Novel spiro bicyclic intermediates

Abstract

The present invention relates to novel spiro-bicyclic intermediates useful in the synthesis of spiro-bicyclic nucleoside analogs.

Description

[Technical Field]

[0001] The present invention relates to novel spiro-bicyclic intermediates useful in the synthesis of spiro-bicyclic nucleoside analogs. [Background technology]

[0002] PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5, is one of the major methyltransferases involved in the mono- and symmetric dimethylation of arginine. Post-translational arginine methylation on histone and nonhistone proteins appears to be important for various biological processes, such as genome organization, transcription, differentiation, spliceosome function, signal transduction, regulation of cell cycle progression, stem cell and T cell fate [Stopa, N. et al., Cell Mol Life Sci, 2015. 72(11):pp. 2041-59] [Geoghegan, V. et al., Nat Commun, 2015. 6:pp. 6758]. Metazoan PRMT5 forms a functional complex with Wdr77, androgen receptor coactivator p44, and methylosome protein 50 (MEP50), also known as Valois. Both elevated protein levels and cytoplasmic accumulation of PRMT5-MEP50 are involved in cancer tumorigenesis and have recently been correlated with poor clinical outcomes [Shilo, K. et al., Diagn Pathol, 2013.8:p.201]. Cell rescue experiments addressing both the catalytic and scaffolding functions of the PRMT5-MEP50 complex, as well as comprehensive enzymatic studies, have demonstrated oncogenic links between protein levels, localization, and enzymatic function [Gu, Z. et al., Biochem J, 2012.446(2):p.235-41] [Di Lorenzo, A. et al., FEBS Lett, 2011.585(13):p.2024-31] [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6):p.432-7]. This correlation makes PRMT5 an essential small molecule drug target for cancer and other diseases [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11):p.2041-59].

[0003] PRMT5 is a member of the type II PRMT subfamily that utilizes S-adenosylmethionine (SAM) to generate symmetrically dimethylated arginine on histone and nonhistone protein substrates and generate S-adenosylhomocysteine ​​(SAH). The crystal structure of the human heterooctameric complex (PRMT5)4 (MEP50)4 cocrystallized with SAH and histone H4 peptide substrates elucidated the mechanisms of methylation and substrate recognition [Antonysamy, S. et al., Proc Natl Acad Sci USA, 2012. 109(44):p.17960-5]. Regulation of PRMT5 activity occurs through multiple and diverse binding partners, post-translational crosstalk, miRNAs, and subcellular localization.

[0004] Methylation of Arg3 on histones H2A and H4 and Arg8 on histone H3 regulates chromatin formation for specific silencing of gene transcripts involved in differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011.36(12):pp.633-41]. Furthermore, PRMT5-mediated methylation of Arg3 on histone H4 may recruit the DNA methyltransferase DNMT3A to couple histone and DNA methylation for long-term gene silencing [Zhao, Q. et al., Nat Struct Mol Biol, 2009.16(3):pp.304-11].

[0005] Non-histone methylation can occur in the cytoplasm or nucleus, depending on the cellular localization of PRMT5. Methylation of Sm proteins D1 and D3, required for nuclear spliceosome assembly, occurs in the cytoplasm as part of a PRMT5-containing "methylosome" [Friesen, WJ et al., Mol Cell Biol, 2001. 21(24): pp. 8289-300]. Further evidence for PRMT5 involvement in splicing was provided by conditional PRMT5 knockout in mouse neural stem cells. PRMT5-deficient cells showed selective retention of introns and skipping of exons with weak 5' donor sites [Bezzi, M. et al., Genes Dev, 2013. 27(17): pp. 1903-16].

[0006] In addition to its role in splicing, PRMT5 influences key pathways involved in cell fate and homeostasis by directly methylating key signaling nodes such as p53 [Jansson, M. et al., Nat Cell Biol, 2008.10(12):pp.1431-9], EGFR [Hsu, J. Met al., Nat Cell Biol, 2011.13(2):pp.174-81], CRAF [Andreu-Perez, P. et al., Sci Signal, 2011.4(190):pp.ra58], PI3K / AKT [Wei, T. Y. et al., Cell Signal, 2014.26(12):pp.2940-50], and NFkB [Wei, H. et al., Proc Natl Acad Sci USA, 2013.110(33):pp.13516-21].

[0007] Because PRMT5 is one of the major sym-Arg methyltransferases and is involved in many cellular processes, increased protein expression is likely an important factor in its tumorigenicity. Interestingly, PRMT5 translation in mantle cell lymphoma (MCL) appears to be regulated by miRNAs. Although MCL cells exhibit lower mRNA levels and a slower PRMT5 transcription rate than normal B lymphocytes, PRMT5 levels and H3R8 and H4R3 methylation are significantly increased [Pal, S. et al., EMBO J, 2007.26(15):pp.3558-69]. Re-expression of miRNAs that bind to the 3'UTR region of PRMT5 reduces PRMT5 protein levels [Wang, L. et al., Mol Cell Biol, 2008.28(20):pp.6262-77]. Surprisingly, prmt5 antisense RNA was found within the human prmt5 gene, supporting the hypothesis of specific translational regulation rather than high mRNA expression [Stopa, N. et al., Cell Mol Life Sci, 2015.72(11):p.2041-59].

[0008] Recently, a novel, subnanomolar, potent PRMT5 inhibitor (EPZ015666) with antitumor activity in multiple MCL xenograft models has been described as the first chemical probe suitable for further investigating the biology and role of PRMT5 in cancer [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6):p.432-7]. International Publication Nos. 2014100695, 2014100719, 2015200680, and 2014100730 disclose compounds useful for inhibiting PRMT5 activity. Devkota, K. et al., ACS Med Chem Lett, 2014.5:293-297, describes the synthesis of a series of analogs of the natural product sinefungin and their ability to inhibit EHMT1 and EHMT2. WO 2003070739 discloses partial and full agonists of the A1 adenosine receptor, their preparation, and their therapeutic use. WO 2012082436 discloses compounds and compositions as modulators of histone methyltransferase and for treating diseases affected by the modulation of histone methyltransferase activity. WO 03074083 discloses a combination therapy for selectively killing methylthioadenosine phosphorylase-deficient cells. Analogs of MTA are described herein as antitoxic agents. Kung, P.-P. et al., Bioorg Med Chem Lett, 2005.15:2829-2833, describe the design, synthesis, and biological evaluation of novel human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) substrates. WO 2012075500 discloses 7-deazapurine modulators of histone methyltransferase. WO 2014035140 discloses compounds and compositions for modulating histone methyltransferase activity. WO 9640686 describes heterocyclic-substituted cyclopentane compounds and methods of using such compounds to inhibit adenosine kinase.

[0009] WO 2016135582 and U.S. Patent Application Publication No. 20160244475 describe substituted nucleoside derivatives useful as anticancer agents. Boyer et al. describe diaryl-erythro-furanosyltubercidin analogs as adenosine kinase inhibitors.

[0010] Nucleoside analogs are a class of compounds with interesting therapeutic activities. They are clinically used to treat a wide range of diseases and disorders, such as viral infections and proliferative diseases. For example, WO 2017 / 032840, WO 2017 / 153186, and WO 2018 / 065365 disclose nucleoside analogs that inhibit protein arginine methyltransferase 5 (PRMT5) activity and are useful for treating PRMT5-mediated disorders.

[0011] It is desirable to develop intermediates and chemical syntheses to enable the preparation of nucleoside analogs with novel substituent patterns.

[0012] Brand et al., JOC 2009, 74, 8779-8786 and Ramakrishna et al., RSC Adv., 2015, 5, 8142-8145, describe the synthesis of spirocyclic compounds. Nowak et al., JOC 2006, 71, 8876-8883, describe the addition of difluorocarbene to 4',5'-unsaturated nucleosides. Redlich et al., Angew. Chem. Int. Ed. Engl. 28 (1989) 777-778, describe the synthesis of chiral cyclobutanones. Summary of the Invention [Means for solving the problem]

[0013] Spirobicyclic nucleosides have been identified that exhibit interesting activity, for example, against PRMT5. Novel intermediates have been developed that can be used to synthesize spiro-bicyclic nucleoside analogs. In particular, these intermediates contain functional groups that can be diversified to provide access to a variety of spiro-bicyclic nucleoside analogs, including cyclopentane-containing nucleoside analogs. Thus, disclosed herein are compounds useful as intermediates for the preparation of spiro-bicyclic nucleoside analogs that may have activity, for example, against PRMT5. Also disclosed herein are spirocyclic nucleoside compounds that may serve as intermediates for further functionalization to provide interesting activity to the spiro-bicyclic nucleoside analogs.

[0014] In one aspect, the present invention provides a compound of formula (A): [ka] [In the formula, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2)m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2)m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group], however, (a) a compound of the formula [ka] wherein Y is —O— or —CH—; 4 is a hydrogen or hydroxyl protecting group, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each independently -C(=O)-C 1~4 alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 alkyl)2-; or wherein Y is -O- or -CH2, and R 4 is methyl and R 2 is ═O or ═CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1~4 alkyl] compounds; (b) the compound has the formula [ka] [In the formula, R v is =O, -OH, or =CH2; (c) the compound has the formula [ka] [In the formula, R w is methyl or H], but not compounds of the formula: (d) the compound has the formula [ka] wherein R is CO2Et or CH2OH, or any stereoisomer thereof, provided that the compound or a salt or solvate thereof is not a compound of the formula:

[0015] In another aspect, the present invention provides a compound of formula (B): [ka] [In the formula, Y is -O- or -CH2-; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group, or a salt or solvate thereof.

[0016] In another aspect, the present invention provides a compound of formula (C): [ka] [In the formula, Y is -O- or -CH2-; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; or R who joined together 4 and R 5 is a diol protecting group; or R who joined together 5 and R 6 is a diol protecting group], However, the compound is [ka] provided that the compound is not

[0017] In another aspect, the present invention provides a compound of formula (D): [ka] [In the formula, Y is -O- or -CH2-; where: [ka] is a single or double bond; [ka] is a single bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, -B(OR b )2, -SC 1~6 Alkyl, -S-aryl, -O-aryl, or C(O)R a and; [ka] is a double bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, or C(O)R a and; R a is hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R btogether form a boronic acid protecting group; R 3 is OR 4 or R 10 and; R 10 is a nucleobase or nucleobase derivative; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; or R who joined together 4 and R 5 is a diol protecting group; or R who joined together 5 and R 6 is a diol protecting group, or a salt or solvate thereof.

[0018] In another aspect, the present invention provides a compound of formula (E): [ka] [In the formula, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) mOR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; x is 0, 1, or 2; m is 0 or 1; R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or a nucleobase derivative], However, if the compound is: [ka] [In the formula, R 5 is hydrogen or -C(=O)-C 1~4 is alkyl; R6 is hydrogen or -C(=O)-C 1~4 is alkyl; or R who joined together 5 and R 6 is -C(CH3)2-, Y is -O- or -CH2-; R 10 teeth, [ka] and Q 1 is CR 6a and; Q 2 is N or CR 6b and; R 6a and R 6b are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 represents alkyl; R 3a -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 cycloalkyl, -OH, or -OC 1~4 is alkyl; R 7a is hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 is alkyl; R 4a -NR 8a R 8b , or C 1~4 is alkyl; R x teeth, [ka] is] or a salt or solvate thereof, provided that the compound is not any compound of the formula (I) or a salt or solvate thereof.

[0019] In another aspect, the present invention provides a compound of formula (H): [ka] [In the formula, R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or nucleobase derivative], or a salt or solvate thereof.

[0020] The present invention will now be further described. In the following sections, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect, unless otherwise expressly stated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous. DETAILED DESCRIPTION OF THE INVENTION

[0021] When describing the compounds of the present invention, the terms used shall be construed in accordance with the following definitions, unless otherwise specified.

[0022] When any variable occurs more than one time in any constituent or in any formula, its definition at each occurrence is independent of its definition at every other occurrence.

[0023] Whenever the term "substituted" is used in this invention, unless otherwise specified or clear from the context, it indicates that one or more hydrogens, particularly 1 to 3 hydrogens, preferably 1 to 2 hydrogens, more preferably 1 hydrogen, of the atom or group designated by the term "substituted" have been replaced with one selected from the designated group, provided that the normal valence is not exceeded and the substitution results in a chemically stable compound, i.e., a compound sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into a therapeutic agent.

[0024] When two or more substituents are present on a moiety, unless otherwise stated or apparent from the context, the substituents may replace hydrogen atoms on the same atom or may replace hydrogen atoms on different atoms of the moiety.

[0025] The prefix "C x~y " (where x and y are integers) as used herein refers to the number of carbon atoms in a given group. Thus, C 1~4 The alkyl group contains 1 to 4 carbon atoms, and 1~3 An alkyl group may contain 1 to 3 carbon atoms, and so on.

[0026] The term "halo" as a group or part of a group is intended to refer generically to fluoro, chloro, bromo, and iodo, unless otherwise stated or clear from the context.

[0027] For example, "C" as a group or part of a group 1~6 The term "alkyl" refers to a group of the formula C n H 2n+1 [wherein n is a number ranging from 1 to 6]. 1~6 The alkyl group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, and more preferably 1 to 2 carbon atoms. 1~6 Alkyl, C 1~4 Alkyl, and C 1~3Alkyl may be straight or branched chain and may be substituted as indicated herein. When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the group may contain.

[0028] C 1~6 Alkyl includes all straight or branched chain alkyl groups having 1 to 6 carbon atoms and thus includes methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), pentyl and its isomers, and hexyl and its isomers, etc.

[0029] Those skilled in the art will be able to identify suitable -OC 1~4 It will be recognized that non-limiting examples of alkyl include methyloxy (also called methoxy), ethyloxy (also called ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

[0030] "C 2~4 The term "alkenyl" as used herein as a group or part of a group refers to a straight or branched chain hydrocarbon group containing a carbon-carbon double bond, containing 2 to 4 carbon atoms, such as, but not limited to, ethenyl, propenyl, butenyl, 1-propen-2-yl, etc.

[0031] "C 3~6 The term "cycloalkyl" as used herein as a group or part of a group refers to a cyclic saturated hydrocarbon group having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0032] The term "aryl" as used herein as a group or part of a group refers to a monocyclic or bicyclic aromatic ring system having 6 to 14 carbon atoms (i.e., C 6~14aryl). Non-limiting exemplary aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl. Aryl is preferably selected from phenyl or naphthyl, more preferably phenyl.

[0033] Whenever a substituent is represented by a chemical structure, "---" represents the bond to the remainder of the molecule.

[0034] Some of the compounds of the present invention may also exist in tautomeric forms. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0035] To the extent that such forms can exist, they are intended to be included within the scope of the present invention even though they are not explicitly indicated in formulas herein.

[0036] As used herein, any chemical formula having bonds shown only as solid lines, and not as solid or dashed wedge bonds, or any chemical formula otherwise shown as having a particular configuration (e.g., R, S) about one or more atoms, contemplates each possible stereoisomer or mixture of two or more stereoisomers. When the stereochemistry of any particular chiral atom is not specified in the structures shown herein, all stereoisomers are contemplated and encompassed as compounds of the invention, either as pure stereoisomers or as mixtures of two or more stereoisomers.

[0037] The compounds described herein include their stereoisomers and tautomeric forms. However, as described in the previous paragraph, when stereochemistry is specified by a bond shown as a solid wedge or dashed wedge bond, or otherwise shown as having a particular configuration (e.g., R, S), the stereoisomer is so specified and defined. Furthermore, when a bond is shown as a wavy bond, unless otherwise defined, this means that the stereochemical configuration at the stereocenter is a mixture of stereoisomers. It will be apparent that this also applies to subgroups of formulae herein.

[0038] It follows that a compound may exist in both stereoisomeric and tautomeric forms, where this is possible.

[0039] The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably above and below.

[0040] Enantiomers are stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.

[0041] Atropisomers (or atropoisomers) are stereoisomers with a specific spatial configuration resulting from restricted rotation about a single bond due to significant steric hindrance. All atropisomeric forms of the compounds described herein are intended to be included within the scope of the present invention.

[0042] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers, i.e., not mirror-image related. When a compound contains a double bond, the substituent can be in the E or Z configuration. Substituents on a divalent cyclic (partially) saturated group can have the cis or trans configuration; for example, when a compound contains a disubstituted cycloalkyl group, the substituent can be in the cis or trans configuration. Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, whenever chemically possible.

[0043] The meanings of all the terms, i.e. enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, are known to those skilled in the art.

[0044] Absolute configuration is specified according to the Cahn-Ingold-Prelog rules. The configuration at asymmetric atoms is specified by either R or S. Resolved stereoisomers of unknown absolute configuration can be designated as (+) or (-), depending on the direction they rotate plane-polarized light. For example, resolved enantiomers of unknown absolute configuration can be designated by (+) or (-) depending on the direction they rotate plane-polarized light.

[0045] For example: [ka] teeth, [ka] This shows a mixture of

[0046] Unless the context dictates otherwise, for example, formula (A) [ka] The compound of [ka] It should be understood that the expression can be expressed as:

[0047] All stereochemically possible configurations are encompassed by these structures.

[0048] Unless the context dictates otherwise, for example, formula (A) [ka] The compound [ka] It should be understood that the term "compound" encompasses any of the compounds of the present invention or mixtures thereof.

[0049] Those skilled in the art will understand that this also generally applies to any other generic formulas of spiro bicyclic nucleoside analogs (including cyclopentane-containing nucleoside analogs) described in this application, unless the context dictates otherwise. Unless the context dictates otherwise, all such forms are included in the generic formula where one possible form is described. All such forms are intended to be included within the scope of the present invention.

[0050] Also, the structure: [ka] Any compound described herein containing the following stereochemistry: [ka] or a mixture of any one or more of these stereochemistries. 4is a nucleic acid base or a nucleic acid base derivative.

[0051] When a specific stereoisomer is identified, this means that the stereoisomer is substantially free of other isomers, i.e., with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2%, and most preferably less than 1% of other isomers. Thus, for example, if a compound is specified as (R), this means that the compound is substantially free of (S) isomers; if a compound is specified as, for example, E, this means that the compound is substantially free of Z isomers; and if a compound is specified as, for example, cis, this means that the compound is substantially free of trans isomers. Stereoisomers may be separated using techniques known in the art, such as chromatographic methods. Functionalization, for example, the introduction of a suitable protecting group such as benzoate (BzCl, pyridine, dichloromethane, etc.), may aid in the separation of stereoisomers using silica gel chromatography, reverse-phase chromatography, or supercritical fluid (SFC) chromatography.

[0052] Salts of the compounds described herein and solvates thereof may be those in which the counterion is pharmaceutically acceptable. Salts of acids and bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are within the scope of the present invention.

[0053] Pharmaceutically acceptable salts include acid addition salts and base addition salts.Such salts can be produced by conventional means, for example, by reacting the free acid or free base form with a suitable acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removing the solvent or medium by standard methods (for example, in vacuo, by lyophilization, or by filtration).Salts can also be prepared by exchanging the counterion of the compound of the present invention in the form of a salt with another counterion, for example, using a suitable ion exchange resin.

[0054] Pharmaceutically acceptable addition salts, as mentioned above or below, are intended to include the therapeutically active non-toxic acid and base addition salt forms which the compounds and their solvates are able to produce.

[0055] Suitable acids include, for example, inorganic acids, such as hydrohalic acids, e.g., hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids, such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc. Conversely, the above salt forms can be converted to the free base form by treatment with an appropriate base.

[0056] The compounds containing acidic protons and their solvates can also be converted into their non-toxic metal addition salt or amine addition salt forms by treatment with appropriate organic and inorganic bases.

[0057] Suitable base salt forms include, for example, ammonium salts, alkali metal salts and alkaline earth metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, and the like, salts with organic bases such as primary, secondary and tertiary, aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; benzathine salts, N-methyl-D-glucamine salts, hydrabamine salts, and salts with amino acids such as arginine, lysine, and the like. Conversely, salt forms can be converted to the free acid forms by treatment with acid.

[0058] The term solvates comprises the hydrates and solvent addition forms that the compounds of the present invention are able to form as well as their salts. Examples of such forms are, for example, hydrates, alcoholates, etc.

[0059] The compounds of the present invention prepared by the methods described below may be synthesized in the form of a mixture of enantiomers, particularly a racemic mixture of enantiomers that can be separated from each other according to resolution methods known in the art. Separation methods for the enantiomeric forms of the compounds, as well as their salts and solvates, include liquid chromatography using chiral stationary phases. The pure stereochemical isomers can also be derived from the corresponding pure stereochemical isomers of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound will be synthesized by a stereospecific preparation method. These methods advantageously use enantiomerically pure starting materials.

[0060] The present invention also encompasses isotopically labeled compounds of the present invention that are identical to the compounds described herein except for the replacement of one or more atoms by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature (or the most abundant one found in nature).

[0061] All isotopes and isotopic mixtures of any particular atom or element identified herein, whether naturally occurring, synthetically produced, naturally abundant, or isotopically enriched, are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S,18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Preferably, the radioisotope is 2 H, 3 H, 11 C, and 18 F. More preferably, the radioisotope is selected from the group 2 H. Deuterated compounds are specifically intended to be included within the scope of the present invention.

[0062] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) are useful for substrate tissue distribution assays. Tritiated isotopes ( 3 H) and carbon-14 isotopes ( 14 C) are useful due to their ease of preparation and detectability. 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred. For example, 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0063] The protecting group referred to herein may be any suitable hydroxyl protecting group. Suitable protecting groups are known in the art, for example, from Wuts, P.G.M. and Greene, T.W.: Protective Groups in Organic Synthesis, Fourth Edition, Wiley, New York, 2006. For example, hydroxyl protecting groups include silyl groups, C 1~4 Alkyl, C1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, or benzoyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; where benzyl, —CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from —CH3 and —OCH3.

[0064] Silyl groups referred to herein may be, for example, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl, or triethylsilyl.

[0065] Diol protecting groups include, for example, -C(C 1~4 The stereochemistry of the compound may be -OR (e.g., -C(CH)-). 4 and -OR 5 In the case where R is in the cis configuration, 4 and R 5 It will be understood by those skilled in the art that -OR can be taken together to form a diol protecting group. Similarly, the stereochemistry of the compound can be determined by -OR 5 and -OR 6 In the case where R is in the cis configuration, 5 and R 6 It will be understood by those skilled in the art that can be taken together to form a diol protecting group.

[0066] The boronic acid protecting group may be, for example, catecholborane, pinacolborane, N-methyliminodiacetic acid (MIDA) boronate, neopentylglycolborane, pinanediolborane, biscyclohexyldiolborane, or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol (MPMP-diol)borane.

[0067] The amino protecting group may be, for example, benzoyl (Bz), tert-butyloxycarbonyl (Boc), benzyl (Bn), acetyl (Ac), diphenylcarbamoyl, benzyloxycarbonyl (cbz), fluorenylmethyloxycarbonyl (Fmoc), CF3C(O)-, trityl (trt), phthaloyl (phth), or =CHN(CH3)2.

[0068] Nucleobases or nucleobase derivatives referred to herein encompass both pyrimidine and purine nitrogenous bases, including modified and protected forms thereof. For example, nucleobases referred to herein include, but are not limited to, adenine, cytosine, guanine, thymine, 6-chloropurine, uracil, adenine, 7-methylguanine, xanthine, hypoxanthine, purine, 2,6-diaminopurine, 5,6-dihydrouracil, 6,8-diaminopurine, inosine, 5-methylcytosine, and 5-hydroxymethylcytosine. A modified or protected nucleobase may be, for example, one in which an amino-protecting group (e.g., benzoyl (Bz), tert-butyloxycarbonyl (Boc), benzyl (Bn), acetyl (Ac), diphenylcarbamoyl, benzyloxycarbonyl (cbz), fluorenylmethyloxycarbonyl (Fmoc), CF3C(O)-, trityl (trt), phthaloyl (phth), or =CHN(CH3)2) is present, or the amino (-NH2) group is replaced with halo (e.g., chloro). Such modified or protected nucleobases may also be referred to as nucleobase precursors. By way of example, the nucleobases or nucleobase derivatives referred to herein may include any purine or pyrimidine nitrogenous base, such as any of the nucleobases referenced above, where one or more substituents R are present on the heteroaryl core of the nitrogenous base in place of hydrogen or another substituent moiety, and R includes, but is not limited to, halo, -NR * R ** , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, -OH, -OC 1~4C substituted with alkyl, 1, 2, or 3 halo atoms 1~4 alkyl, where R * is hydrogen, C 1~4 Alkyl, or -C(O)OC 1~4 alkyl, and R ** is hydrogen, C 3~6 Cycloalkyl, C 1~4 alkyl, or -C(O)OC 1~4 It is alkyl.

[0069] "TBDPS" means tert-butyldiphenylsilyl; "Piv" means pivaloyl; "Bn" means benzyl; "Et" means ethyl; "Me" means methyl; "PMB" means p-methoxybenzyl, "TMS" means trimethylsilyl; "tBu-O" means tert-butoxy; and "Pr" means n-propyl.

[0070] In one aspect, the present invention provides a compound of formula (I): [ka] [In the formula, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 3 -OR 4 or R 10 and; R 10 is a nucleobase or nucleobase derivative; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group], however, (a) a compound of the formula [ka] wherein Y is —O— or —CH—; 4 is a hydrogen or hydroxyl protecting group, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each independently -C(=O)-C 1~4 alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 alkyl)2-; or wherein Y is -O- or -CH2, and R 4 is methyl and R 2 is ═O or ═CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1~4 alkyl] compounds; (b) the compound has the formula [ka] [In the formula, R v is =O, -OH, or =CH2; (c) the compound has the formula [ka] [In the formula, R w is methyl or H], but not compounds of the formula: (d) the compound has the formula [ka] wherein R is CO2Et or CH2OH or any stereoisomer thereof; (e) The compound is: [ka] [In the formula, R 5 is hydrogen or -C(=O)-C 1~4 is alkyl; R 6 is hydrogen or -C(=O)-C 1~4 alkyl; or R together 5 and R 6 is -C(CH3)2-, Y is -O- or -CH2-; R 10 teeth, [ka] and Q 1 is CR 6a and; Q 2 is N or CR 6b and; R 6a and R 6b are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9aand R 9b are each independently hydrogen or C 1~4 represents alkyl; R 3a -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 cycloalkyl, -OH, or -OC 1~4 is alkyl; R 7a is hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 is alkyl; R 4a -NR 8a R 8b , or C 1~4 is alkyl; R x teeth, [ka] is] or a salt or solvate thereof, provided that the compound is not any compound of the formula (I) or a salt or solvate thereof.

[0071] In one aspect, the present invention provides a compound of formula (A): [ka] [In the formula, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NRa 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x Rc or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group], however, (a) a compound of the formula [ka] wherein Y is —O— or —CH—; 4 is a hydrogen or hydroxyl protecting group, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each independently -C(=O)-C 1~4 alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 alkyl)2-; or wherein Y is -O- or -CH2, and R 4 is methyl and R 2 is ═O or ═CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1~4 alkyl] compounds; (b) the compound has the formula [ka] [In the formula, R v is =O, -OH, or =CH2; (c) the compound has the formula [ka] [In the formula, R w is methyl or H], but not compounds of the formula: (d) the compound has the formula [ka] wherein R is CO2Et or CH2OH, or any stereoisomer thereof, provided that the compound or a salt or solvate thereof is not a compound of the formula:

[0072] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula: [ka] wherein Y is —O— or —CH—; 4 is any chemical moiety, and R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each independently -C(=O)-C 1~4 alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 alkyl)2-, or wherein R 4 is methyl, R 2 is ═O or ═CH2, and R 5 and R6 are each independently hydrogen or -C(=O)-C 1~4 It is not a compound of the formula [which is alkyl].

[0073] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula: [ka] or a salt or solvate thereof.

[0074] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula: [ka] or a salt or solvate thereof.

[0075] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula (A-1), (A-2), (A-3), (A-4), (A-5), or (A-6): [ka] or a salt or solvate thereof.

[0076] In one embodiment, the invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), or (A-6a): [ka] or a salt or solvate thereof.

[0077] In one embodiment, the invention relates to compounds of formula (A) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound has the formula (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b): [ka] or a salt or solvate thereof.

[0078] In one embodiment, the present invention relates to compounds of Formula (I) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown for compounds of any of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0079] In one embodiment, the invention relates to compounds of any of (A-1a), (A-3a), (A-1b), or (A-3b), and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein.

[0080] In one embodiment, the invention relates to any of compounds (A-1a), (A-3a), (A-5a), (A-1b), (A-3b), or (A-5b), and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein.

[0081] In one embodiment, the present invention relates to compounds of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 is alkyl; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group, while provided that the compound has the formula: [ka] [In the formula, R w is methyl or H; or [ka] wherein R is CO2Et or CH2OH, or any stereoisomer thereof.

[0082] In one embodiment, the present invention relates to compounds of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) mS(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -OR a , -OPG, -(CH2)C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group, while however, (a) a compound of the formula [ka] wherein Y is —O— or —CH—; 4 is a hydrogen or hydroxyl protecting group, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each independently -C(=O)-C 1~4alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 alkyl)2-; or wherein Y is -O- or -CH2, and R 4 is methyl and R 2 is ═O or ═CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1~4 alkyl] compounds; (b) the compound has the formula [ka] [In the formula, R v is =O, -OH, or =CH2.

[0083] In one embodiment, the present invention relates to a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, wherein: Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) mB(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 is alkyl; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -OR a , -OPG, -(CH2)C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; PG is a hydroxyl protecting group; m is 0 or 1; x is 0, 1, or 2; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group.

[0084] In one embodiment, the present invention relates to compounds of any of formula (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein.

[0085] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1.

[0086] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1; 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2)m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a It is 2.

[0087] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -C(O)OR a , -C(O)NR a 2. -C(O)R a , -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6Alkyl, =O, or =CR a 2; or R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -C(O)OR a , -C(O)NR a 2. -C(O)R a , -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a It is 2.

[0088] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -C(O)OR a , -C(O)NR a 2. -C(O)R a , =O, or =CR a 2;R 2 is hydrogen.

[0089] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is -NH, -CHNH, -OH, -CHOH, =O, or =; R 2 is hydrogen.

[0090] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is -OH, -CHOH, =O, or =; R 2 is hydrogen.

[0091] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is hydrogen; R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -C(O)ORa , -C(O)NR a 2. -C(O)R a , =O, or =CR a It is 2.

[0092] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 2 is -NH, -CHNH, -OH, -CHOH, =O, or =; R 1 is hydrogen.

[0093] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 2 is -OH, -CHOH, =O, or =; R 1 is hydrogen.

[0094] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is hydrogen; R 2 is -(CH2) m NR a 2 or -C(O)NR a It is 2.

[0095] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 2 is -NH2 or -CH2NH2; R 1 is hydrogen.

[0096] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 and R 2 One of the groups is hydrogen and the other is -NR a 2, -CH2NR a 2, -ORa , -CH2OR a , -C(O)OR a , -C(O)R a , S(O) x R c , =O, or =CR a It is 2.

[0097] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 and R 2 One of the groups is hydrogen and the other is -NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C(O)OR a , =O, or =CR a It is 2.

[0098] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is -NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C(O)OR a , -C(O)R a , -B(OR b )2, S(O) xR c , =O, or =CR a 2;R 2 is hydrogen.

[0099] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1 and R 1 is hydrogen; R 2 is -NR a 2, -CH2NR a 2. -CH2OR a , -C(O)R a , -B(OR b )2, S(O) x R c , -C(O)OR d , -OR d , or =C(R a )(R d ) and R a is hydrogen or C 1~6 alkyl; R d is C 1~6 It is alkyl.

[0100] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0.

[0101] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, or =CH2.

[0102] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of them is hydrogen and the other is - -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -C(O)OR a , -C(O)NR a 2, or -B(ORb )2.

[0103] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of the groups is hydrogen and the other is -CHNR a 2, -OR a , -CH2OR a , -C(O)OR a , -C(O)R a , -B(OR b )2, or =CH2.

[0104] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of the groups is hydrogen and the other is -CHNR a 2, -OR a , -CH2OR a , -C(O)OR a , or -B(OR b )2.

[0105] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of the groups is hydrogen and the other is —OH, —CH 2 OH, —CH 2 NH 2 , —C(O)OH, or C(O)OEt.

[0106] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0 and R 1 and R 2 One of the groups is hydrogen and the other is —OH or —CH 2 NH 2 .

[0107] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein, if present, —(CH) m NR a 2 is -(CH2) m NHC 1~6 Alkyl or -(CH2) mIt is NH2.

[0108] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 1 or R 2 -(CH2) m In the case of OPG, PG is a silyl group, —C(═O)—C 1~4 alkyl, or -C(=O)-phenyl.

[0109] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R a is H, methyl, ethyl, or propyl.

[0110] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein, if present, —NR a 2 is -NHR a is.

[0111] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein, if present, —NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C(O)OR a , -C(O)R a , -S(O) x R c , and =CR a 2 are -NH2, -CH2NH2, -OH, -CH2OH, and -C(O)OC, respectively. 1~6 Alkyl, -C(O)-C 1~6 Alkyl, -SR c , and =CH2.

[0112] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein Y is O.

[0113] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein Y is CH.

[0114] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group, or R 5 and R 6 When is in the cis configuration, R 5 and R 6 may optionally be taken together to form a diol protecting group, or R 4 and R 5 When is in the cis configuration, R 4 and R 5 may optionally be taken together to form a diol protecting group.

[0115] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein the hydroxyl protecting group is selected from the group consisting of silyl groups, C 1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1~4 alkyl, or —C(═O)-phenyl; wherein benzyl, —CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from —CH3 and —OCH3; and / or the diol protecting group is —C(C 1~4 alkyl)2-.

[0116] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) and salts and solvates thereof, for example, compounds of any of formula (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) or salts or solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 is hydrogen or a silyl group, C 1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -C(=O)-C 1~4 alkyl, or a hydroxyl protecting group such as -C(=O)-phenyl (wherein benzyl is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); R 5 and R 6is -C(=O)-C 1~4 a hydroxyl protecting group such as alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzoyl, benzyl, and -CH2-naphthyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 5 and R 6 is -C(C 1~4 Diol protecting groups such as alkyl2-.

[0117] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) and salts and solvates thereof, for example, compounds of any of formula (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) or salts or solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 is a silyl group or C 1~4 alkyl (preferably Me); R 5 and R 6 is -C(=O)-C 1~4 alkyl (preferably pivaloyl); or R 5 and R 6 is the diol protecting group -C(C 1~4 alkyl)2- (preferably -C(CH3)2-).

[0118] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b) and salts and solvates thereof, for example, compounds of formula (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b) or a salt or solvate thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4and R 5 is a silyl group, C 1~4 Alkyl, -C(=O)-C 1~4 a hydroxyl protecting group such as alkyl, benzoyl, benzyl, or -CH2-naphthyl (wherein benzoyl, benzyl, and -CH2-naphthyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3); or R 4 and R 5 is -C(C 1~4 a diol protecting group such as alkyl; 6 is hydrogen or a silyl group, C 1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, -C(=O)-C 1~4 alkyl, or a hydroxyl protecting group such as -C(=O)-phenyl (wherein benzyl is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3).

[0119] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b) and salts and solvates thereof, such as compounds of any of formula (A-3), (A-3a), or (A-3b) or salts or solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 and R 5 is -C(=O)-C 1~4 a hydroxyl protecting group such as alkyl, benzoyl, benzyl, or -CH-naphthyl, 2-naphthyl (wherein benzoyl, benzyl, and -CH-naphthyl are optionally substituted with one or two substituents each independently selected from -CH and -OCH); or R taken together 4 and R 5 is -C(C 1~4a diol protecting group such as alkyl; 6 is hydrogen or a silyl group, C 1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, -C(=O)-C 1~4 alkyl, or a hydroxyl protecting group such as -C(=O)-phenyl (wherein benzyl is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3).

[0120] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-3), (A-3a), (A-3b), and salts and solvates thereof, such as compounds of any of formula (A-3), (A-3a), or (A-3b), or a salt or solvate thereof, or any subgroup thereof as described in any other embodiment herein, wherein R taken together 4 and R 5 is the diol protecting group -C(C 1~4 alkyl)2- (preferably -C(CH3)2-); R 6 is a silyl group, benzyl, -CH2-naphthyl, or -C(=O)-C 1~4 alkyl, where benzyl is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0121] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-4), (A-4a), (A-4b), (A-6), (A-6a), or (A-6b) and salts and solvates thereof, for example, compounds of any of formula (A-4), (A-4a), (A-4b), (A-6), (A-6a), or (A-6b) or a salt or solvate thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 , R 5 , and R 6 are each independently hydrogen or a silyl group, C1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1~4 and a hydroxyl protecting group selected from alkyl, or -C(=O)-phenyl (wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3).

[0122] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-1), (A-1a), or (A-1b) and salts and solvates thereof, such as compounds of any of formula (A-1), (A-1a), or (A-1b) or salts or solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 4 is C such as methyl 1~4 alkyl and together with R 5 and R 6 is -C(CH3)2-, etc. 1~4 alkyl)2-.

[0123] In one embodiment, the present invention relates to compounds of any of formula (I), (A), (Aa), (Ab), (A-3), (A-3a), or (A-3b), and salts and solvates thereof, such as compounds of any of formula (A-3), (A-3a), or (A-3b), or a salt or solvate thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 6 is a silyl group, benzyl, -CH2-naphthyl, benzoyl, or -C(=O)-C 1~4 alkyl, wherein benzyl, -CH2-naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3, and together R 5 and R 6 is -C(CH3)2-, etc. 1~4alkyl)2-.

[0124] In one embodiment, the present invention provides: [ka] [ka] [ka] [ka] or a salt or solvate thereof.

[0125] In another aspect, the present invention provides a compound of formula (B): [ka] [In the formula, Y is -O- or -CH2-; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; Or together R 5 and R 6 is a diol protecting group; Or together R 4 and R 5 is a diol protecting group, or a salt or solvate thereof.

[0126] In one embodiment, the present invention relates to compounds of formula (B) and salts and solvates thereof, wherein Y, R 4 , R 5 , and R 6is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0127] In one embodiment, the present invention relates to compounds of Formula (B) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown for compounds of any of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0128] In one embodiment, the present invention provides: [ka] or a salt or solvate thereof.

[0129] In another aspect, the present invention provides a compound of formula (C): [ka] [In the formula, Y is -O- or -CH2-; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; or R who joined together 4 and R 5 is a diol protecting group; or R who joined together 5 and R 6 is a diol protecting group], However, the compound is [ka] provided that the compound is not

[0130] In one embodiment, the present invention relates to compounds of formula (B) and salts and solvates thereof, wherein Y, R 4 , R 5 , and R 6 is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0131] In one embodiment, the present invention relates to compounds of Formula (B) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown for compounds of any of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0132] In one embodiment, the present invention relates to compounds of formula (C) and salts and solvates thereof, or any subgroup thereof as described in any of the other embodiments herein, wherein the compound is: [ka] or a salt or solvate thereof.

[0133] In one embodiment, the present invention relates to compounds of formula (C) and salts and solvates thereof, wherein the compound is: [ka] or a salt or solvate thereof.

[0134] In another aspect, the present invention provides a compound of formula (D): [ka] [In the formula, Y is -O- or -CH2-; where: [ka] is a single or double bond; [ka] is a single bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, -B(OR b )2-SC 1~6 Alkyl, -S-aryl, -O-aryl, or C(O)R a and; [ka] is a double bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, or C(O)R a and; R a is hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R 3 is OR 4 or R 10 and; R 10 is a nucleobase or nucleobase derivative; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; or R who joined together 4 and R 5 is a diol protecting group; or R who joined together 5 and R 6 is a diol protecting group, or a salt or solvate thereof.

[0135] In one embodiment, the present invention relates to compounds of formula (D), and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: Y is -O- or -CH2-; where: [ka] is a single or double bond; [ka] is a single bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, -B(OR b )2-SC 1~6 Alkyl, -S-aryl, -O-aryl, or C(O)R a and; [ka] is a double bond, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, or C(O)R a and; R a is hydrogen or C 1~6 is alkyl; Each R b is hydrogen, or both R b together form a boronic acid protecting group; R 3 is OR 4 or R 10 and; R 10 is a nucleobase or nucleobase derivative; R 4 , R 5 , and R 6 are each independently hydrogen or a hydroxyl protecting group; or R who joined together 4 and R 5 is a diol protecting group; or R who joined together 5 and R 6 is a diol protecting group.

[0136] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 3 is OR 4 is.

[0137] In one embodiment, the invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein the silyl group, if present, is trimethylsilyl, triethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, or dimethylphenylsilyl.

[0138] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: [ka] is a single bond.

[0139] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: [ka] is a double bond.

[0140] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: [ka] is a single bond, and R 1’ and R 2’ one of which is hydrogen, and the other is a silyl group, a C1 alkyl substituted with a silyl group, -OC 1~6 alkyl, or -S-aryl.

[0141] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: [ka] is a double bond and R 1’ and R 2’ one of which is hydrogen or methyl, and the other is a silyl group, a C1 alkyl substituted with a silyl group, -OC 1~6 alkyl, or -S-aryl.

[0142] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 1’ and R 2’ One of them is C 1~6 alkyl, and R 1’ and R 2’ The other of these is C 1~6 Not alkyl or hydrogen.

[0143] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 1’ and R 2’ is hydrogen, and R 1’ and R 2’ The other of these is C 1~6 Not alkyl or hydrogen.

[0144] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, wherein Y, R 4 , R 5 , and R 6 is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0145] In one embodiment, the present invention relates to compounds of Formula (D) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown for compounds of any of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0146] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, wherein the compound is: [ka] or a salt or solvate thereof.

[0147] In another aspect, the present invention provides a compound of formula (E): [ka] [In the formula, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NRa 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Both R b is hydrogen, or both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; x is 0, 1, or 2; m is 0 or 1; R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or nucleobase derivative; PG is a hydroxyl protecting group], However, if the compound is: [ka] [In the formula, R5 is hydrogen or -C(=O)-C 1~4 is alkyl; R 6 is hydrogen or -C(=O)-C 1~4 alkyl; or R together 5 and R 6 is -C(CH3)2-, Y is -O- or -CH2-; R 10 teeth, [ka] and Q 1 is CR 6a and; Q 2 is N or CR 6b and; R 6a and R 6b are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 represents alkyl; R 3a -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 cycloalkyl, -OH, or -OC 1~4 is alkyl; R 7a is hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 is alkyl; R 4a -NR 8a R 8b , or C1~4 is alkyl; R x teeth, [ka] The present invention relates to a compound, or a salt or solvate thereof, which is not one of the following:

[0148] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein: Y is -O- or -CH2-; n is 0 or 1, If n is 1, R 1 is hydrogen and R 2 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a 2; or If n is 1, R 2 is hydrogen and R 1 is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a, -(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, silyl-substituted C 1~6 Alkyl, -O-aryl, ═O, or ═CR a 2 and; If n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; where R 1 or R 2 Binding to [ka] is R 1 or R 2 is hydrogen, -(CH2) m NR a 2, -(CH2) m OR a , -(CH2) m OPG, -(CH2) m C(O)OR a , -(CH2) m C(O)NR a 2, -(CH2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x Rc , silyl group, silyl-substituted C 1~6 When R is alkyl or -O-aryl, it is a single bond or R 1 or R 2 is =O, =CH2, or =CR a If it is 2, it is a double bond; Each R a are independently hydrogen or C 1~6 is alkyl; Both R b together form a boronic acid protecting group; R c is C 1~6 is alkyl or aryl; x is 0, 1, or 2; m is 0 or 1; R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or nucleobase derivative; PG is a hydroxyl protecting group, However, if the compound is: [ka] [In the formula, R 5 is hydrogen or -C(=O)-C 1~4 is alkyl; R 6 is hydrogen or -C(=O)-C 1~4 alkyl; or R together 5 and R 6 is -C(CH3)2-, Y is -O- or -CH2-; R 10 teeth, [ka] and Q 1 is CR 6a and; Q 2 is N or CR 6b and; R 6a and R 6b are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 represents alkyl; R 3a -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 cycloalkyl, -OH, or -OC 1~4 is alkyl; R 7a is hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 is alkyl; R 4a -NR 8a R 8b , or C 1~4 is alkyl; R x teeth, [ka] is neither of the above.

[0149] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 1.

[0150] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein n is 0.

[0151] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein Y is O.

[0152] and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein Y is CH2.

[0153] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein R 1 and R 2 is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0154] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein Y, R 4 , R 5 , and R 6 is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0155] In one embodiment, the present invention relates to compounds of Formula (E) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown in any of the following structures, for example, as shown for compounds of any of Formulas (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b); [ka]

[0156] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein, if present, -NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C(O)OR a , -C(O)R a , -S(O) x R c , =CR a 2 are -NH2, -CH2NH2, -OH, -CH2OH, and -C(O)OC, respectively. 1~6 Alkyl, -C(O)-C 1~6 Alkyl, -SR c , =CH2.

[0157] Y, n, R are defined for any compound of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any of the other embodiments herein. 1 , R 2 , R 5 , and R 6It will be understood that all definitions of are applicable to compounds of formula (E) and salts and solvates thereof. Accordingly, in one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein Y, n, R 1 , R 2 , R 5 , and R 6 and any one or more of are as defined for a compound of any of formula (I), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0158] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, or any subgroup thereof as described in any other embodiment herein, wherein R 5 and R 6 are each independently hydrogen or -C(=O)-C 1~4 alkyl or R together 5 and R 6 is -C(CH3)2-, etc. 1~4 alkyl)2-.

[0159] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is: [ka] [ka] or a salt or solvate thereof.

[0160] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is: [ka] or a salt or solvate thereof.

[0161] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is: [ka] [ka] or a salt or solvate thereof.

[0162] In another aspect, the present invention provides a compound of formula (F): [ka] [In the formula, R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or nucleobase derivative], or a salt or solvate thereof.

[0163] In one embodiment, the present invention relates to compounds of formula (F) and salts and solvates thereof, wherein R 4 , R 5 , and R 6is as defined for a compound of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof as described in any other embodiment herein.

[0164] In one embodiment, the present invention relates to compounds of Formula (F) and salts and solvates thereof, wherein the compounds have the stereochemistry as shown for compounds of any of Formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0165] In one embodiment, the invention relates to compounds of any of Formulae (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), (A-6b), (B), (C), (D), (E), and (F) and salts and solvates thereof or any subgroup thereof as described in any other embodiment herein, wherein a silyl group, if present, is t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl, or triethylsilyl.

[0166] In one embodiment, the present invention relates to compounds of any of formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), (A-6b), (B), (C), (D), (E), and (F) and salts and solvates thereof or any subgroup thereof as described in any other embodiment herein, wherein, if present, -B(OR b )2 is catecholborane, pinacolborane, N-methyliminodiacetic acid (MIDA) boronate, neopentyl glycol borane, pinanediol borane, biscyclohexyldiol borane, or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol (MPMP-diol) borane.

[0167] In one embodiment, the present invention relates to a compound of any of formulas (D), (E), and (F), wherein, if present, R 10 is cytosine, thymine, uracil, or modified or protected forms thereof, or (a-1), (a-2), (a-3), (a-4), and (a-5): [ka] and a bicyclic aromatic heterocyclic ring system selected from the group consisting of: In the formula, R 3a , R 3b , R 3c , R 3d , and R 3e are each independently hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, -OH, or -OC 1~4 and; R 7a is hydrogen, -C(O)OC 1~4 alkyl, or [ka] and; R 7b is hydrogen, C 3~6 Cycloalkyl, C 1~4 Alkyl, or -C(O)OC 1~4 is alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , and R 4g are each independently hydrogen, halo, -NR 8a R 8b , or C 1~4 is alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 is alkyl; Q 1 is N or CR 6a and; Q 2 is N or CR 6b and; Q 3 is N or CR 6c and; Q 4 is N or CR 6d Although; However, Q 3 and Q 4 subject to the condition that the largest of is N; Q 8 is N or CR 6g and; Q 9 is N or CR 6h and; Q 10 is N or CR 6i and; Q 11 is N or CR 6j and; Q 5 is CR 3d and;Q 6 is N;Q7 is CR 4f or Q 5 is CR 3d and;Q 6 is CR 4e and;Q 7 is N; or Q 5 is N;Q 6 is CR 4e and;Q 7 is CR 4f or Q 5 is N;Q 6 is CR 4e and;Q 7 is N; or Q 5 is N;Q 6 is N;Q 7 is CR 4f or Q 5 is N;Q 6 is N;Q 7 is N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , and R 6j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 is alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 It is alkyl.

[0168] In one embodiment, the present invention relates to a compound of any of formulas (D), (E), and (F), wherein, if present, R 10is cytosine, thymine, uracil, or modified or protected forms thereof, or (a-1), (a-2), (a-3), (a-4), and (a-5): [ka] and a bicyclic aromatic heterocyclic ring system selected from the group consisting of: In the formula, R 3a , R 3b , R 3c , R 3d , and R 3e are each independently hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, -OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , and R 4g are each independently hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is N or CR 6a represents; Q 2 is N or CR 6b represents; Q 3 is N or CR 6c represents; Q 4is N or CR 6d Although it represents; However, Q 3 and Q 4 Provided that the largest of denotes N; Q 8 is N or CR 6g represents; Q 9 is N or CR 6h represents; Q 10 is N or CR 6i represents; Q 11 is N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N; Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N; Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N; Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N; Q 6 represents N; Q 7 is CR 4f represents; or Q 5 represents N; Q 6 represents N; Q 7 represents N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R6i , and R 6j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 Represents alkyl.

[0169] In one embodiment, the present invention relates to a compound of any of formulas (D), (E), and (F), wherein, if present, R 10 is cytosine, thymine, uracil, or modified or protected forms thereof, or (a-1), (a-2), (a-3), (a-4), and (a-5): [ka] and a bicyclic aromatic heterocyclic ring system selected from the group consisting of: In the formula, R 3a , R 3b , R 3c , R 3d , and R 3e are each independently hydrogen, halo, -NR 7a R 7b , C 1~4 Alkyl, C 2~4 Alkenyl, C 3~6 Cycloalkyl, -OH, or -OC 1~4 represents alkyl; R 7a represents hydrogen; R 7b is hydrogen, C 3~6 Cycloalkyl, or C 1~4 represents alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f , and R 4g are each independently hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is CR 6a represents; Q 2 is CR 6b represents; Q 3 is N or CR 6c represents; Q 4 is N or CR 6d Although it represents; However, Q 3 and Q 4 Provided that the largest of denotes N; Q 8 is N or CR 6g represents; Q 9 is N or CR 6h represents; Q 10 is N or CR 6i represents; Q 11 is N or CR 6j represents; Q 5 is CR 3d represents ;Q 6 represents N; Q 7 is CR 4f represents; or Q 5 is CR 3d represents ;Q 6 is CR 4e represents ;Q 7 represents N; or Q 5 represents N; Q 6 is CR 4e represents ;Q 7 is CR 4f represents; or Q 5 represents N; Q 6 is CR 4e represents ;Q7 represents N; or Q 5 represents N; Q 6 represents N; Q 7 is CR 4f represents; or Q 5 represents N; Q 6 represents N; Q 7 represents N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i , and R 6j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 Represents alkyl.

[0170] In one embodiment, the present invention relates to a compound of any of formulas (D), (E), and (F), wherein, if present, R 10 is cytosine, thymine, uracil, or modified or protected forms thereof, or (a-1), (a-2), and (a-3): [ka] and a bicyclic aromatic heterocyclic ring system selected from the group consisting of: In the formula, R 3a , R 3b , and R 3c are each independently hydrogen, halo, -NR 7a R 7b , C 1~4 alkyl, or -OC 1~4 represents alkyl; R7a represents hydrogen; R 7b is hydrogen or C 1~4 represents alkyl; R 4a , R 4b , and R 4c are each independently hydrogen, halo, -NR 8a R 8b , or C 1~4 represents alkyl; R 8a and R 8b are each independently hydrogen or C 1~4 represents alkyl; Q 1 is N or CR 6a represents; Q 2 is N or CR 6b represents; Q 3 is N or CR 6c represents; Q 4 is N or CR 6d Although it represents; However, Q 3 and Q 4 Provided that the largest of denotes N; R 6a , R 6b , R 6c , R 6d , R 6e , and R 6f are each independently hydrogen, halogen, C 1~4 Alkyl, -NR 9a R 9b or C substituted with 1, 2, or 3 halo atoms 1~4 represents alkyl; R 9a and R 9b are each independently hydrogen or C 1~4 Represents alkyl.

[0171] In one embodiment, the present invention relates to a compound of any of formulas (D), (E), and (F), wherein, if present, R 10 is a bicyclic aromatic heterocyclic ring system (a-1) [wherein R 3arepresents -NH2 or chloro].

[0172] All possible combinations of the above-described embodiments are considered to fall within the scope of the present invention.

[0173] Pharmacology Spirobicyclic nucleosides have been identified as exhibiting interesting activity, for example, against PRMT5. Novel intermediates have been developed that can be used to synthesize spiro-bicyclic nucleoside analogs. In particular, these intermediates contain functional groups that can be diversified to provide access to a variety of spiro-bicyclic nucleoside analogs. Thus, disclosed herein are compounds useful as intermediates for the preparation of spiro-bicyclic nucleoside analogs that may have activity, for example, against PRMT5. Also disclosed herein are spirocyclic nucleoside analogs that may themselves have PRMT5 inhibitory activity or that may serve as intermediates for further functionalization to provide interesting activity to the spiro-bicyclic nucleoside analogs.

[0174] It has been found that spiro bicyclic nucleoside analogues can inhibit PRMT5 activity.

[0175] In particular, such compounds are capable of binding to the PRMT5 enzyme and competing with the natural substrate SAM (S-adenosyl-L-methionine) to inhibit such enzyme.

[0176] Such compounds or pharmaceutical compositions thereof may be useful in the treatment or prevention, particularly the treatment, of diseases such as blood disorders, metabolic disorders, autoimmune diseases, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, and the like.

[0177] Such compounds or pharmaceutical compositions thereof may be useful in the treatment or prevention, particularly the treatment, of diseases such as allergies, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity, blood disorders, sickle cell anemia, and the like.

[0178] Such compounds or pharmaceutical compositions thereof may be useful in the treatment or prevention, particularly the treatment, of diseases such as autoimmune diseases, proliferative disorders such as cancer, benign tumors or inflammatory diseases.

[0179] Such compounds or pharmaceutical compositions thereof may be useful in the treatment or prevention, particularly the treatment, of diseases such as metabolic disorders including diabetes, obesity; proliferative disorders including cancer, hematopoietic cancer, lung cancer, prostate cancer, melanoma or pancreatic cancer; blood disorders; hemoglobinopathies; sickle cell anemia; beta thalassemia, inflammatory diseases and autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, and the like.

[0180] In some embodiments, inhibition of PRMT5 may be useful in the treatment or prevention, particularly the treatment, of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumor, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma.

[0181] Examples of metabolic disorders that may be treated or prevented, particularly metabolic disorders that may be treated, include, but are not limited to, diabetes or obesity.

[0182] Examples of blood disorders that may be treated or prevented, particularly blood disorders that may be treated, include, but are not limited to, hemoglobinopathies such as sickle cell anemia or β-thalassemia.

[0183] Examples of cancers that can be treated or prevented, particularly cancers that can be treated, include acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal carcinoma, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, papillary carcinoma, breast carcinoma, medullary breast carcinoma), brain tumors (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon carcinoma, rectal carcinoma), and the like. , colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine carcinoma, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia, gallbladder cancer, gastric cancer (e.g., gastric adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., pharyngeal carcinoma, laryngeal carcinoma, nasopharyngeal carcinoma, oropharyngeal carcinoma)), hematopoietic cancer (e.g., acute Leukemias such as lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myeloid leukemia (CML) (e.g., B-cell CML, T-cell CML) and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL); Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom macroglobulinemia"), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma;and lymphomas such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous fat pancreatitis-like T-cell lymphoma, anaplastic large cell lymphoma), and other T-cell NHL; a mixture of one or more of the above leukemias / lymphomas;and multiple myeloma (MM), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma (also known as Wilms' tumor), renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, non-small cell lung cancer (NSCLC), squamous cell lung carcinoma (SLC), lung adenocarcinoma, Lewis lung carcinoma, pulmonary neuroendocrine tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC)) and large cell neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM) (also known as myelofibrosis (MF)), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor), penile cancer (e.g., Paget's disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostatic adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), These include, but are not limited to, keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovial tumor, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva);

[0184] Examples of neurodegenerative diseases that may be treated or prevented, particularly neurodegenerative diseases that may be treated, include, but are not limited to, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-associated dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[0185] Examples of cardiovascular diseases that may be treated or prevented, particularly cardiovascular diseases that may be treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[0186] Examples of inflammatory diseases that may be treated or prevented, particularly inflammatory diseases that may be treated, include inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), upper respiratory tract diseases, ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies and allergic reactions, atherosclerosis, bronchitis, bursitis, and bursitis. inflammation, chronic prostatitis, conjunctivitis, Chagas' disease, chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin conditions (e.g., psoriasis, eczema, hypersensitivity reactions, burns, dermatitis, pruritus (itching)), endometriosis, Guillain-Barré syndrome, infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine, tension headache), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, acidophilia) eosinophilic gastrointestinal diseases (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., selected from Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, morphea, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcer, polymyositis, primary biliary cirrhosis These conditions include, but are not limited to, neuroinflammatory diseases associated with brain diseases (e.g., Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enterocolitis, rheumatic fever, systemic lupus erythematosus, scleroderma, scleroderma, sarcoidosis, spondyloarthropathy, Sjogren's syndrome, thyroiditis, transplant rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injuries), vasculitis, vitiligo, and Wegener's granulomatosis.

[0187] In particular, the inflammatory disease is an acute inflammatory disease (e.g., inflammation resulting from, for example, infection). In particular, the inflammatory disease is a chronic inflammatory disease (e.g., conditions resulting from asthma, arthritis, and inflammatory bowel disease). Such compounds may also be useful in treating inflammation associated with trauma and non-inflammatory muscle pain. Such compounds may also be useful in treating inflammation associated with cancer.

[0188] Examples of autoimmune diseases that may be treated or prevented, particularly autoimmune diseases that may be treated, include arthritis (rheumatoid arthritis, spondyloarthritis, gouty arthritis, e.g., osteoarthritis, systemic lupus erythematosus, degenerative joint diseases such as Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute shoulder pain, psoriasis, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin conditions (e.g., psoriasis, eczema, hypersensitive eczema, burns, dermatitis, pruritus (itching)), enuresis, eosinophilic diseases, gastrointestinal disorders (e.g., peptic ulcer, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal diseases (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastrointestinal esophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)) and disorders that are ameliorated by gastrokinetic agents (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, gastrointestinal disorders such as diabetic gastropathy; food intolerances and food allergies and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costochondritis)).

[0189] An effective therapeutic daily dose would be about 0.005 mg / kg to 50 mg / kg.

[0190] Compounds that may be suitable for the treatment or prevention of cancer or cancer-related conditions may be administered alone or in combination with one or more additional therapeutic agents.

[0191] The pharmaceutical composition may include a pharmaceutically acceptable carrier and an active ingredient.

[0192] The carrier(s) or diluent(s) must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0193] Preparation method In this section, as with all other sections, unless the context indicates otherwise, a reference to a formula also includes all other subgroups and examples thereof defined herein.

[0194] The general preparation of some representative examples of compounds of the present invention is described below and in the specific examples. The compounds are prepared from starting materials that are generally commercially available, prepared by standard synthetic processes commonly used by those skilled in the art, or prepared as described in the specific examples. The following schemes are merely intended to illustrate examples of the present invention and are not intended to limit the present invention in any way.

[0195] Alternatively, compounds of the present invention may also be prepared by analogous reaction protocols as described in the following general schemes, in combination with standard synthetic methods commonly used by those skilled in the art of organic chemistry.

[0196] All variables are defined as set forth herein above unless otherwise indicated or apparent from context.

[0197] Those skilled in the art will understand that in the reactions shown in the schemes, reactive functional groups, such as hydroxy, amino, or carboxy groups, may need to be protected if desired in the final product to prevent their unwanted participation in the reaction. Conventional protecting groups can be used in accordance with standard techniques. This is illustrated in the specific examples.

[0198] Those skilled in the art will appreciate that in the reactions described in the schemes, for example when NaH is used in the reaction, it may be desirable or necessary to carry out the reaction under an inert atmosphere, such as, for example, an N2 gas atmosphere.

[0199] It will be apparent to one skilled in the art that it may be necessary to cool the reaction mixture before reaction work-up (which refers to the series of operations required to isolate and purify the products of a chemical reaction, such as quenching, column chromatography, extraction, etc.).

[0200] Those skilled in the art will appreciate that heating the reaction mixture under stirring may improve the reaction outcome. In some reactions, microwave heating may be used in place of conventional heating to shorten the overall reaction time.

[0201] Those skilled in the art will appreciate that alternative sequences of the chemical reactions shown in the following schemes may also give rise to the desired compounds of the present invention.

[0202] Those skilled in the art will appreciate that the intermediates and compounds depicted in the schemes below can be further functionalized according to methods well known to those skilled in the art. For example, 3a or any other substituent on the nucleobase or nucleobase derivative represents Cl, can be obtained by reaction with NH3 in a typical solvent such as dioxane (e.g., 25% in water) at a typical temperature of about 100°C to give 3a (or any other Cl substituent) can be converted to a compound in which NH2 is represented.

[0203] Those skilled in the art will appreciate that many more compounds of the present invention can be prepared using similar synthetic protocols as described in the following schemes.

[0204] Those skilled in the art will appreciate that if one of the starting materials is available in salt form, it may be necessary to first treat the salt with a base such as, for example, N,N-diisopropylethylamine (DIPEA).

[0205] All variables are defined as set forth herein above unless otherwise indicated or apparent from context.

[0206] In general, the compounds of the present invention can be prepared according to the following general schemes.

[0207] In the following schemes, unless otherwise defined, R is as defined herein. 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group. Those skilled in the art will understand that protecting groups can be utilized in the following schemes as needed, and that any protecting group can be subsequently removed to provide a deprotected compound. For example, when the compounds referenced in the following schemes contain a nucleobase or nucleobase derivative, the nucleobase can be utilized in a protected form, e.g., the NH or OH on the nucleobase can be protected with an amino or hydroxyl protecting group, respectively, or the NH on the nucleobase can be substituted with a halo (e.g., chloro).

[0208] General Scheme 1: Preparation of cyclopentane spirocycle precursors [ka] In General Scheme 1, R 4 is limited to silyl groups, e.g., TBDMS, and together with R 5 and R 6 forms a diol protecting group.

[0209] In General Scheme 1, the following reaction conditions typically apply: 1: (I) is reacted with an oxidizing agent such as phenyliodine(III) diacetate (PIDA) in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50°C; 2: (I) is reacted with PPh3, iodine, and a base such as imidazole in a suitable solvent such as THF at a suitable temperature range such as room temperature; 3: (III) is reacted with a base such as DBU in a suitable solvent such as THF at a suitable temperature range such as 60°C to 90°C.

[0210] General Scheme 2: Preparation of furanose and nucleoside spirocyclic precursors [ka] In General Scheme 2, R is R as defined herein. 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0211] In General Scheme 2, the following reaction conditions typically apply: 1: (V) is reacted with an oxidizing agent such as phenyliodine(III) diacetate (PIDA) in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50°C; 2: (V) is reacted with PPh3, iodine, and a base such as imidazole in a suitable solvent such as THF at a suitable temperature range such as room temperature; 3: (VII) is reacted with a base such as DBU in a suitable solvent such as THF at a suitable temperature range such as 60°C to 90°C.

[0212] General Scheme 3: Preparation of 1,2-cyclobutane [ka] In General Scheme 3, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 Alkyl, -S-aryl, -O-aryl, B(OR b )2, or C(O)R a and R a is hydrogen or C 1~6 Those skilled in the art will recognize that if a protecting group was initially present, after the deprotection step, R 1’ and R 2’ will understand that they are not protected.

[0213] General Scheme 3 shows the synthesis of nucleoside analogs (i.e., OR 4 R 10 It will be understood that this may also be implemented in the form

[0214] In general scheme 3, the following reaction conditions typically apply: 1: (IX) is reacted with oxalyl chloride in a suitable solvent such as DCM, optionally in the presence of a catalytic amount of DMF, at a suitable temperature range, such as 0° C. to room temperature; the acid chloride intermediate is reacted with a base such as triethylamine and an alkene (RHC=CHR) in a suitable solvent such as acetonitrile or toluene at a suitable temperature range, such as 80° C. to 130° C. 2’ Instead of activation with an acid chloride, an alternative method can be used, such as reacting (IX) with 2-chloro-1-methylpyridinium iodide in a suitable solvent, such as acetonitrile, at a suitable temperature range, e.g., 80°C to 110°C. This reaction is carried out in the presence of a base, such as diisopropylethylamine, and an alkene (R 1’ HC=CHR 2’ ) can be carried out in the presence of; 2: When R1' or R2' is a silyl group: (X) is reacted with a fluoride source such as TBAF in the presence of a protic solvent such as HOAc and an aprotic solvent such as THF at a suitable temperature range, for example, 0°C to 60°C; an alternative procedure is to treat (X) with trimethylsilyl triflate (TMS-OTf) in a suitable solvent such as DCM at a temperature range of 0°C to 50°C, for example, room temperature. When R1' or R2' is PhS: deprotection may be carried out in the presence of a reducing agent such as Raney nickel, optionally in the presence of hydrogen, in a solvent such as ethanol or THF at a temperature range of 60°C to 120°C. 3: (XI) is reacted with a reducing agent such as sodium borohydride in a suitable solvent such as methanol at a suitable temperature such as -78°C to 0°C.

[0215] General Scheme 4: Alternative Preparation of 1,2-Cyclobutane [ka] In General Scheme 4, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group1~6 Alkyl, -OC 1~6 Alkyl, or C(O)R a and R a is hydrogen or C 1~6 Those skilled in the art will recognize that if a protecting group was initially present, after the deprotection step, R 1’ and R 2’ will understand that they are not protected.

[0216] General Scheme 4 shows the synthesis of nucleoside analogs (i.e., OR 4 R 10 It will be understood that this may also be implemented in the form

[0217] In General Scheme 4, typically similar conditions as in General Scheme 3 apply.

[0218] General Scheme 5a: Preparation of 1,3-cyclobutanol intermediates [ka] In General Scheme 5a, R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0219] In general scheme 5a, the following reaction conditions typically apply: 1: (XVI) is reacted with a zinc source such as zinc dust or a zinc-copper couple in the presence of a dichloroketene precursor such as trichloroacetyl chloride in a suitable solvent such as diethyl ether or THF at a suitable temperature range, for example, room temperature to 50° C. The resulting (XVII) may be either isolated or converted via step 2 in the same pot. 2: (XVII) reacts with zinc powder in the presence of a protic solvent such as HOAc and an aprotic solvent such as THF at a suitable temperature range, for example, room temperature to 70°C; 3: (XVIII) is reacted with a reducing agent such as sodium borohydride in a suitable solvent such as methanol at a suitable temperature such as −78° C. to 0° C. Depending on the nature of the protecting groups, either (XIXa) or (XIXb) or a mixture thereof may be obtained.

[0220] General Scheme 5b: Preparation of 1,2-cyclobutanol and 1,2-cyclobutanone intermediates [ka] In general scheme 5b, the following reaction conditions typically apply: 1: (XVII) is reacted with a reducing agent, such as sodium borohydride, in a suitable solvent, such as THF, at a suitable temperature, such as 0° C. to room temperature. The resulting intermediate is treated with a sulfonating agent, such as triflic anhydride, together with a base, such as pyridine, in an anhydrous solvent, such as dichloromethane, at a suitable temperature, such as 0° C. The resulting intermediate is then treated with zinc powder in the presence of a protic solvent, such as HOAc, in combination with a solvent, such as methanol, at a suitable temperature, such as 60° C. 2: (LXI) is treated with an oxidizing agent, such as m-CPBA, in a suitable solvent, such as dichloromethane, at a suitable temperature range, such as room temperature to 40°C. 3: (LXII) is reacted with a reducing agent such as sodium cyanoborohydride or lithium borohydride in an alcohol solvent such as isopropyl alcohol at a suitable temperature range such as room temperature to 60°C. 4: (LXIII) is treated with an oxidizing agent, such as, for example, Dess-Martin periodinane (DMP), in a suitable solvent, such as, for example, dichloromethane, at a suitable temperature, such as, for example, room temperature.

[0221] General Scheme 6a: Preparation of cyclobutane methyl alcohol [ka] In General Scheme 6a, R is R as defined herein. 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0222] This chemistry is compatible with 1,2-cyclobutanone and 1,3-cyclobutanone.

[0223] It will be appreciated that when a carboxylic acid-substituted cyclobutyl is prepared, this can be further derivatized by esterification.

[0224] In general scheme 6a, the following reaction conditions typically apply: 1: in the presence of a reagent such as methyltriphenylphosphonium bromide (MePPhBr), in the presence of a base such as potassium tert-butoxide (KOtBu), in a solvent such as THF at a suitable temperature such as 0°C to rt; or using bis(cyclopentadienyl)dimethyltitanium in a suitable solvent system such as toluene and THF at a suitable temperature range such as 50°C to 70°C; 2: In the first step, in the presence of the alkene precursor (XXI) and a solution of 9-BBN in THF, typically under a nitrogen atmosphere at room temperature to reflux temperature, and in the second step, in the presence of an aqueous base, such as aqueous NaOH, and in the presence of an oxidizing agent, such as H2O2, typically at temperatures between 0 °C and rt; 3: Using oxidation conditions well known to those skilled in the art, e.g., Dess-Martin periodinane (in the case of aldehydes, i.e., R aa or with an oxidizing agent such as phenyliodine(III) diacetate (PIDA) in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50° C. (in the case of carboxylic acids, i.e., when R aa is H).

[0225] General Scheme 6b: Preparation of 1,2-cyclobutanemethyl alcohol [ka] In general scheme 6b, R cc is C 1~6 It is alkyl.

[0226] In general scheme 6b, the following reaction conditions typically apply: 1: (XVI) under an inert atmosphere is reacted with an unsaturated reagent such as methyl propiolate in the presence of a metal complex such as methylaluminoxane in a suitable solvent such as DCM at a suitable temperature such as 0° C. to rt; 2: (LXIX) is treated with a hydrogenation catalyst such as Pt / C in a suitable solvent such as ethyl acetate in a hydrogen atmosphere at temperatures between room temperature and 50°C. 3: (LXX) is reacted with a base such as lithium hydroxide in an aqueous solvent mixture such as aqueous methanol in water. The resulting mixture is reacted for a suitable time, such as 3 hours, at a controlled temperature, such as 0° C. to rt. 4: (LXX) is reacted with a reducing agent such as lithium borohydride in the presence of a suitable solvent such as THF at a suitable temperature such as -78°C to room temperature.

[0227] General Scheme 7: Preparation of cyclopropanemethyl alcohol [ka] In General Scheme 7, R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0228] In general scheme 7, the following reaction conditions typically apply: 1: (XXIV) is reacted with zinc powder in the presence of 1 equivalent of a proton source such as HOAc in an aprotic solvent such as THF at a suitable temperature of 0° C. using a short reaction time such as 20 minutes; 2: (XXV) is reacted with a reducing agent such as sodium borohydride in a suitable solvent such as THF at a suitable temperature, for example, between −0° C. and room temperature. The mixture is then treated with an aqueous base such as NaOH (1M) at a suitable temperature range, for example, between room temperature and 50° C.

[0229] General Scheme 8: Alternative preparation of cyclopropanemethyl alcohol [ka] In General Scheme 8, R is R as defined herein. 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5is a diol protecting group.

[0230] In general scheme 8, the following reaction conditions typically apply: 1: (XXVII) is treated with a catalyst such as Rh2(OAc)4 or rhodium(II) triphenylacetate dimer and an alpha diazoketone or diazoester in a suitable solvent such as dichloromethane at a suitable temperature range such as room temperature to 50°C under an inert atmosphere. The catalyst can be a chiral catalyst such as (S)-Ph-Pheox Ru(II) or (R)-Ph-Pheox Ru(II), so the synthesis is asymmetric; 2: (XXVIIIa) is reacted with a reducing agent, such as lithium borohydride, in a suitable solvent, such as THF, at a suitable temperature, such as between −0° C. and room temperature.

[0231] General Scheme 9a: Preparation of cyclopropanols [ka] In General Scheme 9a, R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group. b is a boronic acid protecting group.

[0232] In general scheme 9a, the following reaction conditions typically apply: 1: (XXX) is treated with bromoform under an inert atmosphere in a biphasic solvent system consisting of water and DCM, etc. The reaction requires a phase transfer catalyst such as benzyltriethylammonium chloride and a base such as sodium hydroxide in a suitable solvent at a suitable temperature, such as room temperature. 2: (XXXI) is reacted with a strong base such as nBuLi under an inert atmosphere in a suitable solvent such as THF at a suitable temperature such as −0° C. to low, e.g., −100° C. The resulting mixture is then treated with a borane such as catecholborane and warmed to the same temperature and then 50° C. to form (XXXII) in situ. 2a: (XXXII) is reacted with a mixture of aqueous hydrogen peroxide and a base such as sodium hydroxide in a suitable solvent under an inert atmosphere with a strong base such as nBuLi at room temperature.

[0233] General Scheme 9b: Alternative preparation of cyclopropanols (via cyclopropyl esters) [ka] In General Scheme 9b, -C(O)R bb is -C(O)C 1~6 It is an alkyl or hydroxyl protecting group such as benzoyl.

[0234] In general scheme 9b, the following reaction conditions typically apply: 1: (LXV) is treated with a suitable base, such as potassium carbonate, under an inert atmosphere and reacted with an anhydride, such as benzoic anhydride, in a suitable anhydrous solvent, such as acetonitrile, at a suitable temperature, such as room temperature to 60°C. 2: (LXVI) is treated with diiodomethane and diethylzinc under an inert atmosphere in an anhydrous solvent such as 1,2-dichloroethane at a suitable temperature such as room temperature to 50°C. 3: (LXVII) is reacted with a base such as potassium carbonate in an aqueous solvent mixture such as aqueous methanol in water. The resulting mixture is reacted for a suitable time, such as 3 hours, at a controlled temperature such as 0°C.

[0235] General Scheme 10: Preparation of Nucleoside Analogues [ka] In General Scheme 10, R 1 , R 2 , R 10 and n is as defined herein; R 4 is preferably Me or —C(O)C 1~6 alkyl, and R 5 and R 6 is preferably —C(O)C 1~6 In General Scheme 10, the following reaction conditions typically apply: 1: The intermediate of formula (XXXIV) is reacted with a suitable nucleobase, such as 6-chloropurine, typically in the presence of a reagent such as bis-(trimethylsilyl)acetamide (BSA), for example trimethylsilyl triflate (TMSOTf), in a solvent such as anhydrous CH3CN; typically at temperatures between room temperature and 100°C;

[0236] It will be appreciated that this scheme may be practiced with any suitable nucleobase precursor. 5 or R 6 and / or conversion of a nucleobase precursor to a nucleobase. For example, after coupling, 6-chloropurine may be converted to adenine.

[0237] General Scheme 11: Preparation of Cyclopentane-Containing Nucleoside Analogues [ka]

[0238] In General Scheme 11, R 1 , R 2 , R 10 and n is as defined herein; R 4 is a protecting group, e.g., a silyl group, and together R 5 and R 6 is a diol protecting group.

[0239] In general scheme 11, the following reaction conditions typically apply: 1. Typical deprotection in the presence of a reagent such as tetrabutylammonium fluoride (TBAF); in a suitable solvent such as THF; at a suitable temperature such as rt; 2. Reaction with a suitable reagent, such as for example TfO (triflic anhydride or trifluoromethanesulfonic anhydride), in a suitable solvent, such as for example dichloromethane (DCM), at a suitable temperature, such as for example 0°C; 3. Reaction with a suitable nucleobase precursor in the presence of a base, such as potassium tert-butoxide, in a suitable solvent, such as DMF, at a suitable temperature, such as -10°C to 0°C;

[0240] General Scheme 12: Conversion of alcohol-substituted analogues to amine-substituted analogues [ka] In General Scheme 12, R a , m, and n are as defined herein; R is as defined herein; 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0241] In general scheme 12, the following reaction conditions typically apply: 1: (XL) is reacted with an activating agent such as mesyl chloride in the presence of a suitable base such as pyridine in a suitable solvent such as DCM at temperatures typically between 0°C and 40°C; 2: (XLI) is reacted with an azide such as sodium azide in the presence of a catalyst such as tertbutylammonium iodide (TBAI) in a suitable solvent such as DMF or DMA, typically at a temperature range of 0°C to 120°C; 3: (XLII) is treated with a hydrogenation catalyst such as Pd / C in a suitable protic solvent such as methanol under a hydrogen atmosphere at temperatures between room temperature and 50°C. 4: (XLIII) is treated with acetic acid in a suitable solvent such as dichloromethane and an appropriate aldehyde or ketone. After equilibration at a suitable temperature such as room temperature, reduction is carried out in the presence of a suitable reducing agent such as sodium triacetoxyborohydride (NaBH(OAc)3) at a suitable temperature range of 0°C to room temperature.

[0242] General Scheme 13: Conversion of alcohol-substituted analogues to amine-substituted analogues [ka] In General Scheme 13, R a , m, and n are as defined herein; R is as defined herein; 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0243] In general scheme 13, the following reaction conditions typically apply: 1: (XLI) is treated with a suitable amine without additional solvent at a suitable temperature range of 50°C to 120°C.

[0244] General Scheme 14: Conversion of alcohol-substituted analogues to sulfur-substituted analogues [ka] In General Scheme 14, R c , m, and n are as defined herein; R is as defined herein; 10 or, as defined herein, OR 4 , R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0245] In general scheme 14, the following reaction conditions typically apply: 1: (XLVI) is treated with a suitable thiol in the presence of a suitable base such as sodium hydride in an aprotic polar solvent such as DMF or NMP at a suitable temperature range of 20°C to 120°C. 2: (XXLVII) is treated with a suitable oxidizing agent, such as hydrogen peroxide, in a suitable solvent system, such as acetone and water, at a suitable temperature range of 20°C to 60°C. 3: (XLVII) is treated with a suitable oxidizing agent, such as mCPBA, in a suitable solvent, such as dichloromethane, at a suitable temperature range of 0°C to 30°C.

[0246] General Scheme 15: Conversion of the 3'β stereocenter to α (xylo to ribo) [ka] In general scheme 15, the following reaction conditions typically apply: 1: (L) is oxidized to the corresponding ketone using Dess-Martin periodinane in a solvent such as dichloromethane at a temperature range of 0° C. to room temperature. 2: (LI) can then be reduced with a reagent such as NaBH4 in a solvent such as methanol or ethanol at a temperature range of 0°C to room temperature, or by using DIBAL (diisobutylaluminum hydride) in a solvent such as dichloromethane at a temperature range of -78°C to 0°C.

[0247] Those skilled in the art will appreciate that Scheme 15 can also be applied to other 1,3-cyclobutane nucleoside analogs, as well as 1,2-cyclobutane or cyclopropyl spiro bicyclic nucleoside analogs. For example, general Scheme 15 can also be applied to: [ka] where n, R 1 , and R 2 are as defined herein; the typical reaction conditions described herein for (L) and (LI) apply to (L') and (LI'), respectively.

[0248] General Scheme 16: Reduction of carbonyl to methylene [ka] In General Scheme 16, R 1’ and R 2’ One of the groups is hydrogen or C 1~6 alkyl, and the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, -OC 1~6 Alkyl, -SC 1~6 It is alkyl, -S-aryl, or -O-aryl.

[0249] In general scheme 16, the following reaction conditions typically apply: 1: (LIII) is converted in situ to the hydrazone by treatment with hydrazine, optionally in the presence of an acid such as sulfuric acid, in a suitable solvent such as ethanol at a suitable temperature range of 20°C to 80°C. The hydrazine can be removed by treatment with a base such as potassium tert-butoxide (KOtBu) in a suitable solvent such as DMSO at a temperature range of 4°C to 40°C. Alternatively, (LIII) is converted in situ to the tosylhydrazone by reaction with tosyl-NHNH2 in a suitable solvent such as methanol or ethanol at a suitable temperature range of 60°C to 100°C, followed by reaction with a reducing agent such as sodium borohydride at a suitable temperature range of 20°C to 70°C.

[0250] General Scheme 17: Formation of aminocyclopropanes [ka] In General Scheme 17, R 4 , R 5 , and R 6 are each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group.

[0251] In general scheme 17, the following reaction conditions typically apply: 1: (LV) is hydrolyzed in the presence of an aqueous solvent system such as LiOH in the presence of methanol or THF at a temperature range of 0°C to 20°C. The resulting carboxylic acid is converted to a carboxamide using an activating agent such as HATU in a solvent such as DMF or DCM at a temperature range of 20°C to 50°C using ammonia or ammonium chloride. Finally, rearrangement occurs in the presence of NaOCl or NaOBr, optionally in the presence of sodium hydroxide, in an aqueous solvent at a temperature range of 0°C to 50°C.

[0252] General Scheme 18: Conversion of 2'β stereocenter to α (arabino to ribo) [ka] In General Scheme 18, R is defined as a suitable hydroxyl protecting group, as defined herein, and PG is as defined herein.

[0253] In general scheme 18, the following reaction conditions typically apply: 1: (LVIII) is oxidized to the corresponding ketone using Dess-Martin periodinane in a solvent such as dichloromethane at a temperature range of 0° C. to room temperature. 2: (LIX) can then be reduced with a reagent such as NaBH4 in a solvent such as methanol at a temperature range of 0°C to room temperature, or by using DIBAL in a solvent such as dichloromethane at a temperature range of -78°C to 0°C.

[0254] Those skilled in the art will appreciate that Scheme 18 also applies to other 1,3-cyclobutane or 1,2-cyclobutane spiro bicyclic nucleoside analogs or cyclopropyl spiro bicyclic nucleoside analogs.

[0255] In all of these preparations, the reaction product may be isolated from the reaction medium and, if necessary, further purified by methods generally known in the art, such as extraction, crystallization, trituration, chromatography, and the like.

[0256] Chirally pure forms of the compounds of formula (I) form a preferred group of compounds. Thus, chirally pure forms of intermediates and their salt forms are particularly useful for preparing chirally pure compounds of formula (I). Also, enantiomeric mixtures of intermediates are useful for preparing compounds of formula (I) with the corresponding configuration. [Example]

[0257] Hereinafter, the terms "rt" or "rt" mean room temperature; "RT" or "R t " means retention time; "R f" means retention factor; "Me" means methyl; "MeOH" means methanol; "MeOD" means monodeuterated methanol; "Et" means ethyl; "EtOH" means ethanol; "EA" or "EtOAc" means ethyl acetate; "Ac" means acetyl; "Ac2O" means acetic anhydride; "AcOH" means acetic acid; "Et2O" means diethyl ether; "Int." means intermediate; "DMF" means N,N-dimethylformamide; "THF" means tetrahydrofuran. "LC" means furan; "celite®" means diatomaceous earth; "LCMS" or "LC-MS" means liquid chromatography / mass spectrometry; "GCMS" or "GC-MS" means gas chromatography / mass spectrometry; "CV" means column volume; "HPLC" means high performance liquid chromatography; "TFA" means trifluoroacetic acid; "h" means hour; "MeS" means dimethyl sulfide; "DMSO" means dimethyl sulfoxide; "DMSO-d6" means deuterated dimethyl sulfoxide; "DIPE" means diisopropyl ether; "DCM" means dichloromethane; "PPh3" means triphenylphosphine; "TBAF" means tetrabutylammonium fluoride; "DBU" means 1,8-diazabicyclo[5.4.0]undecene-7; "eq." or "equiv" means equivalent; "KOtBu" means potassium tert-butoxide; and "TBDMSCl" means tert-butyldimethylsilyl chloride. "Bn" means benzyl; "9-BBN" means 9-borabicyclo[3.3.1]nonane; "TfO" means triflic anhydride; "TBDMS" means tert-butyldimethylsilyl or t-butyldimethylsilyl; "aq." means aqueous; "Ts" or "Tos" means tosyl (p-toluenesulfonyl); "DEAD" means diethyl azodicarboxylate; "Bz" means benzoyl; "BnBr" means benzyl bromide; "Bn" means benzyl; "anhyd."" means anhydrous; "p-TsOH" means 4-methylbenzenesulfonic acid; "(R)-MonoPhos" means (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-amine; "BSA" means N,O-bis(trimethylsilyl)acetamide; "TMSOTf" means trimethylsilyl trifluoromethanesulfonate; "Boc" means tert-butyloxycarbonyl; "Prep SFC" means preparative supercritical fluid chromatography; "Piv" means pivaloyl; "PivCl" means pivaloyl chloride; "MePPh3. + Br -" means methyltriphenylphosphonium bromide; "iPrNH2" means isopropylamine; "iPrOH" means isopropyl alcohol; "n-PrNH2" means propylamine; "sat." means saturated; "DMA" means dimethylacetamide; "NMR" means nuclear magnetic resonance; "Chloroform-d" means deuterated chloroform; "DIPEA" means diisopropylethylamine; "TLC" means thin layer chromatography; "brsm" means based on recovered starting material; "w / w" means weight / weight; "ppm" means parts per million; "TEA" means triethylamine; "PE" means petroleum ether; "DMP" means Dess-Martin periodinane; "DIAD" means diisopropyl azodicarboxylate; "methanol-d4" means deuterated methanol; "TBDPS" means tert-butyldiphenylsilyl; "HMDS" means means hexamethyldisilazane; "DMAP" means 4-dimethylaminopyridine; "ESI" means electrospray ionization; "ACN" means acetonitrile; "TBAI" means tetrabutylammonium iodide; "HATU" means N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; "brsm" means recovered output "HMPA" means hexamethylphosphoramide; "m-CPBA" or "mCPBA" means meta-chloroperbenzoic acid; "nBuLi" means n-butyllithium; "EDA" means ethyl diazoacetate; "tBu" means tert-butyl; "DIBAL" or "DIBAl-H" means diisobutylaluminum hydride; "DCE" means 1,2-dichloroethane; and "MAO" means methylaluminoxane.

[0258] [ka] An expression like [ka] This shows a mixture of

[0259] Preparation of intermediates and nucleosides Preparation of cyclobutane Preparation of Compound 1 [ka] To a stirred solution of CAS 54622-95-6 (200 mg, 0.92 mmol, 1 eq) and 1 drop of DMF in DCM (2 mL) was added oxalyl chloride (0.12 mL, 1.37 mmol, 1.5 eq), and the resulting reaction mixture was stirred at room temperature for 4 h. Excess solvent and oxalyl chloride were removed in vacuo for 1 h and carried on to the next step.

[0260] To the acid chloride obtained above in toluene (2 mL) in a sealed tube, vinyltrimethoxysilane (1.35 mL, 9.16 mmol, 10 eq) was added, followed by EtN (0.15 mL, 1.10 mmol, 1.2 eq). The resulting reaction mixture was heated at 120 °C overnight (16 h) and then quenched with HCl (1 M, 10.00 mL). The aqueous phase was extracted with EtOAc (20 × 2 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, Rf = 0.5) to give compound 1 (198 mg, 0.66 mmol, 72%) as a colorless oil (which is a mixture of diastereomers as suggested by NMR spectroscopy).

[0261] Data for the major isomers: 1H NMR(400MHz,chloroform-d)δ 4.91(s,1H),4.68(d,J=5.9Hz,1H),4.57(d,J=5.9Hz,1H),3.35(s,3H),3.01(dd,J=17.5,13.2Hz,1H), 2.56(dd,J=17.5,6.6Hz,1H),2.21(dd,J=13.2,6.6Hz,1H),1.46(s,4H),1.32(s,3H),0.08ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 206.40, 112.65, 106.92, 103.08, 84.66, 79.29, 54.68, 40.91, 26.26, 24.95, 18.64, −2.31 ppm. GC-MS: [M-86] 214, 13.67 min (Method 4) (Molecular ion peak not found)

[0262] Preparation of Compound 2 [ka] To a stirred solution of compound 1 (250 mg, 0.83 mmol, 1 eq) in dry THF (4 mL) was added dropwise acetic acid (0.05 mL, 0.83 mmol, 1 eq) and TBAF (1.66 mL, 1.0 M in THF, 2 eq). The resulting reaction mixture was heated at 50° C. for 1 h. After completion of the starting material (TLC), water (20 mL) was added and extracted with EtOAc (30 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, R f =0.2) to give compound 2 (28 mg, 0.12 mmol, 15%) as a colorless oil, which is a mixture of two (81:19) diastereomers as suggested by NMR spectroscopy. This experiment was repeated three more times to give (30 mg, 13%), (50 mg, 13%), (125 mg, 14%, 20% (brsm)), all of which combined to give compound 2 (232 mg).

[0263] Data for the major isomers: 1 H NMR(300MHz,chloroform-d)δ 5.01(s,1H),4.87(d,J=5.7Hz,1H),4.64(d,J=5.7Hz,1H),3.35(s,3H),3.03-2.96(m,1H),2.83(dd,J=10 .0,4.2Hz,1H),2.20(td,J=11.3,4.2Hz,1H),2.04(td,J=11.2,10.1Hz,1H),1.49(s,3H),1.30ppm(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 200.03, 113.88, 108.56, 99.60, 86.67, 84.74, 55.12, 40.90, 27.01, 26.07, 25.27 ppm. GC-MS: [M+1]229,13.60 min (method 4).

[0264] Preparation of Compound 3 [ka] To a stirred solution of compound 1 (113 mg, 0.38 mmol, 1 eq) (the wavy cyclobutane bond in compound 1 indicates a mixture of multiple isomers obtained previously) in dry DCM (1.5 mL) at room temperature, TMSOTf (0.06 mL, 0.34 mmol, 0.9 eq) was added, and the resulting reaction mixture was stirred at the same temperature for 16 h. Sat. NaHCO3 (5 mL) was carefully added, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give a crude product consisting of the starting material and the product (TLC). The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, R f 0.5) to give compound 1a (40 mg, 0.13 mmol) as a colorless oil, which was a mixture of four (51:20:19:10) diastereomers as suggested by NMR spectroscopy, and compound 3 (31 mg, 0.14 mmol, 36% (65% brsm)) as colorless crystals, which was a single diastereomer as suggested by NMR spectroscopy.

[0265] Data for the major isomer of compound 1a: 1 H NMR(400MHz,chloroform-d)δ 4.89(s,1H),4.64(d,J=5.7Hz,1H),4.60(d,J=5.8Hz,1H),3.31(s,3H),3.21(dd,J=17.5,4.6Hz,1H),2.70(dd,J =17.2,10.1Hz,1H),1.85(dd,J=12.9,10.1Hz,1H),1.47(d,J=0.7Hz,3H),1.30(d,J=0.7Hz,3H),0.12ppm(s,9H).

[0266] Data for compound 3: 1 H NMR(400MHz,chloroform-d)δ 5.01(s,1H),4.87(d,J=5.7Hz,1H),4.64(d,J=5.7Hz,1H),3.35(s,3H),3.07-2.92(m,1H),2.81(ddd,J=17.1 ,10.0,4.0Hz,1H),2.20(td,J=11.2,4.0Hz,1H),2.04(dd,J=11.5,10.9Hz,1H),1.49(s,3H),1.30ppm(s,3H).

[0267] Preparation of Compounds 4 and 5 [ka] To compound 2 (205 mg, 0.90 mmol, 1.00 eq) in MeOH (2 mL) was added NaBH (44 mg, 1.17 mmol, 1.30 eq) at −78° C., and the resulting reaction mixture was stirred at −78° C. for 1 h. The reaction was then quenched by adding saturated NH Cl (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and carried on to the next step.

[0268] To the above obtained alcohol in DCM (2 mL) were added EtN (0.26 mL, 1.80 mmol, 2 eq), benzoyl chloride (0.16 mL, 1.35 mmol, 1.5 eq) at 0 °C, and the resulting reaction mixture was stirred at rt overnight. The reaction was then quenched by adding saturated NaHCO (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 80:20, R f = 0.6 and R f =0.4) to give compound 4 (110 mg, 0.33 mmol, 37%, as a mixture of two (62:38) diastereomers as suggested by NMR spectroscopy) as a colorless oil, and compound 5 (100 mg, 0.43 mmol, 48%, as a mixture of two (62:38) diastereomers as suggested by NMR spectroscopy).

[0269] Compound 4 was purified by Prep SFC (stationary phase: Chiralcel Diacel OJ 20 × 250 mm, mobile phase: CO2, iPrOH) to give compound 4a (63.4 mg, 0.19 mmol, 58% yield, major isomer) and compound 4b (31 mg, 0.09 mmol, 28% yield, minor isomer).

[0270] Data for compound 4a: LCMS: (ESI + ):[M+1] + =335.0, RT 2.18 minutes (method 11)

[0271] Data for compound 4b: LCMS: (ESI + ):[M+1] + =335.1, RT 2.18 minutes (method 11)

[0272] Data for the major isomeric compound 4a: 1H NMR(300MHz,クロロホルム-d)δ 8.13-8.05(m,2H),7.58-7.49(m,1H),7.47-7.36(m,2H),5.60(t,J=8.7Hz,1H),4.88(s,1H),4.86(d,J=5.6Hz,1H),4.61(d,J=5. 6Hz,1H),3.35(s,3H),2.42-2.15(m,2H),2.05-1.85(m,1H),1.79-1.65(m,1H),1.20(d,J=0.7Hz,3H),1.16ppm(d,J=0.7Hz,3H).

[0273] The main heterosexual form of compound 5: 1 H NMR(300MHz,クロロホルム-d)δ 4.94(d,J=5.8Hz,1H),4.87(s,1H),4.77-4.70(m,1H),4.64(d,J=5.8Hz,1H),4.40(bs,1H),3.32(s,3H),2.68-2.53(m,1H),2.2 9-2.20(m,1H),1.74(ddd,J=9.8,8.4,1.4Hz,1H),1.62(dd,J=18.8,8.7Hz,1H),1.50(d,J=0.7Hz,3H),1.33ppm(d,J=0.7Hz,3H).

[0274] Substitution adjustment of compound 1 (large scale)

change

[0275] 26% (23g, 76.33mmol, crude) yellow oil. LCMS(ESI+)m / z:C 14 H 24 Calculated for O5Si [M+H2O]+ = 318.14, found 318.20, RT: 1.678 min, Method 1.

[0276] Substitutional preparation of compound 5 (large scale) [ka] To compound 1 (23 g, 76.33 mmol, 1.00 eq) in dry THF (230 mL) was added dropwise acetic acid (4.57 g, 76.33 mmol, 1.00 eq) and TBAF (152.66 mL, 1.0 M in THF, 2.00 eq). The resulting reaction mixture was heated at 50 °C overnight. After completion of the starting material (TLC), MeOH (200 mL) was added, followed by NaBH (2.9 g, 76.33 mmol, 2.00 eq) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 2 h. The reaction was then quenched by adding saturated NH Cl (200 mL) and extracted with ethyl acetate (300 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, R f =0.2), the front peak was Compound 5a', and the back peak was Compound 5b' (obtained as a mixture of Compound 5b' and Compounds 95a and 95b described below).

[0277] 3.3% yield (580 mg, 2.52 mmol, crude) of compound 5a' as a yellow oil. GCMS (ESI+) m / z: C 11 H 18 Calculated value for O5 [M-Me]-=215.09, measured value 215.09, RT: 6.387 min, Method 1.

[0278] 2.5% yield (30%, 1.5 g, 6.52 mmol, crude) of compound 5b' as a yellow oil (obtained as a mixture of compound 5b' and compounds 95a and 95b described below). GCMS (ESI+) m / z: C 11 H 18 Calculated value for O5 [M-Me]-=215.09, measured value 215.09, RT: 6.377 min, Method 1.

[0279] Preparation of Compound 4a' [ka] Compound 5a' (1.03 g, 4.47 mmol, 1.00 eq) and DMAP (272.67 mg, 2.23 mmol, 0.50 eq) were dissolved in pyridine (10 mL). Benzoyl chloride (1.25 g, 8.94 mmol, 2.00 eq) was then added dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. HCl (1 M, aqueous, 20 mL) was then added to the reaction mixture until a pH of <7 was reached. The product was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified using a C18 column (mobile phase A: water (0.1 mmol / L NHHCO), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40B to 70B in 30 min; 210 / 254 nm). The fractions containing the product were collected and the solvent was evaporated to give compound 4a'.

[0280] 29% yield (430 mg, 1.28 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 8.12-8.05(m,2H),7.57-7.49(m,1H),7.46-7.36(m,2H),5.61(t,J=8.9Hz,1H),4.93-4.83(m,2H),4.66-4.5 8(m,1H),3.36(s,3H),2.45-2.30(m,1H),2.11-1.85(m,2H),1.80-1.66(m,1H),1.21(s,3H),1.16ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ LCMS(ESI+)m / z:C 18 H 22 Calculated for O6 [M+H]+ = 335.14, found 335.14, RT: 1.811 min, Method 1.

[0281] Preparation of Compound 138a [ka] Compound 4a' (430 mg, 1.28 mmol, 1.00 eq) was dissolved in HO (5 mL) and formic acid (5 mL) was added. The mixture was heated to 35°C for 16 hours. The solution was then cooled to room temperature and concentrated in vacuo. This gave 440 mg of crude Compound 138.1a.

[0282] Compound 138.1 (440 mg, crude; mixture of α and β anomers, with the β anomer being the major product) was dissolved in dry pyridine (5 mL) and stirred for 30 min. Acetic anhydride (195.84 mg, 1.92 mmol, 1.50 eq) was added at 0 °C to the stirred solution at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (10 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 10 mL), and the combined organic layers were washed with brine (3 × 10 mL), dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined and the solvent was evaporated to give compound 138a.

[0283] 80% yield over two steps (420 mg, 1.03 mmol, crude; mixture of α and β anomers, β anomer being the major product), colorless oil. LCMS (ESI+) m / z: C 20 H 22 Calculated for O9 [M+H2O]+ = 424.13, found 424.13, RT: 1.523 min, Method 1.

[0284] Preparation of Compound 139a [ka] 6-Chloropurine (121.79 mg, 0.81 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (150.22 mg, 0.74 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, compound 138a (300 mg, 0.74 mmol, 1.00 eq) in MeCN (2.2 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (194.94 mg, 0.88 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with saturated NaHCO (3 × 20 mL) and saturated aqueous NaCl (3 × 20 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected and the solvent was removed in vacuo to give compound 139a.

[0285] 59% yield (220 mg, 0.44 mmol, crude), colorless oil. LCMS(ESI+)m / z:C 23 H 21 Calculated for ClN4O7 [M+H]+ = 501.11, found 501.11, RT: 1.534 min, Method 1.

[0286] Preparation of Compound 140a [ka] Compound 139a (280 mg, 0.56 mmol, 1.00 eq) was dissolved in 1,4-dioxane (2.4 mL) and NH3 (aq. 0.6 mL) was added. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 140a.

[0287] 44% yield (75 mg, 0.25 mmol), off-white solid. 1 H NMR(300MHz,MeOD)δ 8.21(d,J=6.9Hz,2H),6.16(d,J=6.8Hz,1H),5.08-5.01(m,1H),4.61(d,J =3.9Hz,1H),4.40-4.31(m,1H),2.17-2.00(m,2H),1.78-1.59ppm(m,2H). 13 C NMR(75MHz,MeOD)δ 155.90,152.43,149.60,140.12,119.31,88.43,87.24,76.52,73.87,25.86,22.51ppm.LCMS(ESI+)m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.11, RT: 0.446 min, Method 1.

[0288] Preparation of Compound 4b' [ka] Compound 5b' (2.6 g, used as the mixture obtained in the above procedure under "Alternative Preparation of Compound 5" and containing 30% pure compound 5b', 800 mg, 3.47 mmol, 1.00 eq), DMAP (211.67 mg, 1.73 mmol, 0.50 eq) were dissolved in pyridine (10 mL), and then benzoyl chloride (971.60 mg, 6.94 mmol, 2.00 eq) was added dropwise at 0 °C. The resulting solution was stirred at 0 °C for 1 h. HCl (1 M, aqueous, 20 mL) was then added to the reaction mixture until a pH < 7 was reached. The product was extracted with EtOAc (3 × 20 mL), and the combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by C18 column (mobile phase A: water (0.1 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40B to 70B in 30 min; 210 / 254 nm). The fractions containing the product were collected and the solvent was evaporated to give compound 4b.

[0289] 34% yield (400 mg, 1.19 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 8.15-8.06(m,2H),7.59-7.51(m,1H),7.48-7.39(m,2H),5.64-5.52(m,1H),5.04(s,1H),4.63(d ,J=0.8Hz,2H),3.42(s,3H),2.44-2.17(m,3H),2.05-1.88(m,1H),1.35(s,3H),1.30ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ LCMS(ESI+)m / z:C 18 H 22 Calculated for O6 [M+H]+ = 335.14, found 335.14, RT: 1.675 min, Method 1.

[0290] Preparation of Compound 138b [ka] Compound 4b' (400 mg, 1.19 mmol, 1.00 eq) was dissolved in HO (5 mL) and formic acid (5 mL) was added. The mixture was heated to 35 °C for 16 h. The solution was then cooled to room temperature and concentrated in vacuo to give 420 mg of crude compound 138.1b (a mixture of α and β anomers, with the β anomer being the major product).

[0291] Compound 138.1b (420 mg, crude) was dissolved in dry pyridine (5 mL) and stirred for 30 min. Acetic anhydride (181.56 mg, 1.78 mmol, 1.50 eq) was added at 0 °C to the stirred solution at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (10 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 10 mL), and the combined organic layers were washed with brine (3 × 10 mL), dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined, and the solvent was removed in vacuo to give compound 138b.

[0292] 74% yield over two steps (361 mg, 0.88 mmol, crude; mixture of α and β anomers, β anomer being the major product), colorless oil. LCMS (ESI+) m / z: C 20 H 22 Calculated for O9 [M+H2O]+ = 424.13, found 424.13, RT: 1.545 min, Method 1.

[0293] Preparation of Compound 139b [ka] 6-Chloropurine (100.10 mg, 0.65 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (131.95 mg, 0.65 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, compound 138b (241 mg, 0.59 mmol, 1.00 eq) in MeCN (2.2 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (157.21 mg, 0.71 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (20 mL), and washed with saturated NaHCO (3 × 20 mL) and saturated aqueous NaCl (3 × 20 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected and the solvent was removed in vacuo to give compound 139b.

[0294] 71% yield (210 mg, 0.42 mmol, crude), colorless oil. LCMS (ESI+) m / z: C 23 H 21 Calculated for ClN4O7 [M+H]+ = 501.11, found 501.11, RT: 1.597 min, Method 1.

[0295] Preparation of Compound 140b [ka] Compound 139b (295 mg, 0.59 mmol, 1.00 eq) was dissolved in 1,4-dioxane (3.0 mL) and NH3 (aq. 0.8 mL) was added. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 140b.

[0296] 53% yield (92 mg, 0.31 mmol), off-white solid. 1 H NMR(300MHz, methanol-d4)δ 8.23(d,J=9.8Hz,2H),6.07(d,J=5.2Hz,1H),4.83-4.77(m,1H),4.52-4.4 4(m,1H),4.23(d,J=5.1Hz,1H),2.21-2.08(m,2H),2.04-1.92ppm(m,2H). 13 C NMR (75 MHz, CDCl3) data awaited. 13 C NMR(75MHz,MeOD)δ 155.74,152.18,149.31,140.06,119.30,90.77,88.47,73.75,73.71,67.29,26.56,26.01ppm.LCMS(ESI+)m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.11, RT: 0.412 min, Method 1.

[0297] Preparation of Compounds 6a and 6b [ka] To a stirred solution of CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) in acetonitrile (6 mL) was added 2-chloro-1-methylpyridinium iodide (702 mg, 2.75 mmol, 1.5 eq), tert-butyl vinyl ether (2.42 mL, 18.33 mmol, 10 eq), and finally DIPEA (0.96 mL, 5.49 mmol, 3 eq). The resulting reaction mixture was then refluxed for 16 h. The reaction was then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered, and concentrated to give the crude product compound. The crude product, consisting of two isomers, was then purified by silica gel column chromatography (petroleum ether / EtOAc 80:20) to give two isomers: compound 6a as a colorless oil and compound 6b as colorless crystals in pure form.

[0298] Compound 6a (20% yield, 110 mg), R f 0.6 (Oil Etrol / EtOAc 80:20): 1 H NMR(400MHz,クロロホルム-d)δ 5.48(d,J=5.8Hz,1H),5.02(s,1H),4.55(d,J=5.8Hz,1H),4.11(t,J=7.9Hz,1 H),3.32(s,3H),2.98-2.82(m,2H),1.46(s,3H),1.29(s,3H),1.19ppm(s,9H). 13 C NMR(101MHz,クロロホルム-d)δ 200.48,113.42,109.05,102.24,84.87,79.55,74.50,66.55,55.17,50.53,27.99,26.03,25.30ppm.

[0299] Compound 6b (25% yield, 140 mg), R f 0.4 (Oil Etrol / EtOAc 80:20): 1 H NMR(400MHz,クロロホルム-d)δ 5.04(s,1H),4.84(d,J=5.7Hz,1H),4.60(d,J=5.8Hz,1H),4.15(dd,J=6.1,1.8Hz,1H),3.43(s,3H),3 .22(dd,J=17.4,6.1Hz,1H),2.65(dd,J=17.3,1.8Hz,1H),1.48(s,3H),1.29(s,3H),1.22ppm(s,9H). 13 C NMR(101MHz,クロロホルム-d)δ 199.49,114.03,109.00,100.54,86.17,84.47,75.33,67.26,56.19,51.16,28.37,26.03,25.48ppm. GC-MS:[M + ]301, 15.14 points (Method 4).

[0300] Modulation of Compound 7

change

[0301] To the carbonyl chloride obtained above in DCM (25 mL) was added ethoxyacetylene (18.33 mmol, 40% w / w in hexane, 2 eq). The stirred solution was then treated dropwise with triethylamine (1.38 mL, 10.08 mmol, 1.1 eq) at rt. After 30 min, the suspension was heated to reflux and stirred for an additional 16 h. The resulting cloudy mixture was allowed to cool, after which triethylammonium chloride was removed by filtration, and the filtrate was concentrated in vacuo to give a brown oil. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 70:30) to give compound 7 (1.32 g, 4.88 mmol, 53%) as a brown oil, which is a mixture of two (74:26) diastereomers, as suggested by NMR spectroscopy.

[0302] Data for the major isomers: 1 H NMR(400MHz,chloroform-d)δ 5.35(d,J=0.9Hz,1H),5.02(d,J=1.2Hz,1H),4.88(dd,J=5.8,1.2Hz,1H),4.61(dt,J=5.8,0.8Hz ,1H),4.30-4.16(m,2H),3.35(s,3H),1.51(s,3H),1.47(td,J=7.1,1.1Hz,3H),1.30ppm(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 186.52, 182.08, 113.98, 113.40, 106.51, 101.02, 84.32, 79.97, 69.94, 54.84, 25.88, 24.91, 14.00 ppm.

[0303] Preparation of Compound 8 [ka] To a stirred solution of CAS 54622-95-6 (200 mg, 0.92 mmol, 1 eq) in DCM (2 mL), 1 drop of DMF, oxalyl chloride (0.12 mL, 1.37 mmol, 1.5 eq) was added, and the resulting reaction mixture was stirred at room temperature for 4 h. Excess solvent and oxalyl chloride were removed in vacuo for 1 h and carried on to the next step.

[0304] To the acid chloride obtained above in toluene (2 mL) in a sealed tube, 1-(trimethylsilyl)propyne (1.03 mL, 9.16 mmol, 10 eq) was added, followed by EtN (0.15 mL, 1.10 mmol, 1.2 eq). The resulting reaction mixture was heated at 120 °C overnight (16 h) and then quenched with HCl (1 M, 10.00 mL). The aqueous phase was extracted with EtOAc (20 × 2 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10) to give compound 8 (146 mg, 0.47 mmol, 51%) as a colorless oil (which is a mixture of two (82:18) diastereomers, as suggested by NMR spectroscopy).

[0305] Data for the major isomers: 1 H NMR (400 MHz, chloroform-d) δ 4.89 (s, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 3.28 (s, 3H), 1.87 (s, 3H), 1.50 (s, 3H), 1.26 (s, 3H), 0.28 ppm (s, 9H). 13 C NMR (101 MHz, chloroform-d) δ 190.85, 179.55, 164.97, 112.15, 107.42, 107.24, 85.15, 80.81, 54.60, 25.55, 23.60, 10.45, −1.09 ppm. LCMS: (ESI + ):[M+1] +=313.3, RT 1.23 minutes (Method 10)

[0306] Preparation of Compound 9 [ka] To a stirred solution of CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) in toluene (6 mL) was added 2-chloro-1-methylpyridinium iodide (702 mg, 2.75 mmol, 1.5 eq), phenyl vinyl sulfide (0.60 mL, 4.58 mmol, 2.5 eq), and DIPEA (0.96 mL, 5.49 mmol, 3 eq). The resulting reaction mixture was then refluxed for 16 h. The reaction was then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel chromatography (petroleum ether / EtOAc 90:10) to give compound 9 (140 mg, 0.42 mmol, 23%) as a pale yellow oil, which is a mixture of two (82:18) diastereomers as suggested by NMR spectroscopy.

[0307] Data for the major isomers: 1 H NMR (400 MHz, chloroform-d) δ 7.32 (s, 5H), 5.20-5.12 (m, 2H), 5.06 (s, 1H), 4.44 (d, J = 6.1 Hz, 1H), 3.39 (d, J = 8.5 Hz, 1H), 3.36 (d, J = 4.8 Hz, 1H), 3.33 (s, 3H), 1.39 ppm (s, 3H), 1.30 (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 195.94, 158.20, 134.45, 129.25, 129.08, 127.89, 113.36, 107.43, 95.72, 82.32, 77.32, 77.00, 76.68, 76.42, 55.57, 40.93, 26.76, 25.90 ppm.

[0308] Preparation of Compound 10 [ka] To a stirred solution of CAS 39682-04-7 (3.10 g, 10.53 mmol, 1 eq) in DCM (15 mL), 1 drop of DMF, oxalyl chloride (1.35 mL, 15.80 mmol, 1.5 eq) was added, and the resulting reaction mixture was stirred at room temperature for 4 h. Excess solvent and oxalyl chloride were removed in vacuo for 1 h and carried on to the next step.

[0309] To a stirred solution of EtN (2.28 mL, 15.80 mmol, 1.5 eq) and vinyltrimethoxysilane (12.42 mL, 84.29 mmol, 8 eq) in toluene (20 mL) at 80 °C, the acid chloride obtained above in toluene (10 mL) was added over 2 h via syringe pump. The reaction mixture was then refluxed at 120 °C overnight (16 h) and then quenched with HCl (1 M, 40.00 mL). The aqueous phase was extracted with EtOAc (40 × 2 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10) to give compound 10 (2.40 g, 6.37 mmol, 60%) as a colorless oil (which is a mixture of four (56:24:11:9) diastereomers, as suggested by NMR spectroscopy).

[0310] Compound 10 was purified by prep HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50 × 150 mm, mobile phase: 0.25% NH4HCO3 solution in water, CH3CN) to give two fractions: compound 10a (11.5 mg, 0.03 mmol, 5% yield) (50.6 mg, 0.13 mmol, 20% yield) and compound 10b (12 mg, 0.03 mmol, 5% yield).

[0311] compound 10a 1H NMR (400MHz, クロロホルム-d): δ 7.31-7.49(m,5H),5.89(d,J=4.0Hz,1H),4.59-4.72(m,3H),4.12(s,1H),3.02(dd,J=16.3,11.9Hz ,1H),2.65(dd,J=16.1,12.1Hz,1H),1.69(s,3H),1.61-1.67(m,1H),1.30(s,3H),0.00ppm(s,9H). 13 C NMR(101MHz,クロロホルム-d:δ 202.8,137.8,129.7,129.4,129.3,114.2,105.9,104.9,84.2,82.9,73.1,44.6,27.4,26.9,25.0,0.0ppm. LCMS: (ESI + ):[M+1] + =377.4, RT1.31 points (Method 10)

[0312] Compound 10b 1 H NMR (600MHz, クロロホルム-d): δ 7.33-7.37(m,2H),7.29-7.33(m,1H),7.26-7.29(m,2H),6.12(d,J=4.3Hz,1H),4.75(dd,J=4.3,2.1Hz,1H),4.73(d,J=11.4Hz,1H),4. 57(d,J=11.4Hz,1H),4.31(d,J=2.0Hz,1H),2.79(d,J=12.2Hz,2H),1.84(t,J=12.2Hz,1H),1.57(s,3H),1.43(s,3H),0.14ppm(s,9H). 13 C NMR(151MHz,クロロホルム-d:δ 205.7,136.6,128.3,127.7,127.0,115.3,103.8,100.3,85.2,85.1,71.8,43.1,28.2,27.4,22.8,-2.0ppm. LCMS: (ESI + ):[M+18] + =394.3, RT1.35 points (Method 10)

[0313] Modulation of Compound 11 [ka] To a stirred solution of compound 10 (1.60 g, 4.25 mmol, 1 eq) in dry THF (5 mL) was added dropwise acetic acid (0.24 mL, 4.25 mmol, 1 eq) and TBAF (12.75 mL, 1.0 M in THF, 3 eq). The resulting reaction mixture was stirred at rt for 5 h, quenched by adding water (20 mL), and extracted with EtOAc (40 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 80:20, R f =0.5) to give compound 11 (185 mg, 0.61 mmol, 14% (28% brsm)) as a colorless oil, which is a mixture of two (65:35) diastereomers as suggested by NMR spectroscopy. This experiment was repeated once more to give 180 mg, 14%, and these two crops were combined to give compound 11 (365 mg).

[0314] Data for the major isomer of compound 11: 1 H NMR (chloroform-d, 600MHz): δ=7.34-7.38(m,2H),7.31-7.33(m,1H),7.30(br d,J=6.9Hz,2H),6.05(d,J=3.6Hz,1H),4.69(d,J=12.2Hz,1H),4.66(d,J=3.5Hz,1H),4.49(d,J=12.2Hz,1H), 4.20(s,1H),2.64-2.77(m,2H),2.36(td,J=11.3,4.9Hz,1H),2.14-2.22(m,1H),1.50(s,3H),1.34ppm(s,3H). 13 C NMR (chloroform-d, 151 MHz): δ = 203.1, 136.8, 128.6, 128.2, 128.0, 113.4, 106.6, 99.7, 86.6, 83.6, 72.0, 40.7, 27.1, 26.5, 26.0 ppm.

[0315] Preparation of Compound 12 [ka] To compound 11 (350 mg, 1.15 mmol, 1.00 eq) in MeOH (4 mL) (the wavy cyclobutane bond in compound 11 refers to the mixture of multiple isomers obtained previously) was added NaBH (57 mg, 1.50 mmol, 1.30 eq) at −78° C., and the resulting reaction mixture was stirred at −78° C. for 1 h. The reaction was then quenched by adding saturated NH Cl (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 12. The crude product (TLC), consisting of three isomers, was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10 to 80:20) to give three isomers: compound 12a as a colorless oil (Rf 0.4, 165 mg, 47% as a mixture of two diastereomers (91:9) as suggested by NMR spectroscopy), compound 12b as a colorless oil (Rf 0.3, 80 mg, 23% as a mixture of three diastereomers (68:26:6) as suggested by NMR spectroscopy), and compound 12c as a colorless oil (Rf 0.2, 80 mg, 23% as a single pure isomer as suggested by NMR spectroscopy).

[0316] Compound 12a was purified by Prep HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH 4 HCO 3 solution in water, MeOH) to give 86 mg, 0.28 mmol, 53% yield.

[0317] Data for compound 12a 1H NMR(300MHz,chloroform-d)δ 7.39-7.25(m,5H),5.92(d,J=4.2Hz,1H),4.74(d,J=12.0Hz,1H),4.64(d,J=4.2Hz,1H),4.52(d,J=12.1Hz,1H),4.15-4.05(m,1H) ),3.84(s,1H),2.92(d,J=3.4Hz,1H),2.29(t,J=8.7Hz,2H),1.89-1.68(m,2H),1.48(d,J=0.7Hz,3H),1.28ppm(d,J=0.7Hz,3H). LCMS: (ESI + ):[M+18] + =324.3, RT 1.01 min (Method 10)

[0318] Data for the major isomer of compound 12b: 1 H NMR (300 MHz, chloroform-d) δ 7.52-7.35 (m, 5H), 5.93 (d, J = 3.4 Hz, 1H), 4.88-4.81 (m, 1H), 4.71 (d, J = 3.8 Hz, 1H), 4.48 (s, 1H), 4.44-4.37 (m, 1H), 4.33 (dd, J = 8.9, 7.8 Hz, 1H), 3.04 (d, J = 1.1 Hz, 1H) ),2.36(dddd,J=12.3,10.0,2.5,1.2Hz,1H),2.14(dddd,J=11.0,9.8,8.3,2.5Hz, 1H),1.90-1.74(m,1H),1.65(s,3H),1.42(d,J=0.7Hz,3H),1.36-1.30ppm(m,1H).

[0319] Data for compound 12c 1H NMR(300MHz,chloroform-d)δ 7.36-7.20(m,5H),5.91(d,J=3.9Hz,1H),4.69(d,J=12.1Hz,1H),4.56(dd,J=4.0,0.8Hz,1H),4.46(d,J=12.1Hz,1H),4.35-4.24(m,1H),3.77 (t,J=0.6Hz,1H),2.50(d,J=8.7Hz,1H),2.15-2.00(m,2H),2.00-1.84(m,1H),1.81-1.68(m,1H),1.45-1.37(m,3H),1.25ppm(d,J=0.7Hz,3H). LCMS: (ESI + ):[M+18] + =324.4, RT0.94 minutes (method 10)

[0320] Preparation of Compound 13 [ka] To a stirred solution of CAS 39682-04-7 (400 mg, 1.36 mmol, 1 eq) in acetonitrile (6 mL) was added 2-chloro-1-methylpyridinium iodide (521 mg, 2.04 mmol, 1.5 eq), tert-butyl vinyl ether (1.79 mL, 13.59 mmol, 10 eq), and finally DIPEA (0.71 mL, 4.08 mmol, 3 eq). The resulting reaction mixture was then refluxed for 16 h. The reaction was then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel chromatography (petroleum ether / EtOAc 90:10) to give compound 13 (100 mg, 0.27 mmol, 20%, as a single diastereomer but as an unknown diastereomer) as a colorless oil.

[0321] 1H NMR(400MHz,クロロホルム-d)δ 7.39-7.28(m,5H),6.07(d,J=4.3Hz,1H),4.77(d,J=12.0Hz,1H),4.73(dd,J=4.4,2.1Hz,1H),4.68(d,J=2.2Hz, 1H),4.60(d,J=12.0Hz,1H),4.32(t,J=8.3Hz,1H),2.87-2.74(m,2H),1.49(s,3H),1.39(s,3H),1.18ppm(s,9H). 13 C NMR(101MHz,クロロホルム-d)δ 205.64,137.11,128.34,127.78,127.76,114.63,105.73,101.55,85.76,81.73,74.70,72.33,63.74,50.16,28.21,27.86,27.44ppm

[0322] Modulation of Compound 14

change

[0323] 1 H NMR (400MHz, chloroform-d δ 5.27(d,J=4.8Hz,1H),5.20(dd,J=6.3,4.8Hz,1H),4.85(s,1H),4.24(q,J=6.6 Hz,1H),3.41(s,3H),3.33(dd,J=6.5,4.9Hz,2H),1.22(s,9H),1.21ppm(s,9H) 13 C NMR (101 MHz, chloroform-d δ 177.0, 176.8, 106.1, 80.3, 75.2, 74.9, 55.3, 38.8, 38.6, 27.1, 6.7 ppm)

[0324] Preparation of Compound 15 [ka] Compound 14 (47.8 g, 108 mmol, 1.00 eq) was dissolved in DMF (500 mL), and DBU (17.8 mL, 119 mmol, 1.10 eq) was added in one portion to the stirred mixture, which was heated to 90 °C for 18 h. The mixture was cooled to room temperature and concentrated in vacuo to approximately 250 mL. The brown solution was then diluted with n-heptane (1.5 L) and washed with brine (3 × 750 mL). The resulting organic phase was dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 99:1 to 9:1). The product-containing fractions were collected, and the solvent was evaporated to give the desired compound 15 (30.2 mg, 96.1 mmol, 89% yield) as a colorless liquid.

[0325] 1 H NMR(360MHz,chloroform-d)δ 5.76(dt,J=5.1,1.9Hz,1H),5.16(d,J=5.1Hz,1H),5.02(s,1H),4.51(t,J= 1.8Hz,1H),4.08(t,J=2.0Hz,1H),3.46(s,3H),1.23(s,9H),1.21ppm(s,9H) 13 C NMR (101 MHz, chloroform-d) δ 177.3, 177.2, 157.2, 106.2, 84.6, 73.2, 69.7, 56.3, 39.1, 39.0, 27.4, 27.3 ppm

[0326] Preparation of Compound 16 [ka] Zinc powder (25.0 g, 0.38 mol, 1.00 eq) was added to a two-necked round-bottom flask (500 mL) containing demineralized water (100 mL), and the solution was degassed with nitrogen for 15 minutes. Copper(II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was then added, and the stirred solution was degassed and stirred for 45 minutes. The mixture was filtered, and the black solid was washed with degassed water (250 mL) and degassed acetone (250 mL), respectively. The zinc-copper couple was dried in vacuo for 12 hours. Compound 15 (10.0 g, 31.8 mmol, 1.00 eq) was weighed into an oven-dried flask and dissolved in anhydrous diethyl ether (300 mL, dried over 4 Å molecular sieves). Zinc-copper couple (14.6 g, 223 mmol, 7.00 eq) was then added in one portion to the stirred solution in diethyl ether. An oven-dried, pressure-equalizing addition funnel was attached and charged with anhydrous diethyl ether (100 mL) and trichloroacetyl chloride (6.10 mL, 54.1 mmol, 1.70 eq). The reagents were added dropwise over 2.5 h, carefully monitoring the temperature so that it did not exceed 25 °C. After addition, the zinc-copper couple was decanted and rinsed with diethyl ether (100 mL), and the organic layer was diluted with n-heptane (500 mL), followed by washing with NaHCO (aq. sat. 3 × 300 mL) and brine (2 × 250 mL). The organic phase was dried (MgSO), filtered, and the filtrate was concentrated in vacuo at 40 °C to give compound 16 (13.2 g, crude).

[0327] 1 H NMR (360 MHz, chloroform-d) δ 5.84 (d, J = 4.0 Hz, 1H), 5.35 (d, J = 4.4 Hz, 1H), 4.98 (s, 1H), 3.92 (d, J = 18.7 Hz, 1H), 3.51 (s, 1H), 3.40 (d, J = 18.7 Hz, 1H), 1.19 ppm (s, 18H) 13 C NMR (91 MHz, chloroform-d) δ 191.0, 176.3, 175.4, 106.0, 91.4, 83.2, 74.6, 71.2, 55.9, 52.0, 38.5, 26.8 ppm

[0328] Preparation of Compound 17 [ka] Compound 16 (2.64 g, 6.21 mmol, 1.00 eq) was dissolved in THF (45.0 mL), and acetic acid (5.33 mL, 93.1 mmol, 15.0 eq) was added, followed by zinc powder (4.06 g, 62.1 mmol, 10.0 eq) in small portions. The mixture was heated to 50 °C for 5 h. The solution was then cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to a minimum volume, redissolved in EtOAc (200 mL), washed with brine (2 × 75 mL), dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 99:1 to 1:1). The product-containing fractions were collected, and the solvent was evaporated to give the desired compound 17 (1.48 mg, 4.16 mmol, 67% yield) as a colorless oil.

[0329] 1 H NMR (360 MHz, chloroform-d) δ 5.56 (d, J = 4.4 Hz, 1H), 5.26 (dd, J = 4.4, 0.7 Hz, 1H), 4.91 (s, 1H), 3.43-3.51 (m, 2H), 3.42 (s, 3H), 3.33-3.41 (m, 1H), 3.14-3.25 (m, 1H), 1.22 (s, 9H), 1.21 ppm (s, 9H). 13 C NMR (101 MHz, chloroform-d) δ 203.2, 177.2, 176.8, 105.7, 75.7, 75.1, 74.0, 58.3, 55.7, 55.5, 39.0, 38.8, 27.1 ppm

[0330] Preparation of Compound 18a and Compound 18b [ka] Compound 17 (500 mg, 1.40 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and NaBH (64.0 mg, 1.68 mmol, 1.20 equiv) was added portionwise at −78° C. The resulting solution was stirred at −78° C. for 30 min. The reaction was then quenched by adding 20 mL of saturated aqueous NH Cl. The resulting solution was extracted with 2 × 20 mL of ethyl acetate, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected, and the solvent was evaporated to give compound 18a (mixed with 14% compound 18b).

[0331] 75% yield (375 mg, 11.4 mmol), colorless oil. 1 H NMR(400MHz,chloroform-d)δ 5.27(d,J=4.5Hz,1H),5.16(dd,J=4.6,1.9Hz,1H),4.83(d,J=1.9Hz,1H),3.92(p,J=7.1Hz,1H),3.39(s,3H),2. 78-2.86(m,1H),2.74-2.65(m,1H),2.41-2.33(m,1H),2.15-2.21(m,1H),1.23(s,9H),1.20ppm(s,9H).GCMS(ESI + ) m / z:C 18 H 30 Calculated value for O7 [M-CHO] + =327.18, actual value 327.14, RT: 9.317 min, (Method 1).

[0332] Preparation of Compound 19a and Compound 19b [ka] Compound 18a (mixture with compound 18b) (7.00 g, 19.5 mmol, 1.0 eq) and TEA (3.94 g, 39.1 mmol, 2.0 equiv) were dissolved in DCM (70 mL). Benzoyl chloride (5.47 g, 39.1 mmol, 2.0 equiv) was then added dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. The reaction was then quenched with 1 M aqueous HCl until pH < 7. 130 mL of DCM was added to the resulting solution, which was extracted with 1 × 200 mL of HO. The organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (gradient elution: PE / EtOAc 99:1 to 20:1). The product-containing fractions were collected, and the solvent was evaporated to give compound 19a (13% mixture with compound 19b).

[0333] 87% yield (7.90 g, 17.10 mmol), colorless oil. 1 H NMR(400MHz,chloroform-d)δ 8.07-8.01(m,2H),7.60-7.52(m,1H),7.44(dd,J=8.4,7.1Hz,2H),5.38(d,J=4.5Hz,1H),5.21(dd,J=4.5,1.3Hz,1H),4.86-4.78(m,2H),3.40( s,3H),3.05-3.14(m,1H),2.94-2.84(m,1H),2.73(dd,J=12.9,7.3Hz,1H),2.44(dd,J=12.9,7.3Hz,1H),1.29(s,9H),1.22ppm(s,9H).LCMS(ESI + ) m / z:C 25 H 34 Calculated value for O8 [M+NH4] + = 480.26, actual value 480.25, RT: 2.151 min (Method 1).

[0334] Preparation of Compound 19b [ka] Compound 18 (2.28 g, 6.36 mmol, 1.00 eq) was dissolved in THF (60 mL) and benzoic acid (932 g, 7.63 mmol, 1.20 eq) was added, followed by triphenylphosphine (2.01 g, 7.63 mmol, 1.20 eq). The mixture was cooled to 0 °C, and diethyl azodicarboxylate (1.15 mL, 7.31 mmol, 1.20 eq) was added. The mixture was allowed to warm to room temperature after the addition and stirred for 16 h. Subsequently, pentane (120 mL) was added to precipitate triphenylphosphine oxide. The solid was filtered and rinsed with heptane (30 mL). Brine (50 mL) was added to the filtrate, and the product was extracted into heptane (1 × 150 mL, 2 × 100 mL). The combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 99:1 to 4:1). The fractions containing intermediate 30 were collected and the solvent was evaporated to give compound 19b (1.79 mg, 3.88 mmol, 61% yield) as a colorless oil.

[0335] 1 H NMR(400MHz,chloroform-d)δ 7.98-8.04(m,2H),7.52-7.60(m,1H),7.39-7.47(m,2H),5.44(m,1H),5.37(d,J=4.4Hz,1H),5.18(dd,J=4.4,1.5Hz,1H),4.88(d, J=1.5Hz,1H),3.42(s,3H),2.81(ddd,J=13.4,7.5,4.4Hz,1H),2.62-2.72(m,2H),2.52-2.62(m,1H),1.21(s,9H),1.20ppm(s,9H) 13 C NMR (101 MHz, chloroform-d) δ 177.2, 177.0, 166.1, 133.0, 130.0, 129.6, 128.4, 105.7, 81.1, 75.1, 74.3, 65.5, 55.4, 41.3, 39.3, 39.0, 38.8, 27.2, 27.1 ppm

[0336] Preparation of Compound 20 [ka] 6-Cl purine CAS 87-42-3 (1.69 g, 10.9 mmol, 1.1 equiv) was dissolved in MeCN (37 mL) and N,O-bis(trimethylsilyl)acetamide (2.02 g, 9.95 mmol, 1 equiv) was added dropwise. The mixture was heated to 80 °C overnight. After cooling, compound 19a (a 13% mixture with compound 19b) (4.6 g, 9.95 mmol, 1.00 equiv) in MeCN (31 mL) was added, and trimethylsilyl trifluoromethanesulfonate (2.65 g, 11.94 mmol, 1.2 equiv) was added, and the mixture was heated to 80 °C for 2 h. After cooling to rt, the mixture was extracted with EtOAc, twice with saturated NaHCO₃, and once with saturated aqueous NaCl. The organic layer was dried over Na₂SO₄. The solvent was removed in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 30:1). The product-containing fractions were collected and the solvent was evaporated to give compound 20. 86% yield (5.00 g, 8.56 mmol), foamy solid. 1 H NMR(300MHz,chloroform-d)δ 8.81(s,1H),8.21(s,1H),8.09-8.02(m,2H),7.64-7.57(m,1H),7.49(dd,J=8.4,6.9Hz,2H),6.23(t,J=5.2Hz,,1H),6.08(d,J=5 .5Hz,1H),5.83(d,J=4.8Hz,1H),5.44-5.36(m,1H),3.08-2.99(m,1H),2.83-2.63(m,3H),1.32(s,9H),1.16ppm(s,9H).LCMS(ESI + ) m / z:C 29 H 33 Calculated value for ClN4O7 [M+H] + = 585.20, actual value 585.30, RT: 2.226 min (Method 6).

[0337] Preparation of Compound 21 [ka] Compound 20 (4.0 g, 6.8 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (40 mL) and aq. NH3 (10 mL). The mixture was heated to 80 °C overnight. After cooling to rt, the solvent was removed in vacuo. The product was dissolved in MeOH (40 mL) and sodium methoxide (0.37 g, 6.84 mmol, 1.00 equiv) was added. The reaction was stirred at rt for 30 min and then stirred with H-exchange resin until pH = 7. It was then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 21.

[0338] 95% yield (1.90 g, 6.48 mmol), white solid. 1 H NMR(400MHz,D2O)δ8.24(s,1H),8.16(s,1H),5.97(d,J=6.6Hz,1H),4.91(dd,J=6.7,4.5Hz, 1H),4.40(p,J=6.5Hz,1H),4.28(d,J=4.5Hz,1H),2.64-2.42(m,4H),2.29-2.22ppm(m,1H). 13 C NMR(101MHz,DMSO)δ 156.06,153.09,150.02,140.48,119.36,86.86,78.91,75.14,73.28,57.38,45.97,41.03ppm.LCMS(ESI + ) m / z:C 12 H 15 Calculated value for N5O4 [M+H] + = 294.11, actual value 294.12, RT: 1.301 min (Method 8).

[0339] Preparation of Compound 22 [ka] Compound 21 (1.80 g, 6.14 mmol, 1.00 equiv) was dissolved in acetone (18 mL), and 2,2-dimethoxypropane (1.3 g, 12.3 mmol, 2.00 equiv) and perchloric acid (0.12 g, 1.22 mmol, 0.20 equiv) were added at 0 °C. The reaction was stirred at rt for 1 h. The reaction was then added with 1 M aqueous NaOH solution until pH = 7, followed by 50 mL of DCM. Extraction with 1 × 60 mL of HO was performed, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 85:15). The product-containing fractions were collected, and the solvent was evaporated to give compound 22.

[0340] 77% yield (1.58 g, 4.50 mmol), pale yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 8.00(s,1H),7.96(s,1H),5.81(s,1H),5.41(d,J=5.7Hz,1H),4.68(d,J=5.7Hz,1H),3.56(p,J=7.3Hz,1H),2.51(dd,J=12. 1,6.1Hz,1H),2.24(dt,J=12.2,6.4Hz,1H),1.85(dd,J=11.9,7.9Hz,1H),1.23(s,3H),1.21-1.16(m,1H),1.13ppm(s,3H). 13 C NMR(101MHz,DMSO)δ 156.04,153.16,149.37,140.31,118.89,112.93,88.54,84.95,83.96,80.02,57.56,48.94,45.32,26.62,25.34ppm.LCMS(ESI + ) m / z:C 15 H 19 Calculated value for N5O4 [M+H] + = 334.14, actual value 334.10, RT: 0.894 min (Method 3).

[0341] Preparation of Compound 23 [ka] Compound 22 (1.5 g, 4.5 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL), and pyridine (15 mL) and MsCl (0.77 g, 6.75 mmol, 1.5 equiv) were added at 0° C. The reaction was stirred at 40° C. for 3 h. The reaction mixture was then poured into 30 mL of ice water, extracted with 30 mL of dichloromethane, and concentrated under reduced pressure to give compound 23. 97% yield (1.8 g, 4.38 mmol), pale yellow oil. 1 H NMR(300MHz, methanol-d4)δ 8.23(s,1H),8.19(s,1H),6.14(d,J=1.1Hz,1H),5.77(dd,J=5.8,1.1Hz,1H),5.08(d,J=5.8Hz,1H),4.74(q,J=7.1Hz,1H),3.13(dt,J=12.8,6 .4Hz,1H),3.01(s,3H),2.83(dt,J=12.7,6.4Hz,1H),2.54(dd,J=12.8,7.3Hz,1H),1.96(dd,J=12.5,7.1Hz,1H),1.52(s,3H),1.42ppm(s,3H). 13 C NMR (75 MHz, methanol-d4) δ 155.85, 152.30, 148.83, 140.71, 119.06, 113.22, 89.77, 85.02, 84.26, 81.16, 66.42, 43.35, 38.31, 36.62, 25.40, 24.05 ppm. LCMS (ESI + ) m / z:C 16 H 21 Calculated value for N5O6S [M+H] + = 412.12, actual value 412.15, RT: 0.987 min (Method 1).

[0342] Preparation of Compound 24 [ka] Compound 23 (1.80 g, 4.38 mmol, 1.00 equiv) was dissolved in DMF (30 mL), and tetrabutylammonium iodide (0.16 g, 0.43 mmol, 0.10 equiv) and NaN3 (2.8 g, 43.8 mmol, 10.00 equiv) were added at 0 °C. The reaction was stirred at 110 °C for 3 h. The reaction mixture was then poured into 45 mL of ice water, extracted with 2 × 50 mL of dichloromethane, and concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 24.

[0343] 70% yield (1.10 g, 8.56 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.22(s,1H),8.19(s,1H),6.15(s,1H),5.69(dd,J=5.9,0.9Hz,1H),5.18(d,J=5.9Hz,1H),4.04-3.96(m,1H),2.67 -2.49(m,2H),2.26(ddd,J=13.0,5.1,3.2Hz,1H),1.88(ddd,J=13.2,7.8,3.4Hz,1H),1.51(s,3H),1.43ppm(s,3H). 13 C NMR (75 MHz, methanol-d4) δ 155.79, 152.55, 148.94, 140.72, 119.00, 112.94, 89.48, 86.17, 85.95, 84.09, 50.02, 41.14, 36.21, 25.36, 24.01 ppm. LCMS (ESI + ) m / z:C 15 H 18 Calculated value for N8O3 [M+H] + =359.15, Actual value 359.15, RT: 1.216 min, (Method 6).

[0344] Preparation of Compound 25 [ka] Compound 24 (1.0 g, 2.80 mmol, 1.00 equiv) was dissolved in methanol (10 mL) and Pd / C (0.2 g) was added. The reaction was stirred overnight at rt under a hydrogen atmosphere. After completion, the solution was then filtered. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 80:20). The product-containing fractions were collected, and the solvent was evaporated to give compound 25.

[0345] 75% yield (0.75 g, 2.25 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.23(s,1H),8.22(s,1H),6.20(s,1H),5.68(dd,J=5.9,0.8Hz,1H),5.22(d,J=5.9Hz,1H),3.61(t,J=7.9Hz,1H),2.64- 2.57(m,1H),2.52(ddd,J=13.6,8.2,5.0Hz,1H),2.25(dd,J=13.3,7.5Hz,1H),1.80(ddd,J=13.2,8.2,4.9Hz,1H),1.51(s,3H),1.43ppm(s,3H). 13 C NMR (101 MHz, methanol-d4) δ 156.02, 152.54, 148.94, 141.03, 119.01, 112.86, 89.46, 86.35, 85.82, 84.14, 41.40, 40.93, 36.98, 25.35, 23.98 ppm. LCMS (ESI + ) m / z:C 15 H 20 Calculated value for N6O3 [M+H] + =333.16, actual value 333.10, RT: 0.902 min, (Method 3).

[0346] Preparation of Compound 26 [ka] To compound 25 (0.12 g, 0.36 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL), and the mixture was heated to 40 °C for 3 h. The solution was then cooled to room temperature and carefully quenched with NaHCO to pH = 7. The mixture was extracted with CHCl (3 × 2 mL), the combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis Prep T3 OBD column, 19 × 250 mm 10 u; mobile phase A: water (10 mM NHHCO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min). The product-containing fractions were collected, and the solvent was evaporated to give compound 26.

[0347] 76% yield (0.08 g, 0.27 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.25(s,1H),8.17(s,1H),6.01(d,J=6.4Hz,1H),4.90(dd,J=6.3,4.6Hz,1H),4.27(d,J=4.6Hz,1H),3.56(p,J=7.5Hz,1H),2.60( ddd,J=12.9,8.2,4.5Hz,1H),2.45(ddd,J=12.8,8.1,4.6Hz,1H),2.31(dd,J=13.5,7.0Hz,1H),2.13ppm(dd,J=13.1,6.8Hz,1H). 13 C NMR(75MHz,D2O)δ 155.68,152.99,149.17,140.14,119.00,87.04,85.03,75.67,73.84,42.36,40.93,38.77ppm.LCMS(ESI + ) m / z:C 12 H 16 Calculated value for N6O3 [M+H] + = 293.13, actual value 293.2, RT: 1.346 min, (Method 8)

[0348] Preparation of Compound 27 [ka] To compound 25 (0.10 g, 0.30 mmol, 1.00 eq) in DCM (10 mL) was added AcOH (0.5 mL), followed by propanal (0.026 g, 0.44 mmol, 1.50 eq). The reaction was stirred at rt for 30 min. The solution was cooled to 0 °C. NaBH(OAc)3 (0.13 g, 0.62 mmol, 2.00 eq) was slowly added, and the mixture was stirred at rt for 3 h and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 27.

[0349] 62% yield (0.07 g, 0.18 mmol), white solid. 1 H NMR(300MHz,D2O)δ 8.16(d,J=17.6Hz,2H),6.23(s,1H),5.66(d,J=5.9Hz,1H),5.22(d,J=5.9Hz,1H),3.84-3.65(m,1H),2.87-2.67(m,3H),2.59(dd,J=13.9,7 .0Hz,1H),2.41(dd,J=13.7,8.1Hz,1H),1.89(s,3H),1.75(t,J=7.1Hz,1H),1.53(d,J=15.6Hz,4H),1.42(s,3H),0.86ppm(t,J=7.4Hz,3H). 13 C NMR(101MHz,D2O)δ 155.60,152.93,148.72,140.76,114.02,88.29,85.20,85.11,83.277,47 .02,46.58,37.52,33.78,25.23,24.10,22.71,19.04,10.12ppm.LCMS(ESI + ) m / z:C 18 H 26 Calculated value for N6O3 [M+H] + =375.21 Actual value 375.10, RT: 1.285 min, (Method 3).

[0350] Preparation of Compound 28 [ka] To compound 27 (0.10 g, 0.27 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL), and the mixture was heated to 40 °C for 3 h. The solution was then cooled to room temperature and carefully quenched with NaHCO to pH = 7. The mixture was extracted with CHCl (3 × 2 mL), the combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis Prep T3 OBD column, 19 × 250 mm 10 u; mobile phase A: water (10 mM NHHCO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm). The product-containing fractions were collected, and the solvent was evaporated to give compound 28.

[0351] 45% yield (0.040 g, 0.12 mmol), white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.25(s,1H),8.13(s,1H),7.22(s,2H),5.85(d,J=5.6Hz,1H),5.26(s,1H),4.8 1(t,J=5.0Hz,1H),4.07(d,J=4.4Hz,1H),3.37-3.24(s,2H)3.19-3.09(m,1H),2 .41(d,J=9.0Hz,1H),2.35(t,J=7.0Hz,2H),2.26(d,J=12.8Hz,1H),2.17-2.04( m,1H),1.97(d,J=12.5Hz,1H),1.39(h,J=7.3Hz,2H),0.86ppm(t,J=7.4Hz,3H). 13 C NMR(75MHz,DMSO)δ 156.52,153.01,149.98,140.36,119.79,87.94,84.94,75.91,73.70,49.18,47.14,41.00,37.38,23.18,12.33ppm.LCMS(ESI + ) m / z:C 15 H 22 Calculated value for N6O3 [M+H] + =335.18, actual value 335.25, RT: 0.908 min, (Method 3).

[0352] Preparation of compound 29 [ka] Compound 18a (mixture with compound 18b) (6.00 g, 16.8 mmol, 1.00 equiv) was dissolved in THF (60 mL), and triphenylphosphine (8.80 g, 33.6 mmol, 2.00 equiv) and benzoic acid (6.20 g, 50.4 mmol, 3.00 equiv) were added. DIAD (10.0 g, 50.4 mmol, 3.00 equiv) was then added slowly at 0 °C. The mixture was stirred at RT for 1 h and then heated to 50 °C for 2 h. Subsequently, an additional 0.5 eq of triphenylphosphine and 1 eq of DIAD were added at 0 °C and then heated to 50 °C for 1 h. The reaction mixture was cooled to RT and added to saturated aqueous NaHCO (200 mL). The aqueous phase was extracted with EA (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 5:1). The fractions containing the product were collected and the solvent was evaporated to give compound 29.

[0353] 69% yield (12.0 g, 35.92 mmol), yellow oil. 1 HNMR (300MHz, chloroform-d)8.03-7.98(m,2H),7.59-7.53(m,1H),7.43(t,J=7.8Hz,2H),5.47-5.39(m,1H),5.37(d,J=4.5Hz,1H),5.18(dd,J=4 .5,1.5Hz,1H),4.88(d,J=1.6Hz,1H),3.42(s,3H),2.81(m,1H),2.71-2.61(m,2H),2.60-2.50(m,1H),1.21ppm(s,9H),1.20(s,9H).LCMS(ESI + ) m / z:C 25 H 34 Calculated value for O8 [M+NH4] + =480.26, actual value 480.25, RT: 1.557 min, Method 7.

[0354] Preparation of Compound 30 [ka] 6-Cl purine CAS 87-42-3 (1.65 g, 10.7 mmol, 1.1 equiv) was dissolved in MeCN (35 mL) and N,O-bis(trimethylsilyl)acetamide (2.02 g, 9.73 mmol, 1.0 equiv) was added dropwise. The mixture was heated to 80 °C overnight. After cooling, compound 29 (4.5 g, 9.73 mmol, 1.00 equiv) in MeCN (30 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (2.59 g, 11.68 mmol, 1.2 equiv), and the mixture was heated to 80 °C for 2 h. After cooling to rt, the mixture was extracted twice with EtOAc and washed once with saturated NaHCO and saturated aqueous NaCl. The organic layer was dried over NaSO. The solvent was removed in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 30:1). The product-containing fractions were collected and the solvent was evaporated to give compound 30.

[0355] 76% yield (4.30 g, 7.36 mmol), foamy solid. 1 H NMR(300MHz,chloroform-d)δ 8.78(s,1H),8.19(s,1H),8.08-7.98(m,2H),7.63-7.53(m,1H),7.46(dd,J=8.4,6.9Hz,2H),6.25-6.18(m,1H),6.06(d,J=5 .5Hz,1H),5.81(d,J=4.8Hz,1H),5.43-5.32(m,1H),3.02(m,1H),2.86-2.60(m,3H),1.29(s,9H),1.13ppm(s,9H).LCMS(ESI + ) m / z:C 29 H 33 Calculated value for ClN4O7 [M+H] + =585.20, actual value 585.30, RT: 2.227 min, Method 5.

[0356] Preparation of Compound 31 [ka] Compound 30 (4.30 g, 7.35 mmol, 1.00 equiv) was dissolved in 1,4-dioxane (45 mL) and concentrated aqueous NH3 (11 mL). The mixture was heated to 80 °C overnight. After cooling to RT, the solvent was removed in vacuo. The product was dissolved in MeOH (45 mL) and sodium methoxide (0.40 g, 7.35 mmol, 1.00 equiv) was added. The reaction was stirred at RT for 30 min and then stirred with H-exchange resin until pH = 7. It was then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 31.

[0357] 95% yield (2.05 g, 7.00 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.24(s,1H),8.16(s,1H),6.00(d,J=6.6Hz,1H),4.93(dd,J=6.7,4.5Hz,1H),4.44(m,1H),4.31( d,J=4.5Hz,1H),2.57-2.66(m,1H),2.53-2.40(m,2H),2.29ppm(dd,J=13.0,5.7Hz,1H).LCMS(ESI + ) m / z:C 12 H 15 Calculated value for N5O4 [M+H] + =294.11, actual value 294.20, RT: 1.409 min, method 8.

[0358] Preparation of Compound 32 [ka] Compound 31 (2.00 g, 6.82 mmol, 1.00 equiv) was dissolved in acetone (20 mL), and 2,2-dimethoxypropane (1.40 g, 13.6 mmol, 2.00 equiv) and perchloric acid (0.13 g, 1.36 mmol, 0.20 equiv) were added at 0 °C. The reaction was stirred at RT for 1 h. The reaction was then quenched with 1 M aqueous NaOH solution until pH = 7. To the resulting solution, 60 mL of DCM was added, extracted with 1 × 60 mL of HO, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 85:15). The product-containing fractions were collected, and the solvent was evaporated to give compound 32.

[0359] 79% yield (1.80 g, 5.40 mmol), white solid. 1 H NMR(400MHz, methanol-d4)δ 8.23(d,J=5.3Hz,2H),6.15(s,1H),5.67(dd,J=5.9,0.9Hz,1H),5.13(d,J=5.9Hz,1H),4.26-4.15(m,1H),2.4 6(m,2H),2.07(ddd,J=12.7,5.5,1.9Hz,1H),1.75(ddd,J=13.2,7.2,3.1Hz,1H),1.49(s,3H),1.41ppm(s,3H). 13 C NMR (101 MHz, methanol-d4 δ 155.27, 151.41, 148.96, 141.07, 118.94, 89.43, 86.57, 85.45, 83.97, 61.30, 53.40, 44.13, 39.85, 25.40, 24.04 ppm). LCMS (ESI + ) m / z:C 15 H 22 Calculated value for N6O3 [M+H] + =334.15, actual value 334.10, RT: 0.903 min, Method 3.

[0360] Preparation of Compound 33 [ka] Compound 32 (1.00 g, 3.00 mmol, 1.00 equiv) was dissolved in dichloromethane (10 mL), and pyridine (10 mL) and MsCl (0.51 g, 4.50 mmol, 1.5 equiv) were added at 0° C. The reaction was stirred at 40° C. for 3 h. The reaction was then poured into 30 mL of ice water, extracted with 1×20 mL of dichloromethane, and concentrated under reduced pressure to give compound 33.

[0361] 81% yield (1.00 g, 2.43 mmol), white solid. 1 H NMR(400MHz, methanol-d4)δ 8.20(d,J=7.4Hz,2H),6.17(s,1H),5.67(d,J=5.9Hz,1H),5.23(d,J=5.9Hz,1H),4.98(p,J=6.3Hz,1H),3.01(s,3H),2.84(dd,J=11. 6,7.4Hz,1H),2.65(dt,J=13.8,6.3Hz,1H),2.51(dd,J=11.4,6.9Hz,1H),2.04-1.93(m,1H),1.50(s,3H),1.42ppm(s,3H).LCMS(ESI + ) m / z:C 16 H 21 Calculated value for N5O6S [M+H] + = 412.12, actual value 412.15, RT: 1.190 min, Method 3.

[0362] Preparation of Compound 34 [ka] Compound 33 (300 mg, 0.73 mmol, 1.00 equiv) was dissolved in DMF (3 mL), and tetrabutylammonium iodide (27 mg, 0.07 mmol, 0.10 equiv) and NaN3 (474 ​​mg, 7.3 mmol, 10.00 equiv) were added at 0 °C. The reaction was stirred at 110 °C for 3 h. The reaction was then poured into 4 mL of ice water, extracted with 2 × 5 mL of dichloromethane, and concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 34.

[0363] 76% yield (200 mg, 0.56 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.20(d,J=8.1Hz,2H),6.12(s,1H),5.78(dd,J=5.8,1.1Hz,1H),5.07(d,J=5.8Hz,1H),3.65(p,J=7.7Hz,1H),2.64(dt,J=12. 6,6.5Hz,1H),2.27(dd,J=12.4,8.3Hz,1H),1.68(dd,J=12.2,8.0Hz,1H),1.52(s,3H),1.42(s,3H),1.02ppm(t,J=7.3Hz,1H). 13 C NMR(75MHz, methanol-d4)δ 156.01,152.52,148.89,140.57,119.03,113.13,89.70,85.01,84.15,81.69,46.52,41.64,36.43,25.39,24.04,12.46ppm. + ) m / z:C 15 H 18 Calculated value for N8O3 [M+H] + =359.15, actual value 359.20, RT: 1.364 min, method 22.

[0364] Preparation of Compound 35 [ka] Compound 34 (200 mg, 0.56 mmol, 1.00 equiv) was dissolved in methanol (2 mL) and Pd / C (40 mg) was added. The reaction was stirred at rt overnight. After completion, the solution was then filtered. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 80:20). The product-containing fractions were collected, and the solvent was evaporated to give compound 35.

[0365] 70% yield (130 mg, 0.39 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.20(d,J=1.9Hz,2H),6.11(s,1H),5.78(dd,J=5.8,1.0Hz,1H),5.03(d,J=5.8Hz,1H),3.14(p,J=7.9Hz,1H),2.91(d t,J=12.6,6.4Hz,1H),2.54(dt,J=12.4,6.5Hz,1H),2.11(dd,J=12.1,8.6Hz,1H),1.55-1.47(m,4H),1.42ppm(s,3H). 13 C NMR (75 MHz, methanol-d₄) δ 156.01, 152.50, 148.98, 140.38, 118.94, 112.98, 89.51, 85.02, 84.05, 81.51, 43.70, 38.56, 38.44, 25.40, 24.05 ppm. LCMS (ESI + ) m / z:C 15 H 20 Calculated value for N6O3 [M+H] + =333.16, actual value 333.05, RT: 0.966 min, Method 3.

[0366] Preparation of Compound 36 [ka] To compound 35 (155 mg, 0.470 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL), and the mixture was heated to 40 °C for 3 h. The solution was then cooled to room temperature and carefully quenched with NaHCO until pH = 7. The mixture was extracted with CHCl (3 × 2 mL), and the combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis Prep T3 OBD column, 19 × 250 mm 10 u; mobile phase A: water (10 mM NHHCO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm). The product-containing fractions were collected, and the solvent was evaporated to give compound 36.

[0367] 37% yield (50 mg, 0.17 mmol), white solid. 1 H NMR(400MHz,DMSO-d6)δ 8.26(d,J=4.8Hz,1H),8.13(s,1H),7.24(s,2H),5.81(d,J=7.2Hz,1H),5.33(s,2H),4.98(dd,J=7.1,4.1Hz, 1H),3.86(d,J=4.0Hz,1H),3.17(m,3H),2.91-2.69(m,2H),1.85(q,J=10.4Hz,1H),1.67ppm(t,J=9.9Hz,1H). 13 C NMR(101MHz,DMSO)δ 156.50,153.01,150.25,140.36,119.77,86.96,79.77,75.28,73.34,49.06,46.93,41.66ppm.LCMS(ESI + ) m / z:C 12 H 16 Calculated value for N6O3 [M+H] + =293.13, actual value 293.20, RT: 0.948 min, Method 2.

[0368] Preparation of Compound 37 [ka] Compound 33 (190 mg, 0.46 mmol, 1.00 eq) was dissolved in n-PrNH (2 mL), and the mixture was heated to 90 °C for 48 h. The solution was then cooled to room temperature and purified by Prep-HPLC (column: Atlantis Prep T3 OBD column, 19 × 250 mm 10 u; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm). The product-containing fractions were collected, and the solvent was evaporated to give compound 37.

[0369] 68% yield (130 mg, 0.35 mmol), white solid. 1 H NMR(300MHz, methanol-d4)δ 8.21(d,J=2.1Hz,2H),6.14(s,1H),5.80(dd,J=5.9,1.0Hz,1H),5.13(d,J=5.8Hz,1H),2.99(dt,J=13.0,6.3Hz,1H),2.92-2.83(m,2H),2. 66(dd,J=7.7,3.1Hz,2H),2.30(dd,J=12.4,8.7Hz,1H),1.69(dt,J=15.1,7.6Hz,3H),1.52(s,3H),1.43(s,3H),1.01ppm(t,J=7.5Hz,3H). 13 C NMR(75MHz, methanol-d4)δ 165.19,152.54,148.85,140.60,113.16,84.96,84.09,81.85,43.93,40.27, 38.06,35.06,23.99,20.58,20.25,20.25,10.02,9.70ppm.LCMS(ESI+)m / z:C 12 H 16 Calculated value for N6O3 [M+H] + =375.21, actual value 375.20, RT: 1.263 min, method: 3.

[0370] Preparation of Compound 38 [ka] To compound 37 (130 mg, 0.35 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL), and the mixture was heated to 40 °C for 3 h. The solution was then cooled to room temperature and carefully quenched with NaHCO until pH = 7. The mixture was extracted with CHCl (3 × 2 mL), and the combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis Prep T3 OBD column, 19 × 250 mm, 10 u; mobile phase A: water (10 mM NHHCO), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm). The product-containing fractions were collected, and the solvent was evaporated to give compound 38.

[0371] 34% yield (40 mg, 0.12 mmol), white solid. 1 H NMR(400MHz, methanol-d4)δ 8.22(d,J=5.5Hz,2H),5.98(d,J=6.7Hz,1H),5.07(dd,J=6.6,4.3Hz,1H),4.12(d,J=4.3Hz,1H),2.94(tq,J=15.0,7.5,7.0Hz,2H),2.66(dt, J=12.2,6.2Hz,1H),2.51(t,J=7.5Hz,2H),2.14(dd,J=11.8,7.5Hz,1H),2.05-1.90(m,1H),1.52(h,J=7.4Hz,2H),0.95ppm(t,J=7.4Hz,3H). 13 C NMR (101 MHz, methanol-d4) δ 155.91, 152.42, 149.56, 140.10, 119.29, 88.01, 80.72, 75.31, 73.77, 48.59, 44.12, 42.60, 37.53, 22.26, 10.69 ppm. LCMS (ESI + ) m / z:C 12 H 16 Calculated value for N6O3 [M+H] + =335.18, actual value 335.15, RT: 1.937 min, Method 3.

[0372] Preparation of Compound 67.1 [ka] Zinc powder (25.0 g, 0.380 mol) was added to a two-necked round-bottom flask (500 mL) containing demineralized water (100 mL), and the solution was degassed with nitrogen for 15 minutes. Copper(II) sulfate (1.85 g, 11.5 mmol) was then added, and the stirred solution was degassed for 45 minutes. The mixture was filtered, and the solid was washed with degassed water (250 mL) and degassed acetone (250 mL), respectively. The zinc-copper couple was dried in vacuo for 12 hours. A solution of CAS 6991-65-7 (5.00 g, 26.9 mmol, 1.00 eq) in anhydrous EtO (150 mL, dried over 4 Å molecular sieves) was added to zinc-copper couple (12.2 g, 186 mmol, 7.00 eq) in a flame-dried flask under an inert argon atmosphere. A solution of trichloroacetyl chloride (4.29 mL, 37.7 mmol, 1.40 eq) in anhydrous EtO (30 mL) was then added dropwise to the stirred solution over 3 h at 25 °C. After the addition was complete, the stirring was stopped and the organic layer was decanted from the precipitated zinc salts and washed with pentane / EtO (100 mL). The organic phase was washed with NaHCO (aq. sat. 3 × 150 mL) and brine (3 × 100 mL), dried (MgSO), filtered, and the filtrate was concentrated in vacuo to give Compound 67.1 (7.20 g, crude).

[0373] 1 H NMR(250MHz,CDCl3)δ 5.10(d,J=5.7Hz,1H),5.07(s,1H),4.68(d,J=5.7Hz),3.61(dd,J-28.2,18.7,2H),3.52(s,1H),1.43(s,3H),1.34ppm(s,3H). 13 C NMR(63MHz,CDCl3)δ 191.6,113.5,110.0,91.1,87.6,85.3,81.2,57.3,50.0,26.5,25.5ppm.

[0374] Preparation of Compound 93 [ka] Compound 67.1 (63 g, 212.83 mmol, 1.00 eq) was dissolved in THF (630 mL), and then NaBH (16.2 g, 426 mmol, 2.00 eq) was added at 0 °C. The mixture was stirred at 0 °C for 30 min and then added to saturated aqueous NH Cl (1000 mL) at 0 °C. The product was extracted with EtOAc (3 × 1000 mL), and the combined organic layers were dried (Na SO ), filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 70:30). The product-containing fractions were collected, and the solvent was evaporated to give compound 93.

[0375] 72% yield (45 g, 151.00 mmol), pale yellow oil. 1 H NMR(300MHz,chloroform-d)δ 4.99(d,J=5.7Hz,1H),4.95(s,1H),4.68(d,J=5.8Hz,1H),4.21(dd,J=9.7,8.0Hz,1H),3.53(s ,3H),2.89(dd,J=11.8,8.0Hz,1H),2.16(dd,J=11.8,9.7Hz,1H),1.44(s,3H),1.36ppm(s,3H). 13 C NMR(75MHz,DMSO)δ 112.5,108.9,95.9,86.9,84.7,82.0,71.0,56.3,35.4,26.7,25.5ppm.

[0376] Preparation of Compound 94 [ka] Compound 93 (45 g, 151 mmol, 1.00 eq) was dissolved in CHCl (450 mL), and then pyridine (35.8 g, 453.16 mmol, 3.00 eq) and TfO (51.1 g, 181 mmol, 1.20 eq) were added at 0 °C. The mixture was stirred at 0 °C for 1 h. The mixture was added to saturated aqueous NaHCO (500 mL) at 0 °C and then extracted with EtOAc (3 × 500 mL). The organic phase was dried over NaSO. After filtration, the filtrate was concentrated in vacuo. The residue (45 g, crude) was dissolved in AcOH:MeOH (1:1, 20 V), and zinc (136 g, 2092.30 mmol, 20.0 eq) was added. The mixture was stirred at 60 °C for 16 h. The residue was added to saturated aqueous NaHCO3 (500 mL) at 0 °C, the solid was filtered off, the aqueous phase was extracted with ethyl acetate (500 mL), the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 20:1). The product-containing fractions were collected and the solvent was evaporated to give compound 94.

[0377] 69% yield (25.5 g, 217 mmol, 2 steps). 1 H NMR(300MHz,chloroform-d)δ 6.17(t,J=1.1Hz,1H),4.97(s,1H),4.79(d,J=5.9Hz,1H),4.60(d,J=5.9Hz,1H),3.36(s,3H) ),2.99(dd,J=12.1,1.2Hz,1H),2.58(dd,J=12.2,1.1Hz,1H),1.45(s,3H),1.33ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ 133.0,132.3,112.5,107.5,93.6,85.1,81.2,54.5,36.4,26.4,25.3ppm.

[0378] Preparation of Compound 95a [ka] Compound 94 (25 g, 102 mmol, 1.00 eq) was dissolved in DCM (250 mL) and m-CPBA (52.0 g, 302 mmol, 3.00 eq) was added at 0 °C. The mixture was stirred at 40 °C for 16 h. After the mixture was cooled, the solid was removed by filtration, and iPrOH (250 mL) followed by NaBHCN (12.8 g, 203 mmol, 2.00 eq) was added at 0 °C. The mixture was stirred at 60 °C for 2 h. After the mixture was cooled to room temperature, the residue was added to saturated aqueous NaHCO solution, and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 95:5). The product-containing fractions were collected, and the solvent was evaporated to give compound 95a.

[0379] 52% yield (12.1 g, 52.6 mmol, 2 steps), colorless oil. 1 H NMR(400MHz,chloroform-d)δ 5.00(d,J=5.8Hz,1H),4.83(s,1H),4.52(d,J=5.8Hz,1H),4.03-3.97(m,1H),3.41(s,3H),2.2 1-2.09(m,2H),1.74(td,J=11.3,8.9Hz,1H),1.67-1.56(m,1H),1.43(s,3H),1.35ppm(s,3H). 13 C NMR(75MHz,DMSO)δ 111.5,107.3,91.0,85.1,78.1,73.9,54.5,26.7,25.5,23.4,20.0ppm.

[0380] Preparation of Compound 96 [ka] Compound 95a (300 mg, 1.30 mmol, 1.00 eq) was dissolved in DCM (3 mL), and then DMP (1.10 g, 2.60 mmol, 2.00 eq) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was quenched by adding saturated aqueous NaSO (20 mL) and saturated aqueous NaHCO (20 mL), followed by extraction with EtOAc (3 × 20 mL). The organic phase was dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 90:10). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 96.

[0381] 63% yield (187 mg, 0.82 mmol), white solid. 1 H NMR(300MHz,chloroform-d)δ 4.97(s,1H),4.76(d,J=5.9Hz,1H),4.63(d,J=5.9Hz,1H),3.39(s,3H),2.95-2.81(m,2H),2.6 4(ddd,J=12.2,10.6,6.0Hz,1H),2.15(dt,J=12.1,10.4Hz,1H),1.37(s,3H),1.34ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ 206.2,113.1,107.1,101.6,85.0,79.0,54.9,39.5,26.3,25.4,20.0ppm.

[0382] Preparation of Compound 97a [ka] Compound 95a (12.0 g, 52.2 mmol, 1.00 eq) and DMAP (5.79 g, 26.1 mmol, 0.50 eq) were dissolved in pyridine (120 mL). Benzoyl chloride (14.6 g, 104 mmol, 2.00 eq) was then added dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. HCl (1 M, aqueous, 20 mL) was then added to the reaction mixture until a pH of <7 was reached. The product was extracted with EtOAc (3 × 200 mL). The combined organic layers were dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified on a silica gel column using PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 80:20). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 97a.

[0383] 79% yield (13.7 g, 41.0 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 8.04-7.97(m,2H),7.63-7.56(m,1H),7.50-7.44(m,2H),5.37-5.31(m,1H),5.21(d,J=5.8Hz,1H),4.86(s,1H),4.62 (d,J=5.9Hz,1H),3.28(s,3H),2.48-2.34(m,2H),2.01-1.89(m,1H),1.86-1.73(m,1H),1.49(s,3H),1.44ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ 165.1,130.2,132.9,129.5,128.4,112.4,107.7,89.0,85.2,78.7,74.3,55.0,26.4,25.6,22.0,20.8ppm.

[0384] Preparation of Compound 98a [ka] Compound 97a (7.00 g, 21.0 mmol, 1.00 eq) was dissolved in MeOH (70 mL) and HCl (2 M, aq. 70 mL) was added. The mixture was heated to 35° C. for 16 h. The solution was then cooled to room temperature and concentrated in vacuo to give 12 g of crude compound 98a.

[0385] Half of the residue (6 g, crude) was dissolved in dry pyridine (60 mL) and stirred for 30 min. Acetic anhydride (3.10 g, 29.8 mmol, 1.50 eq) was added at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (200 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 200 mL), and the combined organic layers were washed with brine (3 × 200 mL), dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined, and the solvent was removed in vacuo to give compound 98a.

[0386] 40% yield (3.10 g, 8.20 mmol, 2 steps), yellow oil. 1 H NMR(300MHz, methanol-d4)δ 8.06-8.00(m,2H),7.63-7.59(m,1H),7.49(dt,J=4.7,1.9Hz,2H),5.92(d,J=4.7Hz,1H),5.35-5.29(m,1H),5.25(dd,J=4.8,3.0H z,1H),4.98(d,J=3.0Hz,1H),3.35(s,3H),2.33-2.24(m,2H),2.14(s,3H),2.09(s,3H),1.96-1.86(m,1H),1.66-1.57ppm(m,1H). 13 C NMR(101MHz,CDCl3)δ 174.2,174.0,168.9,137.1,136.6,132.3,132.0,109.3,90.4,80.0,78.3,74.4,58.7,57.3,26.2,25.0,23.0ppm.

[0387] Preparation of Compound 99a [ka] 6-Chloropurine (1.40 g, 8.99 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (1.65 g, 8.13 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, compound 98a (3.10 g, 8.20 mmol, 1.00 eq) in MeCN (22 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (2.15 g, 9.68 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with saturated NaHCO (3 × 50 mL) and saturated aqueous NaCl (3 × 50 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected and the solvent was removed in vacuo to give compound 99a.

[0388] 57% yield (2.30 g, 4.60 mmol), white solid. 1 H NMR(400MHz, methanol-d4)δ 8.66(s,1H),8.33-8.28(m,2H),8.12(s,1H),7.70-7.64(m,1H),7.55(t ,J=7.7Hz,2H),6.55(dd,J=7.4,4.2Hz,1H),6.39(d,J=7.5Hz,1H),6.26 (d,J=4.2Hz,1H),5.55(dd,J=9.1,7.6Hz,1H),2.39-2.32(m,2H),2.29(s,3H),2.04(s,3H),1.98(dd,J=12.4,9.9Hz,1H),1.80-1.73ppm(m,1H). 13C NMR (75 MHz, MeOD) δ 170.2, 169.8, 165.6, 151.3, 151.1, 150.4, 146.6, 133.3, 132.1, 129.7, 129.5, 128.4, 88.4, 86.4, 73.9, 72.6, 70.8, 22.0, 20.3, 19.0, 18.8 ppm. LCMS (ESI+) m / z: calculated for C23H21ClNO4O7 [M+H]+ = 501.11, found 501.20, RT: 1.806 min, (Method 3).

[0389] Preparation of Compound 100a [ka] Compound 99a (110 mg, 0.22 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.2 mL) and NH3 (aq. 0.3 mL) was added. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, the solvent was removed in vacuo, and the product was dissolved in MeOH (1.2 mL). Sodium methoxide (11.8 g, 0.22 mmol, 1.00 eq) was added, and the mixture was stirred at room temperature for 30 min, then stirred with hydrogen exchange resin (CAS: 78922-04-0) for 30 min until pH = 7. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 100a.

[0390] 43% yield (30 mg, 0.10 mmol), white solid. 1 H NMR (400 MHz, methanol-d₄) δ 8.27 (s, 1H), 8.22 (s, 1H), 5.98 (d, J = 7.1 Hz, 1H), 5.02 (dd, J = 7.1, 4.4 Hz, 1H), 4.42 (d, J = 4.4 Hz, 1H), 4.17 (t, J = 8.7 Hz, 1H), 2.37-2.29 (m, 1H), 2.10-2.01 (m, 1H), 1.62-1.44 (m, 2H). 13C NMR(75MHz,MeOD)δ 156.2,152.3,148.9,140.6,119.7,91.4,88.5,74.8,73.5,70.0,20.7,20.1ppm.LCMS(ESI + ) m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.00, RT: 0.799 min (Method 3).

[0391] Preparation of Compound 95 [ka] Compound 94 (5.00 g, 20.3 mmol, 1.00 eq) was dissolved in DCM (50 mL), and then m-CPBA (10.4 g, 60.5 mmol, 3.00 eq) was added at 0 °C. The mixture was stirred at 40 °C for 16 h. After the mixture was cooled to room temperature, the solid was removed by filtration, and iPrOH (50 mL) and NaBHCN (2.6 g, 40.63 mmol, 2.00 eq) were added at 0 °C. The mixture was stirred at 60 °C for 2 h. After the mixture was cooled to room temperature, the residue was added to saturated aqueous NaHCO solution, and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 95:5). The product-containing fractions were collected and the solvent removed in vacuo to give Compound 95a and Compound 95b as a 44:56 mixture, respectively.

[0392] 45% yield (2.1 g, 9.13 mmol, 2 steps), colorless oil.

[0393] Preparation of Compound 97 [ka] Compound 95 (2.1 g, 9.13 mmol, 1.00 eq) and DMAP (1.01 g, 4.54 mmol, 0.5 eq) were dissolved in pyridine (20 mL), then benzoyl chloride (2.5 mg, 17.9 mmol, 2.00 eq) was added dropwise at 0 °C, and the resulting solution was stirred at 0 °C for 1 h. HCl (aqueous, 1 M) was then added to the reaction mixture until the pH was < 7. DCM (200 mL) and HO (200 mL) were added to the resulting solution. The product was extracted with DCM (3 × 200 mL), and the combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: C18 column, 20-30 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 30B to 70B in 30 min; 210 / 254 nm). The product-containing fractions were collected and the solvent was evaporated to give Compounds 97a and 97b.

[0394] Compound 97b: 50% yield (1.5 g, 3.96 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 8.08(dt,J=7.1,1.4Hz,2H),7.59-7.53(m,1H),7.48-7.42(m,2H),5.14-5.06(m,1H),4.92(d,J= 6.0Hz,1H),4.87(s,1H),4.58(d,J=6.0Hz,1H),2.42-2.14(m,4H),1.44(s,3H),1.35(s,3H)ppm. 13 C NMR(75MHz,CDCl3)δ 166.2,132.8,130.3,129.6,128.2,112.2,109.4,92.5,85.4,84.2,72.9,55.8,26.4,25.3,24.6,23.8ppm.

[0395] Compound 97a: 25% yield (1.0 g, 2.64 mmol), colorless oil.

[0396] Preparation of Compound 98b [ka] Compound 97b (800 mg, 2.11 mmol, 1.00 eq) was dissolved in MeOH (8 mL) and HCl (2 M, 8 mL) was added. The mixture was heated to 35 °C for 16 h. The solution was then cooled to room temperature, and the filtrate was concentrated in vacuo. The residue (700 mg) was dissolved in anhydrous pyridine (7 mL) and stirred for 30 min. Acetic anhydride (364 mg, 3.56 mmol, 1.5 eq) was added to the stirred solution at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (30 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 30 mL), and the combined organic layers were washed with brine (3 × 200 mL), dried over NaSO, concentrated, and purified by silica chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined and the solvent removed in vacuo to give compound 98b.

[0397] 43% yield (2 steps, 390 mg, 1.03 mmol), yellow oil. 1 H NMR(300MHz,chloroform-d)δ 8.13-8.09(m,2H),7.58-7.53(m,1H),7.47-7.41(m,2H),5.64(d,J=4.9Hz,1H),5.31(d,J=2.0Hz,1H),5.24(dd,J=4. 9,2.2Hz,1H),4.96(d,J=2.2Hz,1H),3.14(s,3H),2.43-2.28(m,2H),2.22-2.15(m,2H),2.13(s,3H),2.06ppm(s,3H). 13 C NMR(75MHz,CDCl3)δ 169.7,169.4,165.8,132.9,130.0,129.7,128.3,105.9,88.9,75.5,74.1,71.5,55.7,25.4,24.1,22.8,20.5ppm.

[0398] Preparation of Compound 99b [ka] 6-Chloropurine (177 mg, 1.13 mmol, 1.10 eq) was dissolved in MeCN (3.2 mL) and N,O-bis(trimethylsilyl)acetamide (208 mg, 1.02 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After cooling, compound 98b (390 mg, 1.03 mmol, 1.00 eq) in MeCN (2.8 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (272 mg, 1.22 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO and saturated aqueous NaCl. The organic layer was dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EA 99:1 to 4:1). The fractions containing the product were collected and the solvent was evaporated to give compound 99b.

[0399] 57% yield (294 mg, 0.58 mmol), white solid. 1 H NMR(300MHz,chloroform-d)δ 8.55(s,1H),8.38(s,1H),7.96-7.88(m,2H),7.58-7.51(m,1H),7.40(t,J=7.7Hz,2H),6.37(d,J=7.5Hz,1H),6.17(dt, J=7.6,4.2Hz,1H),5.91(d,J=5.0Hz,1H),5.38(td,J=5.6,2.7Hz,1H),2.49-2.31(m,4H),2.25(s,3H),2.02ppm(s,3H). 13 C NMR(101MHz,CDCl3)δ 169.7,169.1,166.8,152.2,152.0,151.2,143.6,133.7,131.8,129.6,128.7,1 28.6,87.2,84.2,74.2,73.3,72.1,27.2,21.8,20.6,20.3ppm.LCMS(ESI+)m / z:C 23 H 21 Calculated for ClN4O7 [M+H]+ = 501.11, found 501.10, RT: 1.767 min (Method 3).

[0400] Preparation of Compound 100b [ka] Compound 99b (130 mg, 0.26 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.2 mL) and ammonia (aq. 0.3 mL) was added. The mixture was heated to 80 °C for 16 h. After cooling to room temperature, the solvent was removed in vacuo. The product was dissolved in MeOH (1.2 mL) and sodium methoxide (12 mg, 0.22 mmol, 1.00 eq) was added. The reaction was stirred at room temperature for 30 min, followed by stirring with hydrogen exchange resin (CAS: 78922-04-0) until pH = 7 for 30 min. The solids were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fractions were collected, and the solvent was evaporated to give compound 100b.

[0401] 30% yield (23 mg, 0.07 mmol), white solid. 1 H NMR(400MHz, methanol-d4)δ 8.34(s,1H),8.21(s,1H),6.07(d,J=7.3Hz,1H),4.67(dd,J=7.4,4.1Hz,1H),4.25(ddt,J=7.1,4. 7,1.9Hz,1H),4.07(d,J=4.1Hz,1H),2.39-2.31(m,1H),2.14-2.03(m,2H),1.94-1.83ppm(m,1H). 13 C NMR(101MHz,MeOD)δ 156.2,152.2,148.7,140.7,119.6,89.6,89.1,74.6,74.1,72.1,24.4,24.3ppm.LCMS(ESI + ) m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.00, RT: 0.660 min (Method 3).

[0402] Preparation of Compound 39 [ka] Acetylacetonatobis(ethylene)rhodium(I) (837 mg, 3.24 mmol, 0.02 eq) and (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphepin-4-amine (2.91 g, 8.11 mmol, 0.05 eq) were dissolved in EtOH (625 mL) under a nitrogen atmosphere. The mixture was stirred at room temperature and flushed with nitrogen gas for 15 min. Then, (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25.0 g, 162.16 mmol, 1.00 eq) and potassium vinyltrifluoroborate (45.7 g, 324 mmol, 2.00 eq) were added, and the reaction mixture was stirred and refluxed for 4 h. The reaction mixture (suspension) was cooled to room temperature. The precipitate was filtered off on a Celite pad and washed with ethanol. The filtrate's solvent was evaporated, n-heptane was added to the residue, and the resulting suspension was filtered over a Celite pad and washed with heptane to give a dark brown solid residue. The filtrate was washed with NH4OH (3 x 300 mL), washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give compound 39 (16.2 g, 51% crude yield).

[0403] Preparation of Compound 40 [ka] A solution of compound 39 (16.2 g, 82.6 mmol, 1.00 eq) in THF (200 mL) was added dropwise to a stirred solution of lithium aluminum hydride (24.8 mL, 1 M in THF, 24.8 mmol, 0.30 eq) in THF (400 mL) at −78 °C under a nitrogen atmosphere. The reaction mixture was stirred at −78 °C for 30 min under a nitrogen atmosphere. The reaction was quenched by the dropwise addition of acetone (6.1 mL) followed by water (50 mL) at −78 °C. After the addition, the reaction mixture was warmed to room temperature, and EtOAc (400 mL) was added. The mixture was vigorously shaken. The organic layer was separated, washed three times with water, washed with brine, dried (MgSO), filtered, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 1:1). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 40 (10.7 g, 71% yield).

[0404] Preparation of Compound 41 [ka] Compound 40 (3.10 g, 16.6 mmol, 1.00 eq) was dissolved in pyridine (10.3 mL) and tert-butyldimethylsilyl chloride (2.88 g, 19.1 mmol, 1.15 eq) was added portionwise at room temperature. The mixture was stirred at room temperature for 17 h and diluted with EtOAc (250 mL). The organic layer was washed with brine (4 × 80 mL), dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 7:3). The product-containing fractions were collected and the solvent was evaporated to give the desired compound 41 (3.15 g, 63% yield) as a slightly yellow oil.

[0405] Preparation of Compound 42 [ka] Compound 41 (20.1 g, 43.8 mmol, 1.00 eq) was dissolved in CHCl (400 mL), and the mixture was cooled to −78 °C. Ozone was generated from oxygen gas using an ozone generator (Fischer OZ500 / 5) and bubbled through a glass pipette into the cooled solution. A blue color was observed after 1.5 h, and ozone was added for an additional 20 min at −78 °C. The mixture was then flushed with nitrogen for 5 min (the blue color disappeared), and dimethyl sulfide (25.7 mL, 350 mmol, 8.00 eq) was added at −78 °C. The nitrogen gas flow was stopped, and the mixture was stirred for 1 h while the temperature was raised to −40 °C. The mixture was concentrated in vacuo at 30 °C to a minimum volume, and the resulting yellow oil was redissolved in methanol (220 mL) and water (110 mL). The solution was cooled to 0 °C, and sodium borohydride (19.8 g, 526 mmol, 12.0 eq) was added portionwise. After 1.5 h, the ice bath was removed, and stirring was continued at room temperature. After 4 h of stirring, the mixture was diluted with CHCl (350 mL), and NHCl (aq. sat. 150 mL) was added. The product was extracted into CHCl (3 × 350 mL), and the combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 0:1). The product-containing fractions were collected, and the solvent was evaporated to give the desired compound 42 (8.30 g, 63% yield) as a slightly yellow oil.

[0406] 1 H NMR (400 MHz, chloroform-d): δ = 4.37-4.42 (m, 2H), 4.10-4.15 (m, 1H), 3.55-3.62 (m, 1H), 3.45-3.53 (m, 1H), 2.16-2.26 (m, 1H), 2.01 (dt, J = 12.7, 8.2 Hz, 1H), 1.86 (br s, 1H), 1.57-1.66 (m, 1H), 1.49 (s, 3H), 1.31 (s, 3H), 0.91 (s, 9H), 0.09 ppm (d, J = 2.9 Hz, 6H). 13C NMR (101 MHz, chloroform-d): δ = 111.7, 82.0, 80.9, 72.7, 64.3, 44.7, 34.4, 26.5, 26.0, 24.9, 18.4, -4.5 ppm

[0407] Preparation of Compound 43 [ka] Compound 42 [CAS: 514206-18-9] (8.30 g, 27.4 mmol, 1.00 eq) was dissolved in THF (140 mL). Imidazole (4.67 g, 68.6 mmol, 2.50 eq) and triphenylphosphine (8.03 g, 29.1 mmol, 1.05 eq) were added, followed by the addition of iodine (8.79 g, 34.3 mmol, 1.25 eq) in small portions at room temperature. After 1 h, additional amounts of triphenylphosphine (2.29 g, 8.31 mmol, 0.30 eq) and iodine (2.46 g, 9.60 mmol, 0.35 eq) were added. The reaction was continued for 2 h, and then the mixture was concentrated in vacuo to a minimum volume, and n-heptane (400 mL) was added. Triphenylphosphine oxide was precipitated, and the mixture was sonicated for 30 min. The organic layer was separated by filtration, and the solid was rinsed with n-heptane (100 mL). To the filtrate, sodium thiosulfate (aq. sat. 150 mL) was added, and the product was extracted into n-heptane (3 × 400 mL). The combined organic fractions were dried (MgSO), filtered, and the filtrate was concentrated in vacuo to give compound 43 (9.84 g, calculated yield by HNMR: 87%) as a colorless oil.

[0408] 1H NMR (400MHz, chloroform-d): δ=4.29-4.39(m,1H),4.21(dd,J=6.1,2.4Hz,1H),4.05(dt,J=7.8,5.0Hz,1H),2.97-3.15(m,2H),2.22-2.3 8(m,1H),1.96(dt,J=13.0,7.7Hz,1H),1.56(dt,J=13.0,5.3Hz,1H),1.40(s,3H),1.23(s,3H),0.82(s,9H),0.00ppm(d,J=2.4Hz,6H)

[0409] Preparation of compound 44 [ka] Compound 43 (9.84 g, 23.9 mmol, 1.00 eq) was dissolved in THF (168 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.35 mL, 35.8 mmol, 1.50 eq) was added. The mixture was heated to 65 °C for 2.5 h and then cooled to room temperature. The precipitated DBU-salt was filtered, rinsed with THF, and the filtrate was concentrated in vacuo to a minimum volume. Then, n-heptane (400 mL) and brine (100 mL) were added, and the product was extracted with n-heptane (3 × 400 mL). The combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 1:1). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 44 (6.00 g, 77% yield over two steps) as a colorless liquid.

[0410] 1H NMR (400MHz, クロロホルム-d): δ=5.14-5.20(m,1H),5.11(dd,J=2.6,1.0Hz, 1H),4.62(d,J=5.7Hz,1H),4.46(t,J=5.1Hz,1H),3.90(ddd,J=11.2,6 .5,4.7Hz,1H),2.67(ddtd,J=13.9,11.1,2.7,1.2Hz,1H),2.29-2.35(m,1H),1.50(s,3H),1.35(s,3H),0.92(s,9H),0.11ppm(d,J=2.8Hz,6H) 13 C NMR (101MHz, クロロホルム-d): δ=145.6,113.6,111.2,80.8,80.4,72.3,37.5,26.4,26.0,24.7,18.4,-4.5ppm

[0411] Modulation of Compound 45

change

[0412] 1 H NMR (400MHz, chloroform-d): δ=4.79(dd,J=5.8,1.0Hz,1H),4.55(t,J=5.3Hz,1H),4.11(dt,J=9.8,5.1Hz,1H),3.65(d,J=18.3Hz,1H),3.12(d,J= 18.3Hz,1H),2.36(dd,J=12.9,5.4Hz,1H),2.15(dd,J=12.9,9.8Hz,1H),1.48(s,3H),1.37(s,3H),0.91-0.93(m,9H),0.12ppm(d,J=2.2Hz,6H) 13 C NMR (101 MHz, chloroform-d): δ = 191.8, 112.3, 80.7, 80.1, 71.5, 51.7, 26.1, 25.9, 18.4, -4.6, -4.9 ppm

[0413] Preparation of Compound 46 [ka] Compound 45 (1.25 g, 3.16 mmol, 1.00 eq) was dissolved in THF (30 mL), and zinc (2.07 g, 31.6 mmol, 10.0 eq) and acetic acid (1.45 mL, 25.3 mmol, 8.00 eq) were added. The mixture was heated to 70 °C for 6 h and then cooled to room temperature. The mixture was filtered through Celite, the solid was rinsed with THF, and the filtrate was concentrated in vacuo to a minimum volume. The oil was then redissolved in CHCl (100 mL), and brine (50 mL) was added. The product was extracted into CHCl (3 × 100 mL), and the combined organic fractions were dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 2:3). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 46 (0.648 g, 63% yield over two steps) as a colorless oil.

[0414] 1 H NMR (400 MHz, chloroform-d): δ = 4.49 (t, J = 5.1 Hz, 1H), 4.29-4.34 (m, 1H), 3.88 (dt, J = 10.9, 5.3 Hz, 1H), 3.36 (ddd, J = 18.3, 4.1, 2.4 Hz, 1H), 2.89-2.99 (m, 1H), 2.79-2.87 (m,1H),2.68-2.75(m,1H),2.19(t,J=11.4Hz,1H),1.82(dd,J=11.8,5.7Hz,1H),1 .58(s,1H),1.48(s,3H),1.34(s,3H),0.90-0.94(m,9H),0.11ppm(d,J=2.8Hz,6H) 13 C NMR (101 MHz, chloroform-d): δ = 206.0, 111.1, 85.2, 80.2, 72.3, 56.7, 52.8, 41.3, 34.4, 26.0, 26.0, 24.5, 18.4, -4.4, -4.7 ppm

[0415] Preparation of compound 47 [ka] Compound 46 (600 mg, 1.84 mmol, 1.00 eq), also labeled Intermediate 44, was dissolved in methanol (20.0 mL) and cooled to 0 °C. Sodium borohydride (282 mg, 7.35 mmol, 4.00 eq) was added portionwise, and the mixture was stirred at 0 °C for 1 h. The solution was concentrated in vacuo to a minimum volume, dissolved in CHCl (100 mL), and NHCl (sat. aq. 50 mL) was added. The product was extracted into CHCl (3 × 100 mL), and the combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo to give compound 47 (515 mg, 85% yield), also labeled Intermediate 45, as a 1:1 mixture.

[0416] Preparation of compound 48 [ka] Methyltriphenylphosphonium bromide (1.45 g, 3.98 mmol, 1.30 eq) was weighed into an oven-dried vial and THF (12.0 mL) was added. The heterogeneous solution was cooled to 0 °C, and potassium tert-butoxide (3.98 mL, 1 M in THF, 3.98 mmol, 1.30 eq) was added dropwise. The mixture was stirred at 0 °C for 20 min. The freshly prepared Wittig reagent was added dropwise via syringe to compound 46 (1.00 g, 3.06 mmol, 1.00 eq) dissolved in THF (12.0 mL) at 0 °C. The yellow mixture was stirred at 0 °C for 1.5 h and then at room temperature for 1.5 h. The mixture was concentrated in vacuo to a minimum volume and redissolved in n-heptane (300 mL). To precipitate triphenylphosphine oxide, the mixture was sonicated for 5 min, filtered, and the filtrate was washed with NH4Cl (aq. sat. 2 × 50 mL) and brine (2 × 50 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 7:3). The product-containing fractions were collected and the solvent was evaporated to give the desired compound 48 (931 mg, 94% yield).

[0417] 1 H NMR (400 MHz, chloroform-d): δ = 4.81 (quin, J = 2.4 Hz, 1H), 4.78 (quin, J = 2.4 Hz, 1H), 4.40 (t, J = 5.1 Hz, 1H), 4.26 (dd, J = 5.5, 0.9 Hz, 1H), 3.80 (dt, J = 11.2, 5.5 Hz, 1H), 2.87 (dd, J = 16.1, 2.2Hz,1H),2.54(dq,J=15.9,2.4Hz,1H),2.31-2.46(m,2H),1.95(t,J=11.4Hz,1H),1.76 (dd,J=11.7,5.7Hz,1H),1.45(s,3H),1.32(s,3H),0.91(s,9H),0.10ppm(d,J=2.2Hz,6H) 13C NMR (101 MHz, chloroform-d): δ = 144.7, 110.4, 106.8, 85.3, 79.9, 72.0, 42.5, 41.2, 39.2, 36.8, 26.0, 26.0, 24.5, 18.4, -4.4, -4.6 ppm

[0418] Preparation of compound 49 [ka] Compound 48 (931 mg, 2.87 mmol, 1.00 eq) was dissolved in THF (2.00 mL) and tetrabutylammonium fluoride (10.0 mL, 1 M in THF, 10.0 mmol, 3.50 eq) was added. The mixture was stirred at room temperature for 3 h. The mixture was concentrated in vacuo to a minimum volume, dissolved in EtOAc (250 mL), and washed with NH4Cl (aq. sat. 3 × 50 mL) and brine (3 × 50 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 0:1). The product-containing fractions were collected and the solvent was evaporated to give the desired compound 49 (556 mg, 92% yield).

[0419] 1 H NMR (400MHz, chloroform-d): δ=4.83(quin,J=2.3Hz,1H),4.80(quin,J=2.4Hz,1H),4.46-4.49(m,1H),4.36-4.39(m,1H),3.81(br s,1H),2.82-2.88(m,1H),2.60(dq,J=16.1,2.4Hz,1H),2.38-2.46(m,2H),2.27-2.38(m ,1H),1.97(dd,J=12.0,5.9Hz,1H),1.74(t,J=11.4Hz,1H),1.47(s,3H),1.36ppm(s,3H) 13 C NMR (101 MHz, chloroform-d): δ = 144.1, 110.6, 107.2, 85.4, 78.7, 70.8, 41.7, 41.2, 39.5, 36.6, 25.9, 24.3 ppm

[0420] Preparation of Compound 50 [ka] Potassium 6-chloro-7-deazapurine was prepared as follows: A mixture of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine, CAS 3680-69-1 (100 g, 651 mmol, 1.00 eq) and KOtBu (73.1 g, 651 mmol, 1.00 eq) in THF (1 L) was stirred at room temperature for 45 min until a clear solution was obtained. The solvent was evaporated. The residue was triturated in DIPE. The white solid was filtered off and dried in vacuo at 30 °C to give potassium 6-chloro-7-deazapurine (113 g, 90% yield).

[0421] Compound 49 (647 mg, 3.08 mmol, 1.00 eq) was dissolved in anhydrous CHCl (20.0 mL) and pyridine (0.62 mL, 7.69 mmol, 2.50 eq) was added. The mixture was cooled to 0 °C and trifluoromethanesulfonic anhydride (0.57 mL, 3.39 mmol, 1.10 eq) was added dropwise. The mixture was stirred at 0 °C for 30 min, diluted in CHCl (100 mL), and NaHCO (aq. sat. 40 mL) was added. The product was extracted into CHCl (3 × 100 mL), and the combined organic layers were dried (MgSO), filtered, and the filtrate was concentrated in vacuo and used immediately in the next step.

[0422] Potassium 6-chloro-7-deazapurine (5.90 g, 30.8 mmol, 10.0 eq) was dissolved in anhydrous DMF (35.0 mL) and stirred at 0 °C for 30 min. This was followed by the dropwise addition of crude triflate (1.05 g, 3.08 mmol, 1.00 eq) dissolved in anhydrous DMF (8.00 mL) over 15 min at 0 °C. The mixture was stirred at 0 °C for 2 h, then warmed to room temperature and stirred for an additional 2 h. The mixture was poured into NH Cl (aq. sat. 50 mL), and the product was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried (MgSO), filtered, and the filtrate was concentrated to a minimum volume in vacuo. To the resulting powder, n-heptane (100 mL) was added, and the mixture was sonicated for 10 min. The solid was filtered, rinsed with n-heptane, and the filtrate was concentrated in vacuo to a minimum volume. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc 1:0 to 0:1). The product-containing fractions were collected and the solvent was evaporated to give the desired compound 50 (856 mg, 80% over two steps).

[0423] 1 H NMR (400MHz, chloroform-d): δ=8.64-8.65(m,1H),7.18(d,J=3.7Hz,1H),6.61(d,J=3. 7Hz,1H),5.10(dd,J=6.3,3.1Hz,1H),4.96(td,J=6.8,3.1Hz,1H),4.80(dquin,J=1 8.2,2.4Hz,2H),4.69(d,J=6.5Hz,1H),3.18(dd,J=15.5,2.4Hz,1H),2.75(dd,J=1 5.3,2.6Hz,1H),2.48-2.58(m,2H),2.33-2.44(m,2H),1.55(s,3H),1.35ppm(s,3H) 13 C NMR (101 MHz, chloroform-d): δ = 152.3, 150.6, 143.4, 127.5, 117.9, 112.7, 107.0, 99.8, 85.7, 84.9, 61.5, 43.0, 42.3, 42.2, 38.3, 26.6, 24.7 ppm

[0424] Preparation of Compound 51 [ka] Compound 50 (850 mg, 2.46 mmol, 1.00 eq) was dissolved in 1,4-dioxane (20 mL) and NH (60 mL, 25% in HO) was added. The solution was heated to 100 °C in a pressure reactor for 24 h. The mixture was concentrated in vacuo to a minimum volume and coevaporated twice with toluene. The residue was purified by column chromatography on silica gel (gradient elution: CHCl / MeOH 1:0 to 7:3). The product-containing fractions were collected and the solvent was evaporated to give the desired compound 51 (790 mg, 98% yield).

[0425] 1 H NMR (400 MHz, chloroform-d): δ = 8.33 (s, 1H), 6.89 (d, J = 3.7 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.18 (br s,2H),5.09(dd,J=6.4,2.9Hz,1H),4.93(td,J=6.7,2.9Hz,1H),4.81(quin,J=2.4Hz,1H),4.76(quin,J=2.4Hz,1H),4.67( d,J=6.4Hz,1H),3.16(dd,J=15.6,2.4Hz,1H),2.74(dd,J=15.2,2.4Hz,1H),2.45-2.55(m,2H),2.30-2.45(m,2H),1.97(br s,1H),1.55(s,3H),1.35ppm(s,3H) 13 C NMR (101 MHz, chloroform-d): δ = 156.6, 151.7, 150.5, 143.8, 123.0, 112.4, 106.8, 103.5, 97.6, 85.9, 85.1, 60.8, 43.1, 42.5, 42.3, 38.3, 26.6, 24.7 ppm

[0426] Preparation of Compounds 52, 52a, and 52b [ka] To compound 51 (255 mg, 0.78 mmol, 1.00 eq) was added 9-borabicyclo[3.3.1]nonane (7.81 mL, 0.5 M in THF, 3.91 mL, 5.00 eq), and the mixture was stirred at room temperature for 30 min. The solution was cooled to 0 °C, and NaOH (7.81 mL, 1 M in HO, 7.81 mmol, 10.0 eq) was added, followed by dropwise addition of hydrogen peroxide (1.99 mL, 30% in HO, 19.5 mmol, 25.0 eq). The mixture was stirred at room temperature for 1 h, then diluted with CHCl (250 mL) and washed with NaHCO (aq. sat. 3 × 50 mL) and brine (1 × 50 mL). The organic layer was dried (MgSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: CHCl / MeOH 1:0 to 7:3). The product-containing fractions were collected and the solvent was evaporated to give compound 52 (213 mg, 79% yield) as a 1:1 mixture of diastereoisomers. A sample of intermediate 72 was purified by Prep SFC (stationary phase: Chiralpak Diacel OJ 20 × 250 mm, mobile phase: CO, EtOH + 0.4% iPrNH) to give compound 52a (15 mg) and compound 52b (18 mg).

[0427] [ka] 1 H NMR (400MHz, chloroform-d): δ=8.31(s,1H),6.89(d,J=3.5Hz,1H),6.34(d,J=3.5Hz,1H),5.24(br s,2H),5.02(dd,J=6.8,3.5Hz,1H),4.55(d,J=6.8Hz,1H),2.35-2.52(m,3H), 2.27(dd,J=11.8,8.3Hz,1H),1.76-1.95(m,3H),1.53(s,3H),1.33ppm(s,3H) 13C NMR (101MHz.クロロホルム-d): δ=156.7,151.7,150.4,123.1,112.7,97.7 ,86.2,84.6,66.9,60.3,43.4,43.3,34.1,31.6,30.4,26.5,24.8ppm

[0428]

change

[0429] Modulation of compound 53

change

[0430] Preparation of Compounds 54a and 54b [ka]

[0431] Compound 53 (crude from the previous step) was dissolved in EtOH (4.00 mL), HCl (16.0 mL, 1 M in HO) was added, and the mixture was stirred at room temperature for 2 h. The solution was diluted with water (20 mL), frozen, and lyophilized to give a solid residue. Purification was carried out by prep SFC (stationary phase: Chiralcel Diacel OJ 20 × 250 mm, mobile phase: CO, EtOH + 0.4% i-PrNH) to give compound 54a (14.5 mg, 0.03 mmol, 19% yield over two steps) and compound 54b (15.0 mg, 0.04 mmol, 20% yield over two steps).

[0432] Compound 54a: 1 H NMR (400MHz, DMSO-d6): δ=8.42(d,J=6.9Hz,1H),8.01(s,1H),7.84(s,1H),7.49 (s,1H),7.30(s,1H),7.16(d,J=3.3Hz,1H),6.88(s,2H),6.73(d,J=6.9Hz,1H), 6.53(d,J=3.3Hz,1H),4.71-4.88(m,3H),4.17-4.25(m,1H),3.71(br t,J=4.3Hz,1H),2.71(br d,J=7.7Hz,2H),2.52-2.59(m,1H),2.35(dd,J=13.0,9.8Hz,1H),2.01-2.17( m,2H),1.92(dd,J=13.0,8.5Hz,1H),1.77-1.86(m,1H),1.68-1.77ppm(m,1H). 13 C NMR (101MHz, DMSO-d6): δ=157.4,151.2,149.8,144.8,137.8,132.8,126.2,122.3,114 .6,113.7,112.3,102.7,98.6,77.9,75.5,59.4,42.2,41.6,41.2,38.0,34.1,29.7ppm. LCMS (ESI+): [M+1]+ = 405.3, RT 1.15 min (Method 9)

[0433] Compound 54b: 1 H NMR (400MHz, DMSO-d6): δ=8.42(d,J=6.9Hz,1H),8.01(s,1H),7.84(s,1H), 7.49(s,1H),7.29(s,1H),7.12(d,J=3.3Hz,1H),6.88(s,2H),6.73(d,J=6.9Hz,1H), 6.54(d,J=3.7Hz,1H),4.77-4.89(m,3H),4.24-4.33(m,1H),3.79(t,J=3.9Hz,1H),3.18(d,J=4.5Hz,1H),2.70(br d,J=6.5Hz,2H),2.47(br d,J=4.1Hz,1H),2.29(dd,J=13.6,10.4Hz,1H),2.08-2.19(m,1H),1.74-1.88(m,2H),1.45-1.56ppm(m,1H). 13 C NMR(101MHz,DMSO-d6):δ=157.4,151.2,150.0,144.9,137.8,132.8,126.2,121.9,1 14.6,113.8,112.3,102.7,98.7,77.4,75.7,58.7,42.6,41.9,40.3,33.9,29.6ppm. LCMS(ESI+):[M+1]+=405.2, RT1.13 minutes (Method 9)

[0434] Preparation of Compounds 55a and 55b [ka]

[0435] Compounds 55a and 55b were prepared by processes similar to those used to prepare compounds 54a and 54b.

[0436] Compound 55a 1H NMR (DMSO-d6, 400MHz): δ=8.45(d,J=4.0Hz,1H),8.01(s,1H),7.66(td,J=7.6,1.8Hz,1H),7.11-7.23(m,3H),6.87(br s,2H),6.53(d,J=3.5Hz,1H),4.66-4.88(m,3H),4.14-4.24(m,1H),3.67-3.73(m,1H),3.17(d,J=3.5Hz,1H),2.81(d,J=7.7Hz,2H),2 .54-2.69(m,1H),2.33(dd,J=13.0,9.7Hz,1H),2.10(dd,J=11.2,8.8Hz,1H),1.98-2.05(m,1H),1.90(dd,J=13.0,8.6Hz,1H),1.81(br dd,J=10.7,8.7Hz,1H),1.71ppm(ddd,J=11.3,7.9,3.5Hz,1H) 13 C NMR(DMSO-d6,101MHz): δ=160.9,157.9,151.7,150.4,149.4,136.7,123.1,122 .7,121.6,103.2,99.1,78.4,76.0,59.9,45.1,42.8,41.7,38.6,34.7,29.8ppm LCMS (ESI+): [M+1]+ = 366.3, RT 1.20 min (Method 9)

[0437] Compound 55b 1H NMR(DMSO-d6,400MHz): δ=8.45(d,J=4.0Hz,1H),8.01(s,1H),7.66(td,J=7.6,1.8Hz,1H),7.14-7.24(m ,2H),7.10(d,J=3.5Hz,1H),6.86(s,2H),6.53(d,J=3.5Hz,1H),4.73-4.90(m,3H),4.24-4.33(m,1H),3. 77(t,J=4.0Hz,1H),2.80(d,J=7.5Hz,2H),2.51-2.60(m,1H),2.43(tt,J=7.4,4.0Hz,1H),2.26(dd,J=1 3.6,10.3Hz,1H),2.11(ddd,J=11.2,7.6,4.1Hz,1H),1.73-1.85(m,2H),1.50ppm(dd,J=11.0,8.6Hz,1H) 13 C NMR(DMSO-d6,101MHz): δ=160.9,157.9,151.7,150.5,149.4,136.7,123.2,122.4 ,121.6,103.2,99.2,77.9,76.2,59.3,55.4,45.4,43.1,42.4,40.9,34.4,29.7ppm LCMS (ESI+): [M+1]+ = 366.3, RT 1.20 min (Method 9)

[0438] Modulation of Compound 56

change

[0439] 1 H NMR (500MHz, chloroform-d):δ 5.42(d,J=4.5Hz,1H),5.17,(dd,J=4.5,1.7Hz,1H),4.85-4.83(m,3H),3.39 (s,3H),3.09-3.05(m,2H),2.94-2.85(m,2H),1.21(s,9H),1.20ppm(s,9H). 13 C NMR (125 MHz, chloroform-d): δ 177.4, 177.2, 139.7, 107.6, 105.7, 80.6, 75.6, 74.5, 55.6, 44.8, 41.5, 39.2, 39.0, 27.4, 27.3 ppm.

[0440] Preparation of Compound 57 [ka] CAS 176098-48-9 (1.8 g, 6.87 mmol, 1 eq) was dissolved in EtO (18 mL) and zinc (0.89 g, 13.7 mmol, 2.00 eq) was added. This was followed by the dropwise addition of a solution of trichloroacetyl chloride (1.6 g, 8.9 mmol, 1.3 eq) in EtO (6 mL) with stirring at 0 °C. The resulting solution was stirred at rt for 2 h. Then, at 0 °C, zinc (4.47 g, 68.7 mmol, 10.0 eq) and AcOH (1.8 mL) were added, and the mixture was stirred at rt for 3 h. The residue was added to saturated aqueous NaHCO (50 mL) at 0 °C, the solid was filtered off, the aqueous phase was extracted with EA (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 5:1). The product-containing fractions were collected and the solvent was evaporated to give the title compound 57.

[0441] 55% yield (2.0 g, 7.63 mmol), yellow oil. 1 H NMR(400MHz chloroform-d)δ 7.39-7.31(m,5H),5.99(d,J=4.0Hz,1H),4.79-4.73(m,2H),4.56(d,J=11.8Hz,1H ),4.00(s,1H),3.50-3.35(m,3H),3.28-3.19(m,1H),1.45(s,3H),1.33ppm(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 204.58, 136.96, 128.69, 128.26, 127.83, 111.90, 105.70, 85.25, 82.92, 78.60, 71.91, 59.13, 54.53, 26.26, 25.75 ppm. LCMS (ESI+) m / z: C 15 H 18 Calculated value for O4 [M+H] + =305.13, actual value 305.15, RT: 0.887 min, Method 1.

[0442] Preparation of Compound 58 [ka] Compound 57 (900 mg, 2.96 mmol, 1 eq) was dissolved in MeOH (9 mL), and then NaBH (225 mg, 5.92 mmol, 2 eq) was added at −78 °C. The resulting solution was stirred at −78 °C for 1 h. The mixture was added to saturated aqueous NH Cl (50 mL) at 0 °C, then extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 70:30). The product-containing fractions were collected and the solvent was evaporated to give the title compound 58.

[0443] 55% yield (550 mg, 1.63 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 7.41-7.31(m,5H),5.86(d,J=4.0Hz,1H),4.76(d,J=12.2Hz,1H),4.64(d,J=4.0Hz,1H),4.52(d,J=12.2Hz,1H),3.87-3.74(m,2H),2.9 2(dt,J=12.6,6.4Hz,1H),2.74(dt,J=12.3,6.3Hz,1H),2.24(ddd,J=11.4,7.5,3.4Hz,2H),1.80(s,1H),1.47(s,3H),1.31ppm(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 137.37, 128.58, 128.06, 127.80, 111.78, 104.90, 84.72, 83.18, 79.04, 71.68, 59.85, 46.63, 40.53, 26.52, 25.94 ppm, LCMS (ESI+) m / z: C 17 H 22 Calculated value for O5 [M+H] + =307.15, actual value 307.20, RT: 0.734 min, Method 1.

[0444] Preparation of compound 59 [ka] Compound 58 (1.96 mmol, 600 mg, 1 eq) was dissolved in DMF (6 mL), imidazole (267 mg, 3.92 mmol, 2 eq) and TBDPSiCl (537 mg, 1.96 mmol, 1 eq) were added, and the mixture was stirred at 50 °C for 10 h. The mixture was cooled to room temperature and poured into EtOAc (10 mL), followed by washing with brine (3 × 10 mL). The organic phase was dried over MgSO, filtered, and evaporated to a minimum. To remove the remaining DMF, the resulting residue was dissolved in EtOAc (10 mL), followed by an additional washing step with brine (5 × 10 mL). The residue was purified by column chromatography on silica gel (PE / EtOAc 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 59.

[0445] 56% yield (600 mg, 1.10 mmol), colorless oil. 1 H NMR(400MHz,chloroform-d)δ 7.74-7.59(m,6H),7.44-7.31(m,9H),5.81(d,J=4.0Hz,1H),4.64-4.53(m,2H),4.36(d,J=12.2Hz,1H),3.76(p,J=7.1Hz,1H),3.54(s,1 H),2.69(dt,J=12.5,6.4Hz,1H),2.50(dt,J=12.4,6.4Hz,1H),2.36(td,J=11.2,7.6Hz,2H),1.42(s,3H),1.26(s,3H),1.01ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 135.52, 135.50, 134.83, 129.67, 129.65, 129.61, 128.45, 127.89, 127.74, 127.64, 127.62, 127.59, 111.69, 104.81, 84.56, 83.26, 79.36, 71.55, 60.47, 46.68, 40.66, 26.71, 26.59, 26.56 ppm, LCMS (ESI+) m / z: C 33 H 40 Calculated value for O5Si [M+NH4]+ =562.26, actual value 562.25, RT: 2.657 min, Method 1.

[0446] Preparation of Compound 60 [ka] Compound 59 (530 mg, 0.97 mmol, 1.0 equiv) was dissolved in methanol and Pd / C (106 mg) was added. The reaction was stirred at 50 °C for 48 h. After completion, the solution was then filtered. The filter cake was washed with MeOH, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: PE / EtOAc 99:1 to 80:20). The product-containing fractions were collected and the solvent was evaporated to give compound 60.

[0447] 33% yield (150 mg, 0.33 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 7.64(dt,J=7.9,1.8Hz,4H),7.43-7.34(m,6H),5.80(d,J=3.9Hz,1H),4.48(d,J=3.9Hz,1H),3.96(p,J=7.1Hz ,1H),3.81(s,1H),2.64-2.53(m,2H),2.40(dt,J=12.6,6.7Hz,2H),1.43(s,3H),1.25(s,3H),1.02ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 135.49, 133.87, 129.69, 127.68, 127.66, 111.73, 104.45, 85.99, 79.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69, 26.31, 25.78, 18.95 ppm. LCMS (ESI+) m / z: C 26 H 34 Calculated value for O5Si [M+NH4] + =472.22, actual value 472.25, RT: 1.835 min, Method 1.

[0448] Synthesis of Compound 60.1 [ka] Compound 60 (200 mg, 0.44 mmol, 1 eq) was dissolved in DCM (2 mL), and then DMP (224 mg, 0.52 mmol, 1.2 eq) was added at 0 °C. The mixture was stirred at RT for 2 h. The reaction was quenched by adding 2 mL of saturated aqueous NaSO and 2 mL of saturated aqueous NaHCO, followed by extraction with EtOAc (3 × 20 mL). The organic phase was dried over NaSO. The residue was purified by silica gel chromatography using PE / EA (gradient elution: PE / EtOAc 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 60.1.

[0449] 75% yield (150 mg, 0.33 mmol), pale yellow oil. 1 H NMR (300 MHz, chloroform-d) δ 7.64-7.62 (m, 4H), 7.44-7.36 (m, 6H), 5.96 (d, J = 4.4 Hz, 1H), 4.39-4.21 (m, 2H), 2.76-2.66 (m, 1H), 2.59-2.49 (m, 2H), 2.44-2.37 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.05 (s, 9H). 13 C NMR(75MHz,CDCl3)δ 211.71,135.42,133.70,133.64,129.72,127.68,114.02,102.18,76.21, 75.97,59.28,47.73,44.56,27.31,26.72,22.69,18.94,LCMS(ESI+)m / z:C 26 H 32 Calculated value for O5Si [M+NH4] + =470.20, actual value 470.30, RT: 2.228 min, Method 1.

[0450] Synthesis of Compound 60.2 [ka] Compound 60.1 (130 mg, 0.28 mmol, 1 eq) was dissolved in EtOH (1.3 mL), then NaBH (20 mg, 0.56 mmol, 2 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 30 min. The mixture was added to saturated aqueous NH Cl (30 mL) at 0 °C, then extracted with EtOAc (3 × 30 mL). The organic phase was dried over Na SO . The residue was purified by silica gel chromatography using PE / EA (gradient elution: PE / EtOAc 99:1 to 80:20). The product-containing fractions were collected, and the solvent was evaporated to give compound 60.2.

[0451] 69% yield (90 mg, 0.19 mmol), pale yellow oil. 1 H NMR(300MHz,chloroform-d)δ 7.66-7.60(m,4H),7.42-7.32(m,6H),5.68(d,1H),4.44(dd,J=5.3,4.1Hz,1H),4.03(q,J=7.1Hz,1H),3.72(dd,J= 10.9,5.3Hz,1H),2.71-2.62(m,1H),2.57-2.49(m,1H),2.40-2.32(m,2H),1.46(s,3H),1.27(s,3H),1.03(s,9H). 13 C NMR (75 MHz, chloroform-d) δ 135.49, 134.14, 134.06, 129.55, 127.57, 112.41, 103.70, 78.80, 77.08, 75.66, 60.30, 44.63, 42.54, 26.75, 26.37, 26.11, 18.95, LCMS (ESI+) m / z: C 26 H 34 Calculated value for O5Si [M+NH4] + =472.22, actual value 472.20, RT: 2.062 min, Method 1.

[0452] Preparation of Compound 61 [ka] CAS 6983-40-0 (2.00 g, 11.6 mmol, 1.0 eq) was dissolved in pyridine (20 mL), cooled to 0 °C, and PivCl (1.81 g, 15.08 mmol, 1.3 eq) was added. The mixture was stirred at 0 °C to rt for 17 h. After that, the mixture was slowly poured into ice-cold NH4Cl (aq. 30 mL), and the product was extracted with n-heptane (3 × 50 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: PE / EtOAc 99:1 to 90:10). The product-containing fractions were collected, and the solvent was evaporated to give compound 61.

[0453] 67% yield (2.0 g, 7.81 mmol), colorless oil. 1 H NMR (400 MHz, chloroform-d): δ 6.05-6.11 (m, 1H), 5.48 (s, 1H), 4.56-4.60 (m, 1H), 4.55 (d, J = 3.7 Hz, 1H), 4.34 (d, J = 2.0 Hz, 1H), 1.48 (s, 3H), 1.39-1.41 (m, 3H), 1.19-1.21 ppm (m, 9H). 13 C NMR (101 MHz, chloroform-d): δ 176.9, 158.5, 114.1, 106.4, 88.8, 83.0, 75.3, 38.6, 28.0, 27.2, 26.9 ppm. LCMS (ESI+) m / z: C 13 H 20 Calculated value for O5 [M+H] + =257.13, actual value 257.10, RT: 1.113 min, Method 6.

[0454] Preparation of Compound 62 [ka]

[0455] Compound 61 (2.2 g, 8.5 mmol, 1.0 eq) was dissolved in EtO (22 mL) and Zn(Cu) (10.1 g, 59.5 mmol, 7.0 eq) was added. This was followed by the dropwise addition of a solution of trichloroacetyl chloride (4.4 g, 24.5 mmol, 2.8 eq) in EtO (6 mL) with stirring at 0 °C. The resulting solution was stirred at rt for 2 h. Then, at 0 °C, zinc (5.58 g, 85 mmol, 10.00 eq) and AcOH (2.2 mL) were added, and the mixture was stirred at rt for 3 h. The residue was added to saturated aqueous NaHCO (50 mL) at 0 °C, the solid was filtered off, the aqueous phase was extracted with EA (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 80:20). The product-containing fractions were collected and the solvent was evaporated to give compound 62.

[0456] 60% yield (1.5 g, 5.03 mmol). 1 H NMR(400MHz,chloroform-d)δ 5.99(d,J=3.9Hz,1H),5.35(s,1H),4.60(d,J=3.9Hz,1H),3.44(t,J=4.0Hz,2H) ,3.37(dd,J=13.2,4.6Hz,1H),3.27-3.20(m,1H),1.33(s,3H),1.24ppm(s,9H), 13 C NMR (75 MHz, chloroform-d) δ 202.93, 177.27, 112.18, 105.40, 84.26, 79.34, 78.02, 59.05, 54.40, 38.97, 27.02, 26.07, 25.61 ppm, LCMS (ESI+) m / z: C 15 H 22 Calculated value for O6 [M+H] + =299.14, actual value 299.10, RT: 0.991 min, Method 6.

[0457] Preparation of Compound 63 [ka] Compound 62 (1.54 g, 5.16 mmol, 1 eq) was dissolved in MeOH (15 mL), and then NaBH (0.37 g, 10.3 mmol, 2 eq) was added at −78 °C. The resulting solution was stirred at −78 °C for 1 h. The mixture was added to saturated aqueous NH Cl (50 mL) at 0 °C, then extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: PE / EtOAc 99:1 to 70:30). The product-containing fractions were collected, and the solvent was evaporated to give compound 63.

[0458] 52% yield (780 mg, 2.6 mmol). 1 H NMR(400MHz,chloroform-d)δ 5.84(d,J=3.9Hz,1H),5.13(s,1H),4.48(d,J=3.9Hz,1H),2.89(dt,J=12.5,6.4Hz,1H),2 .49(dt,J=12.6,6.3Hz,1H),2.30-2.23(m,2H),1.49(s,3H),1.28(s,3H),1.22ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 177.50, 112.10, 104.66, 84.38, 79.04, 78.60, 59.54, 46.10, 40.32, 38.95, 27.12, 26.40, 25.85 ppm. LCMS (ESI+) m / z: C 15 H 24 Calculated value for O6 [M+NH4] + =318.20, actual value 318.16, RT: 1.228 min, Method 1.

[0459] Preparation of Compound 64 [ka] Compound 63 (750 mg, 2.50 mmol, 1.0 eq) was dissolved in DMF (8 mL), and imidazole (340 mg, 5.00 mmol, 2.0 eq) and TBDPS (688 mg, 2.50 mmol, 1.0 eq) were added. The mixture was stirred at 50 °C for 10 h. The mixture was cooled to room temperature and poured into EtOAc (15 mL), followed by washing with brine (3 × 15 mL). The organic phase was dried over MgSO, filtered, and evaporated to a minimum. The resulting residue was dissolved in EtOAc (15 mL), after which an additional washing step with brine (5 × 15 mL) was required to remove residual DMF. The residue was purified by column chromatography on silica gel (PE / EtOAc 99:1 to 95:5). The product-containing fractions were collected, and the solvent was evaporated to give compound 64.

[0460] 52% yield (700 mg, 1.30 mmol), white solid. 1 H NMR(300MHz,chloroform-d)δ 7.62(ddd,J=7.8,2.8,1.7Hz,4H),7.36(qt,J=8.7,2.7Hz,6H),5.78(d,J= 3.9Hz,1H),4.91(s,1H),4.38(d,J=3.9Hz,1H),3.98(p,J=7.1Hz,1H),2.67 (dt,J=12.3,6.3Hz,1H),2.35(td,J=12.2,7.5Hz,2H),2.21(dt,J=12.4,6. 3Hz,1H),1.45(s,3H),1.25(d,J=1.9Hz,3H),1.12(s,9H),1.03ppm(s,9H). 13 C NMR (75 MHz, chloroform-d) δ 135.49, 135.45, 133.93, 133.84, 129.63, 129.61, 127.61, 127.59, 112.03, 104.54, 84.38, 79.02, 78.77, 65.54, 60.25, 46.30, 40.56, 38.82, 30.58, 27.02, 26.72, 26.43, 25.88 ppm, LCMS (ESI+) m / z: C 31 H 42 Calculated value for O6Si [M+NH4] +=556.28, actual value 556.20, RT: 2.697 min, Method 3.

[0461] Alternative preparation of compound 60 [ka] Compound 64 (1.37 mmol, 740 mg, 1 eq) was dissolved in MeOH (8 mL) and sodium methoxide (74.0 mg, 1.37 mmol, 1.00 equiv) was added. The reaction was stirred at RT for 30 min and then stirred with H-exchange resin until pH = 7. It was then filtered, and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 80:20). The product-containing fractions were collected, and the solvent was evaporated to give compound 60.

[0462] 36% yield (230 mg, 0.50 mmol), colorless oil. 1 H NMR(300MHz,chloroform-d)δ 7.64(dt,J=7.9,1.8Hz,4H),7.43-7.34(m,6H),5.80(d,J=3.9Hz,1H),4.48(d,J=3.9Hz,1H),3.96(p,J=7.1Hz ,1H),3.81(s,1H),2.64-2.53(m,2H),2.40(dt,J=12.6,6.7Hz,2H),1.43(s,3H),1.25(s,3H),1.02ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 135.49, 133.87, 129.69, 127.68, 127.66, 111.73, 104.45, 85.99, 79.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69, 26.31, 25.78, 18.95 ppm. LCMS (ESI+) m / z: C 26 H 34 Calculated value for O5Si [M+NH4] + =472.22, actual value 472.25, RT: 1.835 min, Method 4.

[0463] Preparation of Compounds 66a and 66b [ka]

[0464] Preparation of Compound 66.1 [ka] ((3aR,5R,6R,6aR)-2,2-Dimethyl-6-(naphthalen-2-ylmethoxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanol (4.71 g, 14.3 mmol, 1.00 eq, CAS: 1217482-83-1) was dissolved in THF (87 mL). Triphenylphosphine (8.98 g, 34.2 mmol, 2.4 eq) and imidazole (2.91 g, 42.79 mmol, 3.3 eq) were added, followed by the portionwise addition of iodine (8.80 g, 34.6 mmol, 2.4 eq). The reaction mixture was stirred at reflux under a nitrogen atmosphere for 2 h. Saturated aqueous NaSO was added, followed by stirring for 5 min. The reaction mixture was then extracted with EtOAc (4 × 100 mL), and the combined organic layers were washed with saturated aqueous NaSO (1 × 200 mL), saturated aqueous NaHCO (1 × 200 mL), and brine (1 × 200 mL), then dried over MgSO, filtered, and the filtrate concentrated in vacuo. n-Heptane was added to the residue, and the mixture was stirred for 5 minutes. The solids were removed by filtration and rinsed with n-heptane, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane / EtOAc gradient 95:5 to 80:20). The product-containing test tubes were combined and concentrated in vacuo to give compound 66.1.

[0465] 87% yield (26.3 g, 12.4 mmol), white solid. 1H NMR (400MHz, クロロホルム-d): δ 7.94-7.83(m,4H),7.54(dd,J=8.54,1.63Hz,1H),7.53-7.48(m,2H),5.75(d ,J=3.74Hz,1H),4.95(d,J=12.10Hz,1H),4.76(d,J=12.10Hz,1H),4.59(t,J =3.96Hz,1H),3.78(m,1H),3.66(dd,J=8.47,4.29Hz,1H),3.55(dd,J=11.00 ,3.08Hz,1H),3.34(dd,J=11.22,4.40Hz,1H),1.62(s,3H),1.38ppm(s,3H). 13 C NMR (100MHz, クロロホルム-d): δ 134.72,133.23,133.20,128.49,127.90,127.75,127.05,126.28,126.16,125.80 ,113.24,103.95,81.71,77.47,76.32,72.46,26.84,26.57,7.30ppm.ESI-MS:m / z 458.0[M+NH4] + R f (n-ヘプタン / EtOAc;1:1)=0.77 LCMS: [M+1] + =458.0[M+1]+,2.29 points (Method 13)

[0466] Modulation of compound 66.2

change

[0467] 65% yield (3.94 g, 12.5 mmol), white solid. 1 H NMR (400MHz, chloroform-d):δ 7.89-7.83(m,4H),7.57(dd,J=8.3,1.61Hz,1H,),7.53-7.47(m,2H),5.83(d,J=3.26Hz,1H),5.02(d,J=12.42Hz,1H),4.8 8(d,J=12.42Hz,1H),4.59(m,1H),4.52(m,1H),4.36(m,1H),4.34(dd,J=4.50,2.15Hz,1H),1.57(s,3H),1.43ppm(s,3H). 13 C NMR (100 MHz, chloroform-d): δ 158.79, 134.77, 133.20, 133.17, 128.45, 127.67, 127.75, 126.92, 126.28, 126.15, 125.74, 114.78, 104.27, 83.94, 77.42, 72.57, 27.91, 27.28 ppm.R f (n-heptane / EtOAc; 1:1) = 0.77. MP: 102.01°C. LCMS:[M+1] +=313.1[M+1]+,2.17 minutes (method 13)

[0468] Preparation of Compound 66.3 [ka] Compound 66.2 (3.88 g, 12.4 mmol, 1.00 eq) was dissolved in anhydrous THF (48 mL) and activated zinc * (5.69 g, 87.0 mmol, 7.00 eq) - prepared as follows - was introduced. A solution of trichloroacetyl chloride (2.28 mL, 20.2 mmol, 1.80 eq) dissolved in anhydrous THF (16 mL) was added dropwise over 1 h at room temperature. The zinc salts were then removed by filtration through Celite® and rinsed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 (3x) and brine (2x). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give compound 66.3 as an orange viscous oil. The product was used immediately as is in the next step.

[0469] (5.85g, crude), 1 H NMR (400MHz, chloroform-d):δ 7.92-7.80(m,4H),7.54-7.48(m,3H),5.84(d,J=3.30Hz,1H),4.94(d,J=11.67Hz,1H),4.86(d,J=11.66Hz,1H),4.62(t ,J=3.96Hz,1H),4.30(d,J=4.40Hz,1H),4.05(d,J=18.27Hz,1H),3.55(d,J=18.27Hz,1H),1.54(s,3H),1.33ppm(s,3H). 13 C NMR (100 MHz, chloroform-d δ 191.48, 134.14, 133.25, 133.11, 128.24, 127.94, 127.77, 127.02, 126.34, 126.27, 125.91, 120.23, 113.94, 104.28, 83.22, 79.22, 78.08, 72.75, 51.45, 26.78, 26.03 ppm.

[0470] * Zinc powder (100 g, 1.54 mol) was added to deionized water (500 mL). The mixture was stirred and nitrogen gas was bubbled through the solution for 10 minutes, after which anhydrous CuSO4 (7.36 g, 46.1 mmol) was added. The suspension was stirred and bubbled for 45 minutes and then filtered. The zinc powder was rinsed with both degassed deionized water (1.25 L) and degassed acetone (550 mL) and then dried overnight in vacuo. The resulting black powder (100 g) was stored under an inert atmosphere.

[0471] Preparation of Compound 66.4 [ka] Compound 66.3 (5.26 g, 12.4 mmol, 1.00 eq) was dissolved in THF (49 mL) and zinc (8.12 g, 124 mmol, 10.0 eq) was added. The reaction mixture was cooled to 0 °C, and glacial acetic acid (3.56 mL, 62.1 mmol, 5.00 eq) was carefully added. The reaction mixture was stirred at room temperature for 20 h, and the zinc was removed by filtration through Celite® and rinsed with EtOAc. The filtrate was washed with saturated NaHCO3 (3x) and brine (3x). The aqueous phase was extracted with EtOAc (1x). The combined organic layers were dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane / EtOAc gradient 95:5 to 75:25). The product-containing fractions were combined, and the solvent was removed in vacuo to give compound 66.4.

[0472] 44% yield (2 steps, 1.94 g, 5.46 mmol), white solid. 1H NMR (400MHz, クロロホルム-d): δ 7.89-7.77(m,4H),7.54-7.48(m,3H),5.77(d,J=4.07Hz,1H),5.04(d,J=12.21Hz,1H) ,4.78(d,J=12.21Hz,1H),4.68(t,J=4.07Hz,1H),3.92(d,J=4.48Hz,1H),3.80(ddd,J= 17.70,6.92,2.24Hz,1H),3.31(ddd,J=17.50,6.11,2.04Hz,1H),3.24(ddd,J=17.91,6 .10,2.44Hz,1H),2.99(ddd,J=17.80,6.82,2.24Hz,1H),1.55(s,3H),1.35ppm(s,3H). 13 C NMR (100MHz, クロロホルム-d): δ 204.66,134.54,133.22,133.11,128.61,127.86,127.79,126.92,126.99,126.41,1 25.61,112.93,104.16,79.91,76.83,75.25,72.46,56.10,55.01,26.32,25.80ppm.R f (n-ヘプタン / EtOAc;1:1)=0.67.MP:101.79°C. LCMS: [M+1] + =355.3[M+1]+,2.08 points (Method 9)

[0473] Modulation of compounds 66a and 66b

change

[0474] LCMS:[M+1] + =357.2[M+1] + , 1.89 minutes (method 13)

[0475] To obtain analytically pure samples of both isomers of Compound 66b and Compound 66a, the mixture of alcohols was protected (t-butyldiphenylsilyl) and the silylated intermediates were separated by silica gel chromatography followed by deprotection with TBAF to give the following isolated products:

[0476] compound 66b [ka] 1H NMR (400MHz, クロロホルム-d): δ 7.96-7.82(m,4H),7.59(dd,J=8.47,1.65Hz,1H),7.55-7.48(m,2H),5.69 (d,J=3.96Hz,1H),5.13(d,J=11.88Hz,1H),4.85(d,J=11.88Hz,1H),4.61 (t,J=4.18Hz,1H),4.28(tt,J=7.10,3.47Hz,1H),3.63(d,J=4.40Hz,1H), 2.76-2.57(m,4H),2.20-1.93(m,1H),1.57(s,3H),1.33-1.31ppm(m,3H). 13 C NMR (100MHz, クロロホルム-d): δ 134.20,133.22,133.14,128.63,127.88,127.74,127.22,126.34,126.26,125.74,112.6 9,104.08,81.55,80.89,76.51,72.45,62.79,42.92,41.91,26.39,25.85ppm.ESI-MS:m / z 379.2[M+Na] + R f (n-ヘプタン / EtOAc;1:1)=0.45 LCMS: [M+1] + =379.2[M+Na]+, 1.89 points (Method 9)

[0477] Compound 66a

change

[0478] LCMS: [M+1] + =357.3[M+1] + , 1.88 points (Method 9)

[0479] Modulation of Compound 141

change

[0480] Methylaluminoxane (MAO, 10 wt.% in toluene, 3.06 mL) was slowly added to a solution containing methyl propiolate (45.15 mg, 0.537 mmol, 1 equiv) in 6 mL of dry CHCl at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 15 min, and then a solution of CAS 6991-65-7 (100 mg, 0.537 mmol, 1 equiv) in dry CHCl (1 mL) was added. After stirring for 2 h, HO (10 mL) was carefully added, and the aqueous phase was washed with EtOAc (3 × 20 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue that was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 80:20) to give the desired compound 141 as a yellow oil (20% yield; 0.272 mmol; 73.6 mg).

[0481] R f :0.25 (petroleum ether / EtOAc 90:10 v / v, UV) 1 H NMR (CDCl3,400MHz): δ=6.91(t,1H,J=1.2Hz),4.96(s,1H),4.96(d,1H,J=5.8Hz),4.74(d,1H,J=5.8Hz),3.72(s ,3H),3.28(s,3H),3.08(dd,1H,J=15.6Hz,1.2Hz),2.68(dd,1H,J=15.6Hz,1.2Hz),1.47(s,3H),1.34(s,3H)ppm. 13 C NMR(CDCl3,125MHz):δ=161.8,145.8,142.9,112.3,108.9,89.2,85.7,82.0,54.8,51.2,37.1,26.3,25.2ppm.LCMS(ESI+)m / z:C 12 H 15 Calculated value for O5 [M-OMe] + =239.1, actual value 239.1, RT: 1.341 min, Method 2.

[0482] Preparation of Compound 142 [ka] Compound 141 (1.20 g, 4.44 mmol, 1.00 eq), EA (12 mL), and Pt / C (300 mg, 20%) were added overnight while bubbling with H (5 atm). The catalyst was then filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 90:10). The front peak was identified as compound 142a, and the back peak was identified as compound 142b.

[0483] 33% (400 mg, 1.47 mmol) Compound 142a as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 5.38 (d, J = 5.8 Hz, 1H), 4.81 (s, 1H), 4.50 (d, J = 5.8 Hz, 1H), 3.64 (s, 3H), 3.32 (s, 3H), 3.16-3.09 (m, 1H), 2.46-2.39 (m, 1H), 2.23-2.13 (m, 1H), 2.07-1.86 (m, 2H), 1.42 (s, 3H), 1.36 ppm (s, 3H). 13 C NMR(101MHz,CDCl3)δ 172.21,111.97,108.13,87.37,84.75,78.91,54.84,51.30,50.09,27.11,26.33,25.28,17.79ppm.GCMS(ESI+)m / z:C 13 H 20 Calculated value for O6 [M-Me] - =257.1, actual value 257.1, RT: 6.909 min, Method 1.

[0484] 50% (600 mg, 1.47 mmol) Compound 142b as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 4.84 (s, 1H), 4.68-4.62 (m, 2H), 3.73 (s, 3H), 3.26 (s, 3H), 3.06-3.00 (m, 1H), 2.77-2.66 (m, 1H), 2.53-2.44 (m, 1H), 2.15-2.02 (m, 1H), 1.90-1.79 (m, 1H), 1.42 (s, 4H), 1.36 ppm (s, 3H). 13C NMR(101MHz,CDCl3)δ 172.68,112.76,109.27,86.67,85.17,85.01,56.06,51.69,50.79,28.87,26.43,25.58,17.29ppm.GCMS(ESI+)m / z:C 13 H 20 Calculated value for O6 [M-Me] - =257.1, actual value 257.1, RT: 7.303 min, Method 1.

[0485] Preparation of Compound 143a [ka] Compound 142a (150 mg, 0.55 mmol, 1.00 eq) was dissolved in dry THF (2 mL). The solution was cooled to −78 °C, and LiAlH (42.82 mg, 1.10 mmol, 2.00 eq) was added. The resulting mixture was stirred at −78 °C for 3 h. The reaction was then quenched by adding 5 mL of HO, 15 mL of aq. NaOH (3 M), and 5 mL of HO. The solution was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 90:10) to give compound 143a.

[0486] 73% (98 mg, 0.40 mmol) off-white solid. 1 H NMR(300MHz,chloroform-d)δ 4.94(d,J=5.8Hz,1H),4.85(s,1H),4.68(d,J=5.8Hz,1H),3.72-3.53(m,2H),3.42(s,3H),2.74-2.58(m,1H) ),2.45-2.33(m,1H),2.23-2.08(m,1H),1.96-1.81(m,1H),1.43(s,3H),1.36(s,3H),1.31-1.23ppm(m,1H). 13C NMR(75MHz,CDCl3)δ 112.23,108.30,87.74,85.57,79.09,62.97,55.26,48.58,26.30,25.73,25.20,15.92ppm.GCMS(ESI+)m / z:C 12 H 20 Calculated value for O5 [M-Me] - =229.1, actual value 229.1, RT: 6.944 min, Method 1.

[0487] Preparation of Compound 144a [ka] Compound 142a (100 mg, 0.36 mmol, 1.00 eq) was dissolved in MeOH / HO (5 / 1, 2 mL). The solution was cooled to 0 °C, and LiOH (17.28 mg, 0.72 mmol, 2.00 eq) was added. The resulting mixture was stirred at rt overnight. The reaction was then quenched by adding 10 mL of aq. CA (1 M), extracted with dichloromethane (3 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The solution was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 90:10) to give compound 144a.

[0488] 53% (51 mg, 0.19 mmol) pale yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 4.93 (s, 1H), 4.86 (d, J = 5.6 Hz, 1H), 4.68 (d, J = 5.7 Hz, 1H), 3.52 (s, 3H), 3.19 (t, J = 9.6 Hz, 1H), 2.46-2.37 (m, 1H), 2.29-2.17 (m, 1H), 2.13-2.02 (m, 2H), 1.42 (s, 3H), 1.33 ppm (s, 3H). 13 C NMR(101MHz,CDCl3)δ 171.59,111.74,107.61,87.26,83.64,79.17,54.50,49.95,25.12,24.28,23.99,14.92ppm.GCMS(ESI+)m / z:C12 H 18 Calculated value for O6 [M-Me] - =243.0, actual value 243.0, RT: 7.490 min, Method 1.

[0489] Preparation of Compound 143b [ka] Compound 142b (150 mg, 0.55 mmol, 1.00 eq) was dissolved in dry THF (2 mL). The solution was cooled to −78 °C, and LiAlH (42.82 mg, 1.10 mmol, 2.00 eq) was added. The resulting mixture was stirred at −78 °C for 3 h. The reaction was then quenched by adding 5 mL of HO, 15 mL of aq. NaOH (3 M), and 5 mL of HO. The solution was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 90:10) to give compound 143b.

[0490] 29% (40 mg, 0.16 mmol) yellow oil. 1 H NMR (300 MHz, chloroform-d) δ 4.91 (s, 1H), 4.69-4.58 (m, 2H), 3.89-3.79 (m, 1H), 3.59-3.50 (m, 1H), 3.47 (s, 3H), 2.55-2.39 (m, 2H), 2.28-2.09 (m, 1H), 1.85-1.70 (m, 1H), 1.61-1.48 (m, 1H), 1.44 (s, 3H), 1.35 (m, 3H), 1.26 ppm (s, 1H). 13 C NMR(101MHz,CDCl3)δ 112.62,110.33,88.92,85.71,85.15,62.21,56.49,47.67,27.82,26.54,25.41,16.19ppm.GCMS(ESI+)m / z:C 12 H 20 Calculated value for O5 [M-Me]-=229.1, measured value 229.1, RT: 7.008 min, Method 1.

[0491] Preparation of Compound 144b [ka] Compound 142b (220 mg, 0.81 mmol, 1.00 eq) was dissolved in MeOH / HO (5 / 1, 2.5 mL). The solution was cooled to 0 °C, and LiOH (38.88 mg, 1.62 mmol, 2.00 eq) was added. The resulting mixture was stirred at rt overnight. The reaction was then quenched by adding 10 mL of aq. CA (1 M), extracted with dichloromethane (3 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product (175 mg, containing compounds 144a and 144b in a 1:2 ratio) was purified by silica gel column chromatography (gradient elution: PE / EtOAc 100:1 to 90:10). The front peak was compound 144a, and the back peak was compound 144b.

[0492] 17% (35 mg, 1.47 mmol, containing Compound 144a and Compound 144b in a 1:15 ratio) off-white solid. 1 H NMR (300 MHz, chloroform-d) δ 4.87 (s, 1H), 4.72-4.65 (m, 2H), 3.33 (s, 3H), 3.06-2.98 (m, 1H), 2.76-2.62 (m, 1H), 2.56-2.44 (m, 1H), 2.19-2.05 (m, 1H), 1.93-1.79 (m, 1H), 1.42 (s, 3H), 1.36 ppm (s, 3H). 13 C NMR(101MHz,CDCl3)δ 176.29,111.92,108.28,85.39,84.00,83.72,55.09,49.96,27.83,25.38,24.53,15.89ppm.GCMS(ESI+)m / z:C 12 H 18 Calculated value for O6 [M-Me] - =243.0, actual value 243.0, RT: 7.634 min, Method 1.

[0493] Preparation of Compound 149 [ka] Compound 143a (138 mg, 0.56 mmol, 1.00 eq) was dissolved in HO (1.5 mL) and formic acid (FA) (1.5 mL) was added. The mixture was heated to 50° C. for 16 h. The solution was then cooled to room temperature and concentrated in vacuo to give 141 mg of compound 149.1.

[0494] Compound 149.1 (141 mg, crude; mixture of α and β anomers, with the β anomer being the major product) was dissolved in dry pyridine (1.5 mL) and stirred for 30 min. Acetic anhydride (85.68 mg, 0.84 mmol, 1.50 eq) was added to the stirred solution at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (5 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 5 mL), and the combined organic layers were washed with brine (3 × 5 mL), dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined, and the solvent was removed in vacuo to give compound 149.

[0495] 74% yield over two steps (150 mg, 0.41 mmol), colorless oil. LCMS (ESI+) m / z: C 16 H 22 Calculated for O9 [M+H2O]+ = 376.20, found 376.20, RT: 1.290 min, Method 1.

[0496] Preparation of Compound 150 [ka] 6-Chloropurine (69.45 mg, 0.45 mmol, 1.10 eq) was dissolved in MeCN (1.1 mL) and N,O-bis(trimethylsilyl)acetamide (BSA) (83.23 mg, 0.41 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, compound 149 (150 mg, 0.41 mmol, 1.00 eq) in MeCN (1.2 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (109.22 mg, 0.49 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), and washed with saturated NaHCO (3 × 10 mL) and saturated aqueous NaCl (3 × 10 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected and the solvent was removed in vacuo to give the title compound 150.

[0497] 60% yield (113 mg, 0.25 mmol, crude), off-white solid. LCMS (ESI+) m / z: C 19 H 21 Calculated for ClN4O7 [M+H]+ = 453.2, found 453.2, RT: 1.324 min, Method 1.

[0498] Preparation of Compound 151 [ka] Compound 150 (113 mg, 0.25 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.2 mL) and NH3 (aq. 0.3 mL) was added. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, the solvent was removed in vacuo, and the product was dissolved in MeOH (1.2 mL). Sodium methoxide (13.5 mg, 0.25 mmol, 1.00 eq) was added, and the mixture was stirred at room temperature for 30 min, then stirred with hydrogen exchange resin (CAS: 78922-04-0) for 30 min until pH = 7. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fractions were collected, and the solvent was removed in vacuo to give compound 151.

[0499] 65% yield (49 mg, 0.15 mmol), off-white solid. 1 H NMR (300 MHz, methanol-d₄) δ 8.46 (s, 1H), 8.18 (s, 1H), 6.03 (d, J = 6.1 Hz, 1H), 4.95-4.89 (m, 1H), 4.49 (d, J = 4.5 Hz, 1H), 3.84-3.58 (m, 2H), 2.86-2.69 (m, 1H), 2.64-2.50 (m, 1H), 2.09-1.89 (m, 1H), 1.88-1.68 (m, 1H), 1.29-1.20 (m, 1H). 13 C NMR(75MHz,MeOD)δ 155.89,152.37,149.24,140.26,118.94,88.06,87.50,75.43,70.22,60.87,27.50,14.50,7.83ppm.LCMS(ESI+)m / z:C 13 H 17 Calculated for N5O4 [M+H]+ = 308.13, found 308.13, RT: 0.524 min, Method 1.

[0500] Preparation of Compound 152 [ka] Compound 143b (186 mg, 0.76 mmol, 1.00 eq) was dissolved in HO (2.0 mL) and formic acid (FA) (2.0 mL) was added. The mixture was heated to 50° C. for 16 hours. The solution was then cooled to room temperature and concentrated in vacuo. This gave 194 mg of crude compound 152.1.

[0501] Compound 152.1 (194 mg, crude) was dissolved in dry pyridine (2.0 mL) and stirred for 30 min. Acetic anhydride (116.28 mg, 1.14 mmol, 1.50 eq) was added at 0 °C and added to the stirred solution at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was then poured into ice-cold water (5 mL) and stirred at room temperature for 30 min. The crude mixture was extracted with CHCl (3 × 5 mL), and the combined organic layers were washed with brine (3 × 5 mL), dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA 100:1 to 10:1). The product-containing fractions were combined, and the solvent was removed in vacuo to give the title compound 152.

[0502] 73% yield over two steps (198 mg, 0.55 mmol, crude), colorless oil. LCMS (ESI+) m / z: C 16 H 22 Calculated for O9 [M+H2O]+ = 376.30, found 376.30, RT: 1.283 min, Method 1.

[0503] Preparation of Compound 153 [ka] 6-Chloropurine (93.17 mg, 0.60 mmol, 1.10 eq) was dissolved in MeCN (1.4 mL) and N,O-bis(trimethylsilyl)acetamide (111.65 mg, 0.55 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, compound 152 (198 mg, 0.55 mmol, 1.00 eq) in MeCN (1.5 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (146.52 mg, 0.66 mmol, 1.20 eq), and the mixture was heated to 80 °C for 2 h. The mixture was cooled to room temperature, diluted with EtOAc (10 mL), and washed with saturated NaHCO (3 × 10 mL) and saturated aqueous NaCl (3 × 10 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 4:1). The product-containing fractions were collected and the solvent was removed in vacuo to give the title compound 153.

[0504] 57% yield (142 mg, 0.31 mmol, crude), off-white solid. LCMS (ESI+) m / z: C 19 H 21 Calculated for ClN4O7 [M+H]+ = 453.2, found 453.2, RT: 1.311 min, Method 1.

[0505] Preparation of Compound 154 [ka] Compound 153 (142 mg, 0.31 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.5 mL) and NH3 (aq. 0.37 mL) was added. The mixture was heated to 80 °C for 16 h. After the mixture was cooled to room temperature, the solvent was removed in vacuo, and the product was dissolved in MeOH (1.5 mL). Sodium methoxide (16.74 mg, 0.31 mmol, 1.00 eq) was added, and the mixture was stirred at room temperature for 30 min, then stirred with hydrogen exchange resin (CAS: 78922-04-0) for 30 min until pH = 7. The resulting mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 5:1). The product-containing fracti...

Claims

1. Formula (A) 【Chemistry 1】 [In the formula, Y is -O-; n is 0, R １ and R ２ One of the groups is hydrogen and the other is -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(CH ２ ) ｍ OPG, -(CH ２ ) ｍ C(O)OR ａ , -(CH ２ ) ｍ C(O)NR ａ ２ , -(CH ２ ) ｍ C(O)R ａ , -(CH ２ ) ｍ B (OR ｂ ) ２ , -(CH ２ ) ｍ S (O) ｘ R ｃ , or =CH ２ and Here, R １ Or R ２ Binding to 【Chemistry 2】 is R １ Or R ２ is hydrogen, -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(CH ２ ) ｍ OPG, -(CH ２ ) ｍ C(O)OR ａ , -(CH ２ ) ｍ C(O)NR ａ ２ , -(CH ２ ) ｍ C(O)R ａ , -(CH ２ ) ｍ B (OR ｂ ) ２ , -(CH ２ ) ｍ S (O) ｘ R ｃ , a silyl group, a C substituted with a silyl group １～６ When it is alkyl or -O-aryl, it is a single bond or R １ Or R ２ , =O, =CH ２ , or =CR ａ ２ is a double bond; Each R ａ are independently hydrogen or C １～６ is alkyl; Each R ｂ is hydrogen or both R ｂ together form a boronic acid protecting group which is catechol borane, pinacol borane, N-methyliminodiacetic acid boronate, neopentyl glycol borane, pinanediol borane, biscyclohexyldiol borane, or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol borane; R ｃ is C １～６ is alkyl or aryl; PG is a silyl group, C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH 2 -naphthyl, benzoyl, -C(=O)-C 1-4 alkyl, or -C(=O)-phenyl, where benzyl, -CH 2 -naphthyl, and benzoyl are hydroxyl protecting groups optionally substituted with one or two substituents each independently selected from -CH 3 and -OCH 3 ; m is 0 or 1; x is 0, 1, or 2; R ４ , R ５ , and R ６ are each independently hydrogen or a silyl group, C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH 2 -naphthyl, benzoyl, -C(=O)-C 1-4 alkyl, or -C(=O)-phenyl, where benzyl, -CH 2 -naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH 3 and -OCH 3 , a hydroxyl protecting group; Or together R ５ and R ６ is a diol protecting group, -C(C 1-4 alkyl) 2 -; Or together R ４ and R ５ is a diol protecting group, -C(C 1-4 alkyl) 2 -; the silyl groups are selected from t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl, and triethylsilyl; however, (c) the compound has the formula 【Chemistry 5】 [In the formula, R ｗ is methyl or H; (d) the compound has the formula 【Chemistry 6】 [In the formula, R is CO ２ Et or CH ２ OH] or any stereoisomer thereof, or a salt or solvate thereof, provided that the compound is not a compound of the formula:

2. The compound has the formula (A-1a), (A-3a), (A-1b), or (A-3b): 【Chemistry 7】 or a salt or solvate thereof.

3. R １ and R ２ One of the groups is hydrogen and the other is -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(CH ２ ) ｍ OPG, -C(O)OR ａ , -C(O)NR ａ ２ , or -B(OR ｂ ) ２ 3. The compound according to claim 1 or 2,

4. The compound is 【Chemistry 8A】 【Chemistry 9】 【Chemistry 10A】 2. The compound according to claim 1, which is selected from the group consisting of:

5. Formula (B) 【Chemistry 12】 [In the formula, Y is -O-; R ４ , R ５ , and R ６ are each independently hydrogen or a silyl group, C 1-4 alkyl, C 1-4 alkyl-O-C 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH 2 -naphthyl, benzoyl, -C(=O)-C 1-4 alkyl, or -C(=O)-phenyl, where benzyl, -CH 2 -naphthyl, and benzoyl are optionally substituted with one or two substituents each independently selected from -CH 3 and -OCH 3 , a hydroxyl protecting group; Or together R ５ and R ６ is a diol protecting group, -C(C 1-4 alkyl) 2 -; Or together R ４ and R ５ is a diol protecting group, -C(C 1-4 alkyl) 2 -; the silyl group is selected from t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl, and triethylsilyl, or a salt or solvate thereof.

6. The compound is 【Chemistry 13】 6. The compound according to claim 5, which is a compound selected from the group consisting of:

Images