylene group, C １～１０ a straight-chain alkylene-C(O)- group, C １～１０ a branched alkylene-C(O)- group, C １～１０ a cyclic alkylene-C(O)- group, C １～１０ a straight-chain alkenylene group, C １～１０ a branched alkenylene group, C １～１０ a cyclic alkenylene group, 【Transformation 3】 Selected from; in the formula, each L ｘ These are independently selected from hydrogen, linear alkyl groups, branched alkyl groups, and cyclic alkyl groups; (iv) Each X is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (v) X １ and X ２ Each is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (vi) Y is selected from hydrogen, linear alkyl groups, branched alkyl groups, and cyclic alkyl groups; (vii) Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from, in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC ３ ~C ６ Branched alkyl groups, -NHC ３ ~C ６ cyclic alkyl group, -N(C １ ~C ６ linear alkyl group) ２ , -N(C ３ ]] ３ ~C ６ branched alkyl group) ２ , -N(C ３ ~C ６ cyclic alkyl group) ２ , -NH C(O)C １ ~C ６ linear alkyl group, -NH C(O)C ３ ~C ６ branched alkyl group, -NH C(O)C ３ ~C ６ cyclic alkyl group, -C(O)NH C １ ~C ６ linear alkyl group, -C(O)NH C ３ ~C ６ branched alkyl group, -C(O)NH C ３ ~C ６ cyclic alkyl group, -NH aryl group, -N(aryl group) ２ , -NH C(O)aryl group, -C(O)NH aryl group, -NH heteroaryl group, -N(heteroaryl group) ２ , -NH C(O)heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ linear alkyl group, C ３ ~C ６ branched alkyl group, C ３ ~C ６ cyclic alkyl group, C ２ ~C ６ linear alkenyl group, C ２ ~C ６ branched alkenyl group, cyclic alkenyl group, C １ ~C ６ linear hydroxyalkyl group, C ３ ~C ６ branched hydroxyalkyl group, C ３ ~C ６ cyclic hydroxyalkyl group, C １ ~C ６ linear aminoalkyl group, C ３ ~C ６ branched aminoalkyl group, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.]

2. Compound of formula (Ia): 【Chemistry 4】 The tautomer, the deuterated derivative of the compound of formula (Ia), the deuterated derivative of the tautomer of the compound of formula (Ia), and any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is selected from alkenyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) B is hydrogen, 【Transformation 5】 Selected from; in the formula, V is selected from O and NR; R １ and R ２ Each of these is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; Each R ｘ These are independently selected from hydrogen, hydroxyl group, amino group, sulfonyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; 【Transformation 6】 C1-10 linear alkylene groups are: C, D, E, and F are selected from hydrogen, linear alkoxy groups, branched alkoxy groups, cyclic alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups; (iii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear, branched, and cyclic alkyl group; (iv) R y is selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (v) Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from, in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.] A compound of formula (I) according to claim 1, selected from the following.

3. Compound of formula (Ib): 【Transformation 7】 The tautomer, the deuterated derivative of the compound of formula (Ib), the deuterated derivative of the tautomer of the compound of formula (Ib), and any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is selected from alkenyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) B is hydrogen, 【Transformation 8】 Selected from; in the formula, V is selected from O and NR; R １ and R ２ Each of these is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; Each R ｘ These are independently selected from hydrogen, hydroxyl group, amino group, sulfonyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; C, D, E, and F are selected from hydrogen, linear alkoxy groups, branched alkoxy groups, cyclic alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups; (iii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear, branched, and cyclic alkyl group; (iv) R y is selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (v) Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from, in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.] A compound of formula (I) according to claim 1, selected from the following.

4. Compound of formula (Ic): 【Chemistry 9】 The tautomer, deuterated derivative of the compound of formula (Ic), deuterated derivative of the tautomer of the compound of formula (Ic), and any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is selected from alkenyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) B is hydrogen, 【Chemistry 10】 Selected from; in the formula, V is selected from O and NR; R １ and R ２ Each of these is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; Each R ｘ These are independently selected from hydrogen, hydroxyl group, amino group, sulfonyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; C, D, E, and F are selected from hydrogen, linear alkoxy groups, branched alkoxy groups, cyclic alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups; (iii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear, branched, and cyclic alkyl group; (iv) R y is selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (v) Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from, in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.] A compound of formula (I) according to claim 1, selected from the following.

5. Compound of formula (Id): 【Chemistry 11】 The tautomer, a deuterated derivative of the compound of formula (Id), a deuterated derivative of the tautomer of the compound of formula (Id), and any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is selected from alkenyl groups, cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) B is hydrogen, 【Chemistry 12】 Selected from; During the ceremony, V is selected from O and NR; R １ and R ２ Each of these is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; Each R ｘ These are independently selected from hydrogen, hydroxyl group, amino group, sulfonyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; m, n, p, and q are independently selected from 0, 1, 2, 3, and 4; C, D, E, and F are selected from hydrogen, linear alkoxy groups, branched alkoxy groups, cyclic alkoxy groups, cycloalkyl groups, heterocycloalkyl groups, aryl groups, and heteroaryl groups; (iii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) R y is selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (v) Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from, in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.] A compound of formula (I) according to claim 1, selected from the following.

6. A 【Chemistry 13】 The compound according to claim 1, wherein the compound is an aryl group, heteroaryl group, or alkenyl group.

7. B, 【Chemistry 14】 And R １ and R ２ However, each is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, or a cyclic alkyl group, or together forms a cycloalkyl group or heterocyclic group; where the cycloalkyl group or heterocyclic group optionally contains 0, 1, or 2 C atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ It is optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups. for example, B, 【Chemistry 15】 R is selected from linear alkyl groups, branched alkyl groups, and cyclic alkyl groups, and preferably R is a t-butyl group, or B, 【Chemistry 16】 R is selected from linear alkyl groups, branched alkyl groups, cyclic alkyl groups, aryl groups, and heteroaryl groups, or B, 【Chemistry 17】 R is selected from linear alkyl groups, branched alkyl groups, cyclic alkyl groups, aryl groups, and heteroaryl groups. The compound according to any one of claims 1 to 6.

8. B, [Chemistry 18] or 【Chemistry 19】 The compound according to claim 7.

9. B, 【Chemistry 20】 R is selected from linear alkyl groups, branched alkyl groups, cyclic alkyl groups, aryl groups, and heteroaryl groups; and R' is selected from linear alkyl groups, branched alkyl groups, cyclic alkyl groups, and -C(O)-C １ ~C ６ Linear alkyl group, -C(O)-C ３ ~C ６ Branched alkyl groups, and -C(O)-C ３ ~C ６ Selected from cyclic alkyl groups, for example, B, 【Chemistry 21】 Selected from, The compound according to any one of claims 1 to 6.

10. B, 【Chemistry 22】 And; R １ and R ２ However, each is independently selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ They come together to form a cycloalkyl group or a heterocyclic group; R ３ and R ４ However, each is independently selected from hydrogen, hydroxyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group. for example, B, 【Chemistry 23】 Selected from, The compound according to any one of claims 1 to 6.

11. B, 【Chemistry 24】 And in the formula, m is either 0 or 1; R １ and R ２ However, each is independently selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group, or R １ and R ２ Together they form a cycloalkyl group or a heterocyclic group. for example, B, 【Chemistry 25】 Selected from, The compound according to any one of claims 1 to 6.

12. B, 【Chemistry 26】 And; in the formula, each R ｘ The compound according to any one of claims 1 to 6, wherein the compound is independently selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a linear alkylene group, a branched alkylene group, a cyclic alkylene group, a heterocycloalkyl group, an aryl group, and a heteroaryl group.

13. B, 【Chemistry 27】 and; each R ｘ The compound according to any one of claims 1 to 6, wherein the compound is independently selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a linear alkylene group, a branched alkylene group, a cyclic alkylene group, a heterocycloalkyl group, an aryl group, and a heteroaryl group.

14. B, 【Chemistry 28】 and; each R ｘ However, each is independently selected from hydrogen, hydroxyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; p and q are independently selected from 0, 1, 2, 3, and 4; and C and D are independently selected from linear alkoxy group, branched alkoxy group, cyclic alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group. for example, B, 【Chemistry 29】 That is, The compound according to any one of claims 1 to 6.

15. B, 【Transformation 30】 and; each R ｘ However, each is independently selected from hydrogen, a hydroxyl group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a linear alkylene group, a branched alkylene group, a cyclic alkylene group, a heterocycloalkyl group, an aryl group, and a heteroaryl group; p and q are independently selected from 0, 1, 2, 3, and 4; and C, D, and E are independently selected from hydrogen, a linear alkoxy group, a branched alkoxy group, a cyclic alkoxy group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group. for example, B, 【Chemistry 31】 Selected from, The compound according to any one of claims 1 to 6.

16. B, 【Chemistry 32】 And; R ｘ However, independently, F is selected from hydrogen, hydroxyl group, linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkoxy group, branched alkoxy group, cyclic alkoxy group, linear alkylene group, branched alkylene group, cyclic alkylene group, heterocycloalkyl group, aryl group, and heteroaryl group; and F is selected from linear alkoxy group, branched alkoxy group, cyclic alkoxy group, cycloalkyl group, heterocycloalkyl group, aryl group, and heteroaryl group. for example, B, 【Transformation 33】 That is, The compound according to any one of claims 1 to 6.

17. The compound according to claim 1, wherein one of X1 and X2 is selected from hydrogen, an amino group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group.

18. One of X1 and X2 is -NH ２ , -NHC(O)CH ３ , and 【Transformation 34】 A compound according to claim 1, selected from the following.

19. The compound according to any one of claims 1 to 6, 17, or 18, wherein Z is hydrogen, -CN, -CO₂H, -C(O)NHCN, -C(O)Rz, -CO₂Rz, or -C(O)NHSO₂Rz; and Rz is selected from hydrogen, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a carbocyclic group, an amino group, a heterocyclic group, an aryl group, and a heteroaryl group. 【Request Item 20】 【Chemistry 35】 【Transformation 36】 【Chemistry 37】 【Transformation 38】 【Chemistry 39】 【Chemistry 40】 【Chemistry 41】 【Chemistry 42】 【Chemistry 43】 【Chemistry 44】 【Chemistry 45】 【Chemistry 46】 【Chemistry 47】 【Chemistry 48】 【Chemistry 49】 [Transformation 50] 【Chemistry 51】 【Chemistry 52】 【Chemistry 53】 【Chemistry 54】 【Transformation 55】 【Transformation 56】 【Chemistry 57】 【Transformation 58】 A compound according to claim 1, a tautomer thereof, a deuterated derivative thereof, a deuterated derivative of a tautomer thereof, or any pharmaceutically acceptable salt thereof, selected from the above.

21. Compound of formula (II): 【Chemistry 59】 The tautomer, a deuterated derivative of the compound of formula (II), a deuterated derivative of the tautomer of the compound of formula (II), or any of the aforementioned pharmaceutically acceptable salts [wherein, (i) G is selected from cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) Y １ It either does not exist or is -O-; (iii) Y ２ It is either absent or selected from -O-, -NHC(O)-, and aryl groups; (iv) Y ３ It is either absent, or selected from -O- and aryl groups; (v) H is C １～１０ Linear alkylene group, C ３～１０ Branched alkylene group, C ３～１０ Cyclic alkylene group, -C(O)-C １～１０ Linear alkylene group, -C(O)-C ３～１０ Branched alkylene group, -C(O)-C ３～１０ Cyclic alkylene group, C １～１０ Linear alkylene-C(O)- group, C ３～１０ Branched alkylene-C(O)- group, C ３～１０ Cyclic alkylene-C(O)- group, C １～１０ Linear alkenylene group, C ３～１０ Branched alkenylene group, and C ３～１０ Selected from cyclic alkenylene groups; (vi) p, q, and r are independently selected from 0, 1, 2, 3, 4, 5, and 6; (vii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, and a cyclic alkoxy group; (viiii) L does not exist, or 【Transformation 60】 Selected from; in the formula, R Ｌ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ix) Each X is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (x)X １ and X ２ Each is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a -NHC(O) alkyl group, a -NHC(O) arylalkyl group, and a -NHC(O) heteroarylalkyl group; (xi)Z is hydrogen, linear alkyl group, branched alkyl group, cyclic alkyl group, heteroaryl group, -CN, -CO ２ H, -C(O)R ｚ , -C(O)NHCN, -CO ２ R ｚ , and -C(O)NHSO ２ R ｚ Selected from; in the formula, R ｚ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, carbocyclic groups, amino groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally contain 0, 1, or 2 carbon atoms. １ ~C ６ Halogen groups, hydroxyl groups, thiol groups, amino groups, cyano groups, and -C(O)OC groups are substituted with linear alkyl groups, branched alkyl groups, and cyclic alkyl groups. １ ~C ６ Linear alkyl group, -C(O)OC ３ ~C ６ Branched alkyl group, -C(O)OC ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -C(S)OC １ ~C ６ Linear alkyl group, -C(S)OC ３ ~C ６ Branched alkyl group, -C(S)OC ３ ~C ６ Cyclic alkyl group, -C(S)NHC １ ~C ６ Linear alkyl groups, -C(S)NHC ３ ~C ６ Branched alkyl group, -C(S)NHC ３ ~C ６ Cyclic alkyl groups, -C(O)O-arylalkyl groups, -C(O)O-heteroarylalkyl groups, -OC(O)C １ ~C ６ Linear alkyl group, -OC(O)C ３ ~C ６ Branched alkyl group, -OC(O)C ３ ~C ６ Cyclic alkyl group, -NHC １ ~C ６ Linear alkyl groups, -NHC3 to C ６ Branched alkyl groups, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ linear alkyl group) ２ , -N(C ３ ~C ６ branched alkyl group) ２ , -N(C ３ ~C ６ cyclic alkyl group) ２ , -NH C(O)C １ ~C ６ linear alkyl group, -NH C(O)C ３ ~C ６ branched alkyl group, -NH C(O)C ３ ~C ６ cyclic alkyl group, -C(O)NH C １ ~C ６ linear alkyl group, -C(O)NH C ３ ~C ６ branched alkyl group, -C(O)NH C[[ID=...]] (remaining content translated in the same way as above) ２ , -NH C(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ linear alkyl group, C ３ ~C ６ branched alkyl group, C ３ ~C ６ cyclic alkyl group, C ２ ~C ６ linear alkenyl group, C ２ ~C ６ branched alkenyl group, cyclic alkenyl group, C １ ~C ６ linear hydroxyalkyl group, C ３ ~C ６ branched hydroxyalkyl group, C ３ ~C<000​​​​​​​​​​​​​​​​ ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.]

22. Compound of formula (IIa): 【Chemistry 61】 The tautomer, the deuterated derivative of the compound of formula (IIa), the deuterated derivative of the tautomer of the compound of formula (IIa), and any of the aforementioned pharmaceutically acceptable salts [wherein, (i) G is selected from cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (ii) Y １ It either does not exist or is -O-; (iii) Y ２ It is either absent or selected from -O-, -NHC(O)-, and aryl groups; (iv) Y ３ It is either absent, or selected from -O- and aryl groups; (v) H is C １～１０ Linear alkylene group, C ３～１０ Branched alkylene group, C ３～１０ Cyclic alkylene group, -C(O)-C １～１０ Linear alkylene group, -C(O)-C ３～１０ Branched alkylene group, -C(O)-C ３～１０ Cyclic alkylene group, C １～１０ Linear alkylene-C(O)- group, C ３～１０ Branched alkylene-C(O)- group, C ３～１０ Cyclic alkylene-C(O)- group, C １～１０ Linear alkenylene group, C ３～１０ Branched alkenylene group, and C ３～１０ Selected from cyclic alkenylene groups; (vi) p, q, and r are independently selected from 0, 1, 2, 3, 4, 5, and 6; (vii) Each R is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, a cyclic alkyl group, a linear alkoxy group, a branched alkoxy group, and a cyclic alkoxy group; (viiii) L does not exist, or: 【Transformation 62】 Selected from; in the formula, R Ｌ This is selected from hydrogen, linear alkyl groups, branched alkyl groups, cyclic alkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; Here, the linear alkyl group, branched alkyl group, cyclic alkyl group, linear alkenyl group, branched alkenyl group, cyclic alkenyl group, carbocyclic group, linear heteroalkenyl group, branched heteroalkenyl group, heterocyclic group, aryl group, and heteroaryl group may optionally have 0, 1, or 2 C １ ~C ６ halogen group, hydroxy, thiol, amino, cyano, -C(O)OC １ ~C ６ linear alkyl group, -C(O)OC ３ ~C ６ branched alkyl group, -C(O)OC ３ ~C ６ cyclic alkyl group, -C(O)NHC １ ~C ６ linear alkyl group, -C(O)NHC ３ ~C ６ branched alkyl group, -C(O)NHC ３ ~C ６ cyclic alkyl group, -C(S)OC １ ~C ６ linear alkyl group, -C(S)OC ３ ~C ６ branched alkyl group, -C(S)OC ３ ~C ６ cyclic alkyl group, -C(S)NHC １ ~C ６ linear alkyl group, -C(S)NHC ３ ~C ６ branched alkyl group, -C(S)NHC ３ ~C ６ cyclic alkyl group, -C(O)O-arylalkyl group, -C(O)O-heteroarylalkyl group, -OC(O)C １ ~C ６ linear alkyl group, -OC(O)C ３ ~C ６ branched alkyl group, -OC(O)C ３ ~C ６ cyclic alkyl group, -NHC １ ~C ６ linear alkyl group, -NHC3~C ６ branched alkyl group, -NHC ３ ~C ６ Cyclic alkyl group, -N(C １ ~C ６ (Linear alkyl group) ２ , -N(C ３ ~C ６ (Branched alkyl group) ２ , -N(C ３ ~C ６ (Cyclic alkyl group) ２ ,-NHC(O)C １ ~C ６ Linear alkyl group, -NHC(O)C ３ ~C ６ Branched alkyl group, -NHC(O)C ３ ~C ６ Cyclic alkyl group, -C(O)NHC １ ~C ６ Linear alkyl group, -C(O)NHC ３ ~C ６ Branched alkyl group, -C(O)NHC ３ ~C ６ Cyclic alkyl group, -NHaryl group, -N(aryl group) ２ -NHC(O)aryl group, -C(O)NHaryl group, -NH heteroaryl group, -N(heteroaryl group) ２ -NHC(O) heteroaryl group, -C(O)NH heteroaryl group, C １ ~C ６ Linear alkyl group, C ３ ~C ６ Branched alkyl group, C ３ ~C ６ Cyclic alkyl group, C ２ ~C ６ Linear alkenyl group, C ２ ~C ６ Branched alkenyl group, cyclic alkenyl group, C １ ~C ６ Linear hydroxyalkyl group, C ３ ~C ６ Branched hydroxyalkyl groups, C ３ ~C ６ Cyclic hydroxyalkyl group, C １ ~C ６ Linear aminoalkyl group, C ３ ~C ６ Branched aminoalkyl groups, C ３ ~C ６ Cyclic aminoalkyl group, C １ ~C ６ Linear alkoxy group, C ３ ~C ６ Branched alkoxy group, C ３ ~C ６ Cyclic alkoxy group, C １ ~C ６ Linear thioalkyl groups, C ３ ~C ６ Branched thioalkyl groups, C ３ ~C ６ Cyclic thioalkyl groups, C １ ~C ６ Linear haloalkyl group, C ３ ~C ６ Branched haloalkyl groups, C ３ ~C ６ Cyclic haloalkyl group, C １ ~C ６ Linear haloaminoalkyl group, C ３ ~C ６ Branched haloaminoalkyl groups, C ３ ~C ６ Cyclic haloaminoalkyl group, C １ ~C ６ Linear halothioalkyl group, C ３ ~C ６ Branched halothioalkyl groups, C ３ ~C ６ Cyclic halothioalkyl group, C １ ~C ６ Linear haloalkoxy group, C ３ ~C ６ Branched haloalkoxy group, C ３ ~C ６ [Optionally substituted with at least one group selected from cyclic haloalkoxy groups, benzyloxy, benzylamino, benzylthio groups, 3- to 6-membered heterocycloalkenyl groups, 3- to 6-membered heterocyclic groups, and 5- and 6-membered heteroaryl groups.] A compound of formula (II) according to claim 21, selected from the above.

23. G is 【Transformation 63】 or 【Chemistry 64】 A compound according to claim 21 or 22, selected from aryl groups such as the following. 【Request Item 24】 【Chemistry 65】 【Chemical 66】 【Transformation 67】 A compound according to claim 21, a tautomer thereof, a deuterated derivative thereof, a deuterated derivative of a tautomer thereof, and a pharmaceutically acceptable salt of any of the foregoing, selected from among.

25. Compounds of formula (III), (IV), or (V): 【Transformation 68】 The tautomer, deuterated derivatives of the compound of formula (III), (IV), or (V), deuterated derivatives of the tautomer of the compound of formula (III), (IV), or (V), or any of the aforementioned pharmaceutically acceptable salts [wherein, (i) A is a compound according to any one of claims 1 to 6, 17, 18, 20-22, or 24; (ii) J is either absent or selected from cycloalkyl groups, heterocyclic groups, aryl groups, and heteroaryl groups; (iii) Z １ Z ２ , and each X is independently selected from hydrogen, a hydroxyl group, an amino group, a linear alkyl group, a branched alkyl group, and a cyclic alkyl group; (iv) L is, 【Transformation 69】 In the formula, s is between 1 and 50. (v) p, q, and r are independently selected from 1, 2, 3, 4, 5, and 6.

26. The compound according to claim 25, wherein J is absent or is a cyclohexyl group. 【Request Item 27】 【Chemistry 70】 The compound of formula (III) according to claim 25, a tautomer thereof, a deuterated derivative thereof, a deuterated derivative of a tautomer thereof, or any of the aforementioned pharmaceutically acceptable salts. 【Request Item 28】 【Chemistry 71】 A compound of formula (IV) according to claim 25, a tautomer thereof, a deuterated derivative thereof, a deuterated derivative of a tautomer thereof, or any of the aforementioned pharmaceutically acceptable salts. 【Request Item 29】 【Chemistry 72】 A compound of formula (V) according to claim 25, a tautomer thereof, a deuterated derivative thereof, a deuterated derivative of a tautomer thereof, or any of the aforementioned pharmaceutically acceptable salts.

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