Novel spirobicyclic intermediates

Abstract

To provide nucleoside analogues and intermediates having novel substituent patterns, which inhibit protein arginine methyltransferase 5 (PRMT5) activity, and methods for preparing the same.SOLUTION: The present invention provides spirobicyclic nucleoside analogues represented by the formula below.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] PR, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5 MT5 is the major methyltransferase involved in the mono- and symmetric dimethylation of arginine. Post-translational arginine methylation on histone and non-histone proteins is , genome organization, transcription, differentiation, spliceosome function, signal transduction and cell cycle progression It appears to be important in various biological processes such as regulation, stem cell and T cell fate [S topa,N.et al.,Cell Mol Life Sci,2015.72( 11):p.2041-59][Geoghegan, V. et al., Nat Co mmun, 2015.6:p.6758]. Metazoan PRMT5 is involved in Wdr77, and The gen receptor coactivator p44 and the methylosomal protein also known as Valois. It forms a functional complex with PRMT5-MEP50. Both increased plasma concentration and cytoplasmic accumulation are involved in cancer tumorigenesis, and in recent years, poor clinical outcomes have been reported. It is correlated with good [Shilo, K. et al., Diagn Pathol, 201 3.8:p.201]. Both the catalytic and scaffolding functions of the PRMT5-MEP50 complex are involved. The cell rescue experiments addressed this issue include comprehensive enzymatic studies as well as protein concentration, localization, and demonstrated a carcinogenic link between α- and β-glucanase and enzyme 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][Ch an-Penebre, E. et al., Nat Chem Biol, 2015.1 1(6):pp.432-7]. This correlation may make PRMT5 an essential small molecule for cancer and other diseases. Turning molecular drug targets [Stopa, N. et al., Cell Mol Life Sci,2015.72(11):p.2041-59].

[0003] PRMT5 utilizes S-adenosylmethionine (SAM) to mediate histone and non-histone To generate symmetrically dimethylated arginine on protein substrates and to generate S-adenosylhomosyl It is a member of the type II PRMT subfamily that produces SAH (steroidal antihistamine). and human heterooctameric complex (PRMT5)4 co-crystallized with histone H4 peptide substrates The crystal structure of (MEP50)4 explained the mechanism of methylation and substrate recognition [Ant onysamy,S.et al.,Proc Natl Acad Sci US A, 2012.109(44):p.17960-5]. Regulation of PRMT5 activity is through various binding partners, post-translational modification crosstalk, miRNAs, and subcellular localization of This happens.

[0004] Methylation of Arg3 of histones H2A and H4 and Arg8 of histone H3 is essential for differentiation, Cloning for specific inhibition of gene transcripts involved in transformation, cell cycle progression, and tumor suppression Regulating matin formation [Karkhanis, V. et al., Trends Bio Chem Sci, 2011.36(12):p.633-41]. Furthermore, histone H4 PRMT5-mediated methylation of Arg3 in chromatin is mediated by the DNA-methyltransferase DNase. Recruiting MT3A to regulate histone and DNA methylation for long-term gene silencing It may be conjugated [Zhao, Q. et al., Nat Struct Mol Biol,2009.16(3):p.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, which are required for the assembly of the nuclear spliceosome, is possible. occurs in the cytoplasm as part of a "methylosome" containing PRMT5 [Friesen ,WJet al.,Mol Cell Biol,2001.21(24):p. Further evidence for PRMT5 involvement in splicing is provided by This was provided by conditional PRMT5 knockout in mouse neural stem cells. T5-deficient cells show selective retention of introns and exons with weak 5' donor sites. [Bezzi, M. et al., Genes Dev, 201 3.27(17):p.1903-16].

[0006] In addition to its role in splicing, PRMT5 also mediates the regulation of p53 [Jansson, M. et al., Nat Cell Biol, 2008.10(12):p.1431- 9], EGFR [Hsu, JMet al., Nat Cell Biol, 201 1.13(2):p.174-81], CRAF[Andreu-Perez,P.et al., Sci Signal, 2011.4(190):p.ra58], PI3K / AKT[Wei,TYet al.,Cell Signal,2014.26( 12):p.2940-50], NFkB[Wei, H. et al., Proc Na tl Acad Sci USA,2013.110(33):p.13516-2 Direct methylation of key signaling nodes such as α-glucan, β-glucan, and β-glucan regulates cell fate and homeostasis. Affects important pathways involved in sexuality.

[0007] PRMT5 is one of the major sym-Arg methyltransferases and is expressed in many cells. Because it is involved in cellular processes, increased protein expression may be important in its tumorigenic potential. Interestingly, P in mantle cell lymphoma (MCL) RMT5 translation appears to be regulated by miRNAs. MCL cells are similar to normal B Although they exhibit less PRMT5 mRNA and a slower transcription rate than lymphocytes, The concentration and methylation of H3R8 and H4R3 are significantly increased [Pal, S. et al. ,EMBO J,2007.26(15):p.3558-69]. 3'U of PRMT5 Re-expression of miRNAs that bind to the TR region reduces PRMT5 protein levels [W ang,L.et al.,Mol Cell Biol,2008.28(20):p Surprisingly, prmt5 antisense RNA showed high mRNA expression found in the human prmt5 gene, supporting the hypothesis of specific translational regulation rather than expression level [ Stopa,N.et al.,Cell Mol Life Sci,2015.72 (11):p.2041-59].

[0008] More recently, a novel nanomolar concentration of ribozyme has been reported with antitumor activity in multiple MCL xenograft models. A potent PRMT5 inhibitor (EPZ015666) has been shown to improve PRMT5 biology and cancer It has been described as the first chemical probe suitable for further validation of its role in [Chan-Penebre, E. et al., Nat Chem Biol, 201 5.11(6):p.432-7]. International Publication No. 2014100695 Pamphlet, Brochure No. 2014100719, Brochure No. 2015200680, and the same pamphlet No. 2014100730, which are useful for inhibiting PRMT5 activity. The compound is disclosed in Devkota, K. et al., ACS Med Chem Lett, 2014.5: pp.293-297, a series of natural product sinefungin The synthesis of analogs and the ability of these analogs to inhibit EHMT1 and EHMT2 are described. WO 2003070739 pamphlet describes partial and partial cleavage of the A1 adenosine receptor. This application discloses full agonists, their preparation, and their therapeutic use. The brochure No. 2012082436 is a modulator of histone methyltransferase and and diseases affected by the regulation of histone methyltransferase activity. The present invention discloses compounds and compositions for treating rheumatoid arthritis. RET is a combination therapy that selectively kills methylthioadenosine phosphorylase-deficient cells Analogs of MTA are described herein as antitoxic agents. g,P.-P.et al.,Bioorg Med Chem Lett,2005. 15:pp.2829-2833 describes a novel human 5'-deoxy-5'-methylthioadenosidase This paper describes the design, synthesis, and biological evaluation of methyltransferase (MTAP) substrates. The International Publication No. 2012075500 pamphlet describes histone methyltransferase 7-deazapurine modulators are disclosed. The present invention discloses compounds and compositions for modulating histone methyltransferase activity. WO 9640686 describes the synthesis of heterocyclic substituted cyclopentanols. The present invention describes compounds and methods of using such compounds to inhibit adenosine kinase. do.

[0009] International Publication No. 2016135582 and U.S. Patent Application Publication No. 201602 No. 44475 describes substituted nucleoside derivatives useful as anticancer agents. Oyer et al. reported diaryl-erythrophores as adenosine kinase inhibitors. Lanosyltubercidin analogues are described.

[0010] Nucleoside analogues are a class of compounds with interesting therapeutic activity. It is used clinically to treat a wide range of diseases and disorders, including viral infections and proliferative diseases. For example, International Publication Nos. 2017 / 032840 and 2017 / 15318 Pamphlet No. 6 and Pamphlet No. 2018 / 065365 are protein alginates. Inhibits PRMT5 activity and PRMT5-mediated disorders The present invention discloses nucleoside analogs useful for treating

[0011] To enable the preparation of nucleoside analogues with novel substituent patterns, intermediates and chemical synthesis.

[0012] Brand et al., JOC 2009, 74, 8779-8786 and Ram akrishna et al,RSC Adv.,2015,5,8142-8145 Nowak et al., JOC 200 describe the synthesis of spirocyclic compounds. 6,71,8876-8883 are difluorocarboxylates of 4',5'-unsaturated nucleosides Redlich et al., Angew. Chem. Int. t. Ed. Engl. 28 (1989) 777-778 is the synthesis of chiral cyclobutanones It describes: Summary of the Invention [Means for solving the problem]

[0013] Spiro bicyclic nucleosides have shown interesting activity against, for example, PRMT5. Novel intermediates that can be used to synthesize spiro-bicyclic nucleoside analogues have been identified. In particular, these intermediates include cyclopentane-containing nucleoside analogues. Diversified to provide access to a variety of spiro bicyclic nucleoside analogs, including Therefore, as used herein, for example, a functional group capable of inhibiting PRMT5 is included. Compounds useful as intermediates for the preparation of spiro bicyclic nucleoside analogs may have the formula Also disclosed herein are spiro bicyclic nucleoside analogs that offer interesting activity. Spirocyclic nucleosides that may serve as intermediates for further functionalization to provide Oside compounds are disclosed.

[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, -(CH 2) 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 Is it 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, -(CH 2) 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 N R 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 1~6Alkyl or -O-aryl If present, 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 bond Protective groups, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-O- C 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzoyl Jill, -C(=O)-C 1~4alkyl, or —C(═O)-phenyl; R 2 is -OH, ═O, -CH—OH, or ═CH; R 5 and R 6 are each Standing, -C(=O)-C 1~4 Alkyl, benzoyl, benzyl, or -CH2- naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are -CH3 and - OCH3 optionally substituted with one or two substituents each independently selected from or R together 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. or a salt or solvate thereof, provided that:

[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 solution thereof Concerning solubility.

[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 a hydrogen or hydroxyl protecting group; or teeth 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 With alkyl and the other is a silyl group, a C optionally substituted with a silyl group. 1~6 Alkyl, -O- C 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 a hydrogen or hydroxyl protecting group; or teeth 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 solvent thereof Related to Japanese things.

[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, -(CH 2) m C(O)R a , -(CH2) m B(OR b )2, -(CH2) m S(O) x Rc , Silyl group, silyl-substituted C 1~6 Alkyl, =O, or =CR a Is it 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, -(CH 2) 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 N R 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 cor =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 Alkyl or -O-aryl If present, 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 6are each independently a hydrogen or a hydroxyl protecting group; or together are Became 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; R 6 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 R7b , 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 or The present invention relates to a salt or solvate of

[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 a hydrogen or a hydroxyl protecting group; or together are Became R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or a nucleobase derivative], or a salt or solvate thereof Regarding.

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

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

[0022] When any variable occurs more than one time in any constituent or in any formula, its definition is Each is independent of its definition in any other case.

[0023] Whenever the term "substituted" is used in this invention, unless otherwise specified or Unless otherwise clear from the context, one of the atoms or groups designated in the expression using "substituted" or more hydrogen atoms, particularly 1 to 3 hydrogen atoms, preferably 1 to 2 hydrogen atoms, more preferably 1 hydrogen atom It indicates that the element is replaced with one selected from the group shown. , but do not exceed the normal valence and are chemically stable by substitution, i.e., from the reaction mixture The compound is sufficiently robust to amenable isolation to a useful degree of purity and formulation into a therapeutic drug. It shall be.

[0024] When more than one substituent is present on a moiety, unless otherwise stated or apparent from the context. Unless otherwise specified, these substituents replace hydrogen on the same atom or A hydrogen atom may be substituted for a different atom.

[0025] The prefix "Cx~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 Alkyl groups have 1 to 4 carbon atoms. Contains C atoms 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 used unless otherwise stated or clear from the context. Unless otherwise specified, fluoro, chloro, bromo, and iodo are used collectively.

[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, where n is a number ranging from 1 to 6. 1~6 Archi The alkyl group has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and more preferably 1 to 3 carbon atoms. C 1~6 Alkyl, C 1~4 Archi Lu, and C 1~3 Alkyl may be straight or branched chain and may be substituted as indicated herein. Where a subscript is used herein after a carbon atom, the subscript The letters refer to the number of carbon atoms that the group may contain.

[0028] C 1~6 Alkyl is any straight or branched chain alkyl group having 1 to 6 carbon atoms. and therefore 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, and the like.

[0029] Those skilled in the art will be able to identify suitable -OC 1~4 Non-limiting examples of alkyl include methyloxy (methoxy). oxy), ethyloxy (also called ethoxy), propyloxy, isopropyl butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy You will recognize that tyloxy is one example.

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

[0031] "C 3~6 The term "cycloalkyl" as used herein as a group or part of a group In the case of cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, It represents a cyclic saturated hydrocarbon group having 6 carbon atoms.

[0032] The term "aryl" as used herein as a group or part of a group refers to an alkyl group having 6 to 1 Monocyclic or bicyclic aromatic ring systems having 4 carbon atoms (i.e., C 6~14 aryl) Non-limiting exemplary aryl groups include phenyl, naphthyl, and phenanthryl groups. , anthracyl group, indenyl group, azulenyl group, biphenyl group, biphenylenyl group, and and fluorenyl groups. Aryl is preferably selected from phenyl and naphthyl. and more preferably selected from phenyl.

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

[0034] Some of the compounds of the present invention may also exist in tautomeric forms. The term "tautomeric forms" refers to compounds of different energetic types that are interconvertible via a low energy barrier. For example, proton tautomers (prototropic tautomers) are structural isomers of different energies. Interconversions via proton transfer, e.g., keto-enol and enolic Valence tautomers involve the isomerization of some of the bonding electrons. This includes interconversions through rearrangement of the

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

[0036] As used herein, the term "wedge bond" refers to a bond that is either solid or dashed. Any chemical formula with bonds shown only as solid lines, not solids, or with bonds around one or more atoms Any chemical compound otherwise shown as having a particular configuration (e.g., R, S) Each chemical formula contemplates each possible stereoisomer or a mixture of two or more stereoisomers. The stereochemistry of any particular chiral atom is specified in the structures shown herein. If not, all stereoisomers are available as pure stereoisomers or as mixtures of two or more stereoisomers. Mixtures of these compounds are contemplated and encompassed as compounds of the present invention.

[0037] The compounds described herein include their stereoisomers and tautomeric forms. However, as described in the previous paragraph, the stereochemistry can be represented as a solid wedge or dashed wedge bond. or otherwise shown as having a particular configuration (e.g., R, S). When a compound is specified by a bond between two or more atoms, the stereoisomer is so specified and defined. Furthermore, when a bond is shown as a wave bond, unless otherwise defined, this means that The stereochemical configuration at the stereocenter means a mixture of stereoisomers. It should be clear that this also applies to subgroups of expressions in

[0038] Thus, a compound may exist in both stereoisomeric and tautomeric forms, if possible. This means that it can exist in the form

[0039] The terms "stereoisomer," "stereoisomeric form," or "stereochemically isomeric form" refer to 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 isomers in which the rotation around a single bond is disrupted due to significant steric hindrance. A stereoisomer is a stereoisomer that has a specific spatial configuration resulting from restricted rotation. All atropisomeric forms of the compounds described above are intended to be included within the scope of the present invention. It has been done.

[0042] Diastereomers (or diastereoisomers) are stereoisomers that are not enantiomers If the compound contains a double bond, the substituents may be in the E or Z configuration. Substituents on a divalent cyclic (partially) saturated group may be in the cis or trans configuration. For example, if the compound contains a disubstituted cycloalkyl group, the substituent may have a cis Therefore, whenever chemically possible, the present invention provides Enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, It includes cis isomers, trans isomers, and mixtures thereof.

[0043] All of the terms, i.e., enantiomers, atropisomers, diastereomers, racemates The meanings of isomer, E isomer, Z isomer, cis isomer, trans isomer and mixtures thereof are as defined in the It is well known to the trade.

[0044] The absolute configuration is specified according to the Cahn-Ingold-Prelog rules. The configuration in the isoform is specified by either R or S. Resolved isoforms of unknown absolute configuration are Isomers are either (+) or (-) depending on the direction they rotate plane polarized light. For example, resolved enantiomers of unknown absolute configuration can be represented by (-). It can be designated by (+) or (-) depending on the direction it rotates 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 recognize that this is the case unless the context dictates otherwise. Spiro bicyclic nucleoside analogues (including cyclopentane-containing nucleoside analogues) It will be understood that this also applies generally to any other general formula. Unless otherwise indicated, all such forms are included in the general formula where only 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. This may also be considered as OR 4 but a nucleic acid base or nucleic acid base derivative This rule applies when:

[0051] When a particular stereoisomer is identified, this means that said stereoisomer substantially displaces other isomers. Free of other isomers, i.e., less than 50%, preferably less than 20%, more preferably less than 10% less than 5%, even more preferably less than 2%, most preferably less than 1% Therefore, if a compound is specified as, for example, (R), this means that this compound This means that the compound is substantially free of the (S) isomer, and if the compound is identified as, for example, E, When the compound is a Z-isomer, this means that the compound is substantially free of the Z-isomer, If a compound is specified as, for example, cis, this means that the compound substantially contains the trans isomer. Stereoisomers can be identified by techniques known in the art, e.g., chromosomes. Separation may also be achieved using lithographic methods. Functionalization, e.g., benzoates (BzCl, pyridinium phosphate, etc.), The introduction of suitable protecting groups such as dimethylformamide (dichloromethane, dichloromethane, etc.) can be achieved by silica gel chromatography. Chromatography, reversed-phase chromatography, or supercritical fluid (SFC) chromatography It may be useful to separate stereoisomers using

[0052] Salts of the compounds described herein and solvates thereof may be prepared by dissolving the compounds in a solvent or solvent mixture containing 1,000 or more amines, preferably 1,000 or more amines, in which the counter ion is pharmaceutically acceptable. Salts of acids and bases that are not pharmaceutically acceptable may also be used, for example, as pharmaceutically acceptable salts. All salts may find use in the preparation or purification of compounds of the present invention. Whether or not it is permitted is within the scope of the present invention.

[0053] Pharmaceutically acceptable salts include acid addition salts and base addition salts. can be prepared by conventional means, for example, by reacting any of the compounds with the appropriate acid or base in free acid or free base form. optionally in a solvent or in a medium in which the salt is insoluble, followed by standard procedures by (e.g., in vacuo, by freeze-drying, or by filtration) the solvent or medium Salts may also be formed by removing a counter ion of a compound of the invention in salt form, e.g. For example, it can be prepared by exchanging with a different counter ion using a suitable ion exchange resin.

[0054] The above or below pharmaceutically acceptable addition salts may give rise to compounds and solvates thereof. The term "therapeutic active agent" includes non-toxic acid and base addition salt forms which may be used in the treatment of atopic dermatitis, as well as in the treatment of rhodium.

[0055] Suitable acids include, for example, inorganic acids, for example, hydrohalic acids such as hydrochloric acid or hydrobromic acid. Acids such as sulfuric acid, nitric acid, phosphoric acid; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid Acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butane diacid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanol benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid Conversely, the salt forms of the above may be prepared by the addition of suitable salts. It can be converted to the free base form by treatment with base.

[0056] Compounds containing acidic protons and their solvates can be treated with appropriate organic and inorganic bases. It can also be converted into their non-toxic metal addition salt or amine addition salt forms by treating them with a can.

[0057] Suitable base salt forms include, for example, ammonium salts, alkali metal salts, and alkaline earth metal salts. metal salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, etc. salts with organic bases, such as primary, secondary and tertiary, aliphatic and aromatic amines; For example, methylamine, ethylamine, propylamine, isopropylamine, and four butylamines. Aminomethylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine amine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine Phosphorus, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine Benzathine salts, N-methyl-D-glucamine salts, hydroxybenzoates, quinolines and isoquinolines; These include lavamin salts, as well as salts with amino acids such as arginine and lysine. The salt form can be converted to the free acid form by treatment with acid.

[0058] The term solvates refers to the hydrate forms and solvent addition forms that the compounds of the present invention are able to form. Examples of such forms include hydrates and alcohol solvates. There are things etc.

[0059] The compounds of the present invention prepared by the methods described below may be mixtures of enantiomers, particularly those of the art. It is present in the form of a racemic mixture of enantiomers that can be separated from each other according to resolution methods known in the art. Methods for separating the enantiomeric forms of compounds, and their salts and solvates include: The pure stereochemical isomers are obtained by liquid chromatography using a chiral stationary phase. , may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that: The reaction must occur stereospecifically. Preferably, a particular stereoisomer is desired. In some cases, the compounds will be synthesized by stereospecific methods of preparation. Enantiomerically pure starting materials are advantageously used.

[0060] The present invention also provides atomic masses or mass numbers commonly found in nature (or the most commonly found in nature). One or more atoms are replaced by atoms having a different atomic mass or mass number than the one (most abundant) Isotopically labeled compounds of the invention that are identical to the compounds described herein except for the presence of a methyl group are also available. Contains.

[0061] All isotopes and isotopic mixtures of any particular atom or element identified herein Substances may be naturally occurring, synthetically produced, or naturally abundant. Conformationally enriched forms are also contemplated as being within the scope of the compounds of the present invention. Exemplary isotopes that can be incorporated include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, Isotopes of 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, 1 23 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br, and 82 Br is mentioned. Preferably, the radioisotope is 2 H, 3 H, 11 C, and 18 Selected from the group F More preferably, the radioisotope is 2 In particular, deuterated compounds are within the scope of the present invention. It is intended to be included within the scope of

[0062] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C) is a group Useful for tissue distribution assays. 3 H) and carbon-14 Position ( 14 C) are useful due to their ease of preparation and detectability. element (i.e., 2 Substitution with heavier isotopes such as H results in greater metabolic stability The specific therapeutic benefit provided (e.g., increased in vivo half-life or reduced dosage requirements) ) and may therefore be preferred. For example, 15 O. 13 N, 11 C, and 18 Positron-emitting isotopes such as F are suitable for positron emission to probe substrate receptor occupancy. It is useful for PET studies.

[0063] The protecting groups referred to herein can be any suitable hydroxyl protecting group. Protecting groups are described, for example, in Wuts, P.G.M. and Greene, T.W.: ... ective Groups in Organic Synthesis,Fourt h Edition, Wiley, New York, 2006, in the field of For example, hydroxyl protecting groups include silyl groups, C1~4 Alkyl, C 1~ 4 alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH 2-naphthyl or benzoyl, -C(=O)-C 1~4 Alkyl, or -C(=O )-phenyl; where benzyl, -CH2-naphthyl, and benzoyl is optionally one or two substituents each independently selected from -CH3 and -OCH3; are selectively replaced.

[0064] Silyl groups referred to herein include, for example, t-butyldimethylsilyl, t-butyldi phenylsilyl, triisopropylsilyl, trimethylsilyl, or triethylsilyl It's okay to have it.

[0065] Diol protecting groups include, for example, -C(C 1~4 alkyl)2 (e.g., -C(CH3)2) The stereochemistry of the compound may be -OR. 4 and-OR 5 is in the cis configuration In this case, R 4 and R 5 It will be understood by those skilled in the art that these can be taken together to form a diol protecting group. Similarly, the stereochemistry of the compound is -OR 5 and-OR 6 is in the cis configuration In this case, R 5 and R 6 It will be understood by those skilled in the art that the can be taken together to form a diol protecting group. It will be possible.

[0066] Boronic acid protecting groups include, for example, catecholborane, pinacolborane, N-methylimino Diacetic acid (MIDA) boronate, neopentyl glycol borane, pinanediol borane , biscyclohexyldiolborane, or 1-(4-methoxyphenyl)-2-methyl It may also be propane-1,2-diol (MPMP-diol) borane.

[0067] Amino protecting groups include, for example, benzoyl (Bz), tert-butyloxycarbonyl ( Boc), benzyl (Bn), acetyl (Ac), diphenylcarbamoyl, benzyl oxycarbonyl (cbz), fluorenylmethyloxycarbonyl (Fmoc), CF3 C(O)-, trityl (trt), phthaloyl (phth), or =CHN(CH3)2 may be.

[0068] The nucleobases or nucleobase derivatives referred to herein include modified and protected forms thereof. This includes both pyrimidine and purine nitrogenous bases, including modified forms. The nucleobases referred to in this document are adenine, cytosine, guanine, thymine, 6-chloropropane, Phosphorus, uracil, adenine, 7-methylguanine, xanthine, hypoxanthine, purine , 2,6-diaminopurine, 5,6-dihydrouracil, 6,8-diaminopurine These include, but are not limited to, 5-methylcytosine, 5-hydroxymethylcytosine, and 5-hydroxymethylcytosine. Modified or protected nucleobases include, for example, amino protecting groups (e.g., benzoyl tert-butyloxycarbonyl (Boc), benzyl (Bn), acetyl diphenylcarbamoyl, benzyloxycarbonyl (cbz), fluorene Fmoc, CF3C(O)-, trityl (trt), thallyl (phth), or =CHN(CH3)2) is present, or amino (- NH2) groups may be substituted with halo (e.g., chloro). Such modified or protected nucleobases may also be referred to as nucleobase precursors. The nucleobases or nucleobase derivatives referred to herein are any of the nucleobases referenced above. or any purine or pyrimidine nitrogenous base, wherein one or more of the The substituent R is present on the heteroaryl core of the nitrogen base in place of hydrogen or another substituent moiety. wherein R is, but is not limited to, halo, -NR * R ** , C 1~4 Alkyl, C2 ~4 Alkenyl, C 3~6 Cycloalkyl, -OH, -OC 1~4 Alkyl, 1, 2 C substituted with one or three halo atoms 1~4 alkyl, where R * is water Basic, C 1~4 Alkyl, or -C(O)OC 1~4 alkyl, and R ** is water Basic, C 3~6 Cycloalkyl, C 1~4 alkyl, or -C(O)OC 1~4 It is alkyl.

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

[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, -(CH 2) 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 Is it 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, -(CH 2) m S(O) x R c , silyl group, silyl-substituted C1~6 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 N R 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 Alkyl or -O-aryl If present, 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 bond Protective groups, e.g., C 1~4Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-O- C 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzoyl Jill, -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 Standing, -C(=O)-C 1~4 Alkyl, benzoyl, benzyl, or -CH2- naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are -CH3 and - OCH3 optionally substituted with one or two substituents each independently selected from or R together 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 wis 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. Not; (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 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 or The present invention relates to a salt or solvate of

[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)NR a 2, -(CH 2) mC(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 Is it 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, -(CH 2) 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 N R 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 Alkyl or -O-aryl If present, 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 bond Protective groups, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-O- C 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzoyl Jill, -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 Standing, -C(=O)-C 1~4 Alkyl, benzoyl, benzyl, or -CH2- naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are -CH3 and - OCH3 optionally substituted with one or two substituents each independently selected from or R together 5 and R 6 is -C(C 1~4alkyl)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. or a salt or solvate thereof, provided that:

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

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

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

[0075] In one embodiment, the present invention provides compounds of formula (A) and salts and solvates thereof, or compounds of formula (A) as defined herein. Any subgroup thereof as described in any other embodiment herein, wherein the compound is , 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 present invention provides compounds of formula (A) and salts and solvates thereof, or compounds of formula (A) as defined herein. Any subgroup thereof as described in any other embodiment herein, wherein the compound is , 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 present invention provides compounds of formula (A) and salts and solvates thereof, or compounds of formula (A) as defined herein. Any subgroup thereof as described in any other embodiment herein, wherein the compound is , 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 are represented by the 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) has the stereochemistry as shown for either compound.

[0079] In one embodiment, the present invention provides a method for producing a compound of formula (A-1a), (A-3a), (A-1b), or (A-1c). A-3b) and salts and solvates thereof, or any other embodiment herein. It also relates to any subgroup thereof described in any of the above.

[0080] In one embodiment, the present invention provides (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 of the other embodiments herein.

[0081] In one embodiment, the present invention provides a compound 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-2 b), (A-3b), (A-4b), (A-5b), or (A-6b) The compounds and salts and solvates thereof, or any of the other embodiments herein, For any subgroup thereof, Y is -O- or -CH2-; n is 0 or 1, If n is 1, R1 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, substituted with silyl group Replaced 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, -(CH 2) 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 N R 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 Alkyl or -O-aryl If present, 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, 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. This is subject to the condition that there is no

[0082] In one embodiment, the present invention provides a compound 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-2 b), (A-3b), (A-4b), (A-5b), or (A-6b) The compounds and salts and solvates thereof, or any of the other embodiments herein, For any subgroup thereof, 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, -(CH 2) 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 Is it 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, -(CH 2) m S(O) x R c , silyl group, silyl-substituted C1~6 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 N R a 2, -OR a , -OPG, -(CH2)C(O)OR a , -(CH2) m C(O)N R 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 Alkyl or -O-aryl If present, 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, while however, (a) a compound of the formula [ka] wherein Y is —O— or —CH—; 4 is a hydrogen or hydroxyl bond Protective groups, e.g., C 1~4 Alkyl, t-butyldimethylsilyl, C 1~4 Alkyl-O- C 1~4 Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, benzoyl Jill, -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 Standing, -C(=O)-C 1~4 Alkyl, benzoyl, benzyl, or -CH2- naphthyl (wherein benzyl, -CH2-naphthyl, and benzoyl are -CH3 and - OCH3 optionally substituted with one or two substituents each independently selected from or R together 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] do.

[0083] In one embodiment, the present invention provides a compound 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-2 b), (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) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, substituted with silyl group Replaced 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, -(CH 2) 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 N R a 2, -OR a , -OPG, -(CH2)C(O)OR a , -(CH2) m C(O)N R 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 Alkyl or -O-aryl If present, 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 C1~6 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 provides a compound represented by formula (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-7), (A-8), (A-9), (A-10), (A-11), (A-12), (A-13), (A-14), (A-15), (A-16), (A-17), (A-18), (A-19), ( 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 compound of any one of (A-3b), (A-4b), (A-5b), or (A-6b) and salts and solvates thereof, or any of the compounds thereof as described in any of the other embodiments herein. Relates to any subgroup.

[0085] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, n is 1.

[0086] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, n is 1; R 1 is hydrogen and R 2 teeth, -(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 in 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)N R a 2, -(CH2) m C(O)R a , -(CH2) m S(O) x R c , silyl group, silyl C substituted with a hydroxyl group 1~6 Alkyl, -O-aryl, ═O, or ═CR a It is 2 .

[0087] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 is hydrogen and R 2 teeth, -(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 1~6 Alkyl, =O, or =CR a 2; or R 2 is hydrogen and R 1 teeth , -(CH2) m NR a 2, -(CH2) mOR a , -(CH2) m OPG, -C(O) OR a , -C(O)NR a 2. -C(O)R a , -(CH2) m S(O) x R c , Cyril C substituted with a group or silyl group 1~6 Alkyl, -O-aryl, ═O, or ═CR a It is 2.

[0088] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where 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)N R a 2. -C(O)R a , =O, or =CR a 2;R 2 is hydrogen.

[0089] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 -NH2, -CH2 NH2, -OH, -CH2OH, =O, or =; R 2 is hydrogen.

[0090] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 -OH, -CHO H, ═O, or ═; R 2 is hydrogen.

[0091] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 is hydrogen; R 2 teeth, -(CH2) m NR a 2, -(CH2) m OR a , -C(O)OR a , -C(O)NR a 2. -C(O)R a , =O, or =CR a It is 2.

[0092] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 2 -NH2, -CH2 NH2, -OH, -CH2OH, =O, or =; R 1 is hydrogen.

[0093] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R2 -OH, -CHO H, ═O, or ═; R 1 is hydrogen.

[0094] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 is hydrogen; R 2 teeth, -(CH2) m NR a 2 or -C(O)NR a It is 2.

[0095] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 2 is -NH2 or -CH 2NH2;R 1 is hydrogen.

[0096] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 and R 2 One of the hydrogen, and the other is -NR a 2, -CH2NR a 2, -OR a , -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 provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 and R 2 One of the hydrogen, and the other is -NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C (O)OR a , =O, or =CRa It is 2.

[0098] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 is -NR a 2, -CH 2NR a 2, -OR a , -CH2OR a , -C(O)OR a , -C(O)R a , -B(O R b )2, S(O) x R c , =O, or =CR a 2;R 2 is hydrogen.

[0099] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 1 and R 1 is hydrogen; R 2 teeth, -NR a2, -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 provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, n is 0.

[0101] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the 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 provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the 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(OR b )2.

[0103] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the 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 provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the 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 provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the hydrogen, and the other is —OH, —CHOH, —CHNH, —C(O)OH, or C (O)OEt.

[0106] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed therein, where n is 0 and R 1 and R 2 One of the The other is —OH or —CH 2 NH 2 .

[0107] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed above, where, if present, -(CH) m NR a 2 is, -(CH2) m NHC 1~6 Alkyl or -(CH2) m It is NH2.

[0108] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed in the formula, R 1 or R 2 Ga-(CH2) m OPG In this case, PG is a silyl group, -C(=O)-C 1~4 Alkyl, or -C(=O)-phenyl It is.

[0109] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed in the formula, R a is H, methyl, ethyl, or propyl is.

[0110] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed in the formula (I), where, if present, -NR a 2 is -NHR a Yes do.

[0111] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed in the formula (I), where, 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 1~6 Alkyl, -C(O)-C 1~6 Alkyl, -SR c , and =CH It is 2.

[0112] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed, Y is O.

[0113] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed, Y is CH2.

[0114] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup listed in the formula, R 4 , R 5 , and R 6 are each independently is a hydroxyl protecting group, or R 5 and R 6 is in the cis configuration, R 5 and R 6 teeth, Optionally, together they may form a diol protecting group, or R 4 and R 5 System distribution If it is in the order of R 4 and R 5 can optionally be taken together to form a diol protecting group. do.

[0115] In one embodiment, the present invention provides a compound represented by 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) Any of the compounds and salts and solvates thereof, or any of the other embodiments described herein. For any subgroup thereof listed above, wherein the hydroxyl protecting group is a silyl group, C 1~4 Alkyl, C 1~4 Alkyl-OC 1~4 Alkyl, tetrahydropyranyl, allyl, Benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1~4 Alkyl, young is selected from -C(=O)-phenyl; where benzyl, -CH2-naphthyl, and Benzoyl is one or two independently selected from -CH3 and -OCH3. and / or the diol protecting group is -C(C 1~4 a Rukill)2-.

[0116] In one embodiment, the present invention provides a compound represented by formula (I), (A), (Aa), (Ab), (A-1) , (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) Any of the compounds and salts and solvates thereof, for example, compounds of the formula (A-1), (A-1a), (A (A-1b), (A-2), (A-2a), or (A-2b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 4 is hydrogen or a silyl group, C 1~4 Alkyl, C 1~4 a Rukill-OC 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -C(=O )-C 1~4 alkyl or hydroxyl protecting groups such as -C(=O)-phenyl wherein benzyl is one or two independently selected from -CH3 and -OCH3; optionally substituted with substituents; R 5 and R 6 is -C(=O)-C 1~ 4) Hydroxyl groups such as alkyl, benzoyl, benzyl, or -CH2-naphthyl Protecting groups (where benzoyl, benzyl, and -CH2-naphthyl are -CH3 and -OC H3) optionally substituted with one or two substituents each independently selected from or together with R 5 and R 6 is -C(C 1~4 alkyl)2- and other di- It is a diamine protecting group.

[0117] In one embodiment, the present invention provides a compound represented by formula (I), (A), (Aa), (Ab), (A-1) , (A-1a), (A-1b), (A-2), (A-2a), or (A-2b) Any of the compounds and salts and solvates thereof, for example, compounds of the formula (A-1), (A-1a), (A (A-1b), (A-2), (A-2a), or (A-2b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 4 is a silyl group or C 1~4 Alkyl (preferably Me) and;R 5 and R 6 is -C(=O)-C 1~4 Alkyl (preferably pivaloyl) or R together 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 provides a compound represented by 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, the formulas (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A (A-3b), (A-5), (A-5a), or (A-5b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 4 and R 5 is a silyl group, C 1~4 Alkyl, -C(=O )-C 1~4 Hydrogen such as alkyl, benzoyl, benzyl, or -CH2-naphthyl -naphthyl protecting groups (where benzoyl, benzyl, and -CH2-naphthyl are -CH3 and -OCH3, optionally substituted with one or two substituents each independently selected from or R together 4 and R 5 is -C(C 1~4 alkyl)2- and diol protecting groups such as R 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 -C(=O)-phenyl, etc. Hydroxyl protecting groups (wherein benzyl is independently selected from -CH3 and -OCH3) and optionally substituted with one or two substituents selected from the group consisting of:

[0119] In one embodiment, the present invention provides a compound represented by 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, a compound of formula (A-3), (A-3a), or (A-3b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 4 and R 5 is -C(=O)-C 1~4 Alkyl, benzo hydroxyl protecting groups such as -CH2-naphthyl, -CH2-naphthyl, and -CH2-naphthyl; (where benzoyl, benzyl, and -CH2-naphthyl are -CH3 and -OCH3 and optionally substituted with one or two substituents each independently selected from or together with R 4 and R 5 is -C(C 1~4 Diols such as alkyl2- is a protecting group; R 6 is hydrogen or a silyl group, C 1~4 Alkyl, C 1~4 Alkyl-O- C 1~4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, - C(=O)-C 1~4 Alkyl or hydroxyl groups such as -C(=O)-phenyl a protecting group (wherein benzyl is one or more independently selected from -CH3 and -OCH3) is optionally substituted with two substituents).

[0120] In one embodiment, the present invention provides a compound represented by formula (I), (A), (Aa), (Ab), (A-3) , (A-3a) and (A-3b) and salts and solvates thereof, for example, A compound of any one of formula (A-3), (A-3a), or (A-3b) or a salt thereof or solvates thereof, or any of the other embodiments described herein. Regarding the subgroups, in the formula, the combined R 4 and R 5 is the diol protecting group -C(C 1~4 Al -C(CH3)2- (preferably -C(CH3)2-); R 6is a silyl group, benzyl, - CH2-naphthyl or -C(=O)-C 1~4 alkyl, where benzyl is Optionally, one or two substituents each independently selected from —CH3 and —OCH3 has been replaced by

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

[0122] In one embodiment, the present invention provides a compound represented by formula (I), (A), (Aa), (Ab), (A-1) , (A-1a), or (A-1b), and salts and solvates thereof; For example, a compound of formula (A-1), (A-1a), or (A-1b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 4 is C such as methyl 1~4 Alkyl and together TA R 5 and R 6 is -C(CH3)2-, etc. 1~4 alkyl)2-.

[0123] In one embodiment, the present invention provides a compound represented by formula (I), (A), (Aa), (Ab), (A-3) , (A-3a), or (A-3b), and salts and solvates thereof; For example, a compound of formula (A-3), (A-3a), or (A-3b) or a salt or solvate thereof, or any of the other embodiments thereof as described herein. For any subgroup of 6 is a silyl group, benzyl, -CH2-naphthyl, benzo Ile, or -C(=O)-C 1~4 alkyl, where benzyl, -CH2-naphthyl methyl and benzoyl are each independently one or more selected from -CH3 and -OCH3; optionally substituted with two substituents, and together R 5 and R 6 is -C(CH 3) 2- and other -C(C 1~4 alkyl)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 thereof, or Regarding solvates.

[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 6 are the formulas (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. as defined in

[0127] In one embodiment, the present invention relates to compounds of formula (B) and salts and solvates thereof, wherein The compounds are represented by the 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) has the stereochemistry as shown for either compound.

[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 a hydrogen or hydroxyl protecting group; or teeth 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 are the formulas (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. as defined in

[0131] In one embodiment, the present invention relates to compounds of formula (B) and salts and solvates thereof, wherein The compounds are represented by the 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) has the stereochemistry as shown for either compound.

[0132] In one embodiment, the present invention provides compounds of formula (C) and salts and solvates thereof, or compounds of formula (C) as described herein. Any subgroup thereof as described in any other embodiment 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 And 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 Reel 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 With alkyl and the other is a silyl group, a C optionally substituted with a silyl group. 1~6Alkyl, -O- C 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 a hydrogen or hydroxyl protecting group; or teeth 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 solvent thereof Related to Japanese things.

[0135] In one embodiment, the present invention provides a compound of formula (D), and salts and solvates thereof, or With respect to any subgroup thereof 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 The other is a silyl group, a C substituted with a silyl group, 1~6 Alkyl, -OC 1~6 Archi Le, -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 With alkyl The other is a silyl group, a C substituted with a silyl group 1~6 Alkyl, -OC 1~6 Al Kill 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 a hydrogen or hydroxyl protecting group; or teeth 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 provides compounds of formula (D) and salts and solvates thereof, or For any subgroup thereof as described in any other embodiment of the document, wherein R 3 is OR 4 is.

[0137] In one embodiment, the present invention provides compounds of formula (D) and salts and solvates thereof, or Any subgroup thereof as described in any other embodiment of the present disclosure, wherein In this case, the silyl group is trimethylsilyl, triethylsilyl, tert-butyldiphenyl silyl, triisopropylsilyl, or dimethylphenylsilyl.

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

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

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

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

[0142] In one embodiment, the present invention provides compounds of formula (D) and salts and solvates thereof, or For any subgroup thereof as described in any other embodiment of the document, 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 provides compounds of formula (D) and salts and solvates thereof, or For any subgroup thereof as described in any other embodiment of the document, wherein R 1’ and R 2’ is hydrogen, and R 1’ and R 2’ The other of these is C 1~6 Archi It is not hydrogen 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 are the formulas (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. as defined in

[0145] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, wherein The compounds are represented by the 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) has the stereochemistry as shown for either compound.

[0146] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, wherein And 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, -(CH 2) 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 Is it 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, -(CH 2) 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 N R 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 1~6Alkyl or -O-aryl If present, 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 death; 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 a hydrogen or a hydroxyl protecting group; or together are Became 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] 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 provides compounds of formula (E) and salts and solvates thereof, or compounds of formula (E) as defined herein. For 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, -(CH 2) 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 Is it 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, -(CH 2) 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 N R 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 Alkyl or -O-aryl If present, 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 a hydrogen or a hydroxyl protecting group; or together are Became 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 provides compounds of formula (E) and salts and solvates thereof, or compounds of formula (E) as defined herein. and n is 1. do.

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

[0151] In one embodiment, the present invention provides compounds of formula (E) and salts and solvates thereof, or compounds of formula (E) as defined herein. and n is 0. For any subgroup described in any other embodiment herein, wherein Y is O. do.

[0152] and salts and solvates thereof, or as described in any of the other embodiments herein. Any subset thereof, 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 are the formulas (A), (Aa), (Ab), (A-1), (A-2), (A -3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3 a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A any of the compounds (A-3b), (A-4b), (A-5b), or (A-6b), or is defined for any subgroup thereof as described in any of the other embodiments herein. That is exactly right.

[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 6are the formulas (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. as defined in

[0155] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein The compounds are represented by the 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) As shown for either compound (A-6b), for example, the compound may have the following structure: having the stereochemistry shown in either of the structures; [ka]

[0156] In one embodiment, the present invention provides compounds of formula (E) and salts and solvates thereof, or compounds of formula (E) as defined herein. For any subgroup thereof as described in any other embodiment of the present disclosure, -NR a 2, -CH2NR a 2, -OR a , -CH2OR a , -C(O)OR a ,- C(O)R a , -S(O) x R c , =CR a2 is -NH2, -CH2NH2 respectively , -OH, -CH2OH, -C(O)OC 1~6 Alkyl, -C(O)-C 1~6 Al Kill, -SR c , =CH2.

[0157] 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 a compound of the present invention Y, n as defined for any subgroup thereof as set forth in any of the other embodiments of the present document. , R 1 , R 2 , R 5 , and R 6 All definitions of the formula (E) and salts and solvents thereof It will be understood that the present invention is applicable to hydrates of hydroxybenzoates. With respect to compounds of formula (E) and salts and solvates thereof, 1 , R 2 , R 5 , and R 6 Any one or more of the formulas (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) Any compound, or any subcomponent thereof, as described in any of the other embodiments herein. As defined for the group.

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

[0159] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein And 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 And 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 And 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 a hydrogen or a hydroxyl protecting group; or together are Became R 5 and R 6 is a diol protecting group; R 10 is a nucleobase or a nucleobase derivative], or a salt or solvate thereof Regarding.

[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 6 are the formulas (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. As defined.

[0164] In one embodiment, the present invention relates to compounds of formula (F) and salts and solvates thereof, wherein The compounds are represented by the 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) has the stereochemistry as shown for either compound.

[0165] In one embodiment, the present invention provides a compound 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-2 b), (A-3b), (A-4b), (A-5b), (A-6b), (B), (C), ( Any of the compounds of (D), (E), and (F) and salts and solvates thereof or the compounds of the present invention Any subgroup thereof as described in any other embodiment, wherein, if present, The silyl group is t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, It is preferably pyrsilyl, trimethylsilyl, or triethylsilyl.

[0166] In one embodiment, the present invention provides a compound 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-2 b), (A-3b), (A-4b), (A-5b), (A-6b), (B), (C), ( Any of the compounds of (D), (E), and (F) and salts and solvates thereof or the compounds of the present invention With respect to any subgroup thereof described in any other embodiment, wherein, when present: -B(OR b )2 is a catecholborane, pinacolborane, N-methyliminodiacetic acid ( MIDA) boronate, neopentyl glycol borane, pinanediol borane, bis(trimethylsilyl)borane Cyclohexyldiolborane, 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): , where, if present, R 10 is cytosine, thymine, uracil, or modified versions thereof. A protected or unprotected form, 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 -O- C 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)O-C1 ~4 is alkyl; R4a , 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;Q 7 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;Q6 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 6 j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b , or 1 , C substituted with 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): , where, if present, R 10 is cytosine, thymine, uracil, or modified versions thereof. A protected or unprotected form, 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 -O- C 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 4 is N or CR 6d Although it represents; However, Q 3 and Q 4 Provided that the largest of denotes N; Q8 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 , R 6i , and R 6 j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R9b , or 1 , C substituted with 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): , where, if present, R 10 is cytosine, thymine, uracil, or modified versions thereof. A protected or unprotected form, 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 -O- C 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 6 j are each independently hydrogen, halogen, or C 1~4 Alkyl, -NR 9a R 9b , or 1 , C substituted with 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): , where, if present, R 10 is cytosine, thymine, uracil, or modified versions thereof. In a protected or protected form, 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 , C1~4 alkyl, or -OC 1~4 represents alkyl; R 7a 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, hmm, C 1~4 Alkyl, -NR 9a R 9b or substituted with 1, 2, or 3 halo atoms C 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): , where, if present, R 10 is a bicyclic aromatic heterocyclic ring system (a-1) [wherein R 3a teeth , -NH2 or chloro].

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

[0173] Pharmacology Spiro bicyclic nucleosides have shown interesting activity against, for example, PRMT5. Novel intermediates that can be used to synthesize spiro-bicyclic nucleoside analogues have been identified. In particular, these intermediates include various spiro-bicyclic nucleoside analogues. It contains functional groups that can be varied to provide access to the body. For example, the preparation of spiro bicyclic nucleoside analogs that may have activity against PRMT5 has been investigated. Also disclosed herein are compounds useful as intermediates for the preparation of P Interest in spiro-bicyclic nucleoside analogs with potential RMT5 inhibitory activity Spin-binding proteins that may serve as intermediates for further functionalization to provide deep activity Bicyclic nucleoside analogs are disclosed.

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

[0175] In particular, such compounds bind to the PRMT5 enzyme and inhibit the natural substrate SAM (S-adenosyltransferase). It can inhibit such enzymes by competing with thiamin-L-methionine.

[0176] Such compounds or pharmaceutical compositions thereof can be used to treat blood disorders, metabolic disorders, autoimmune diseases, cancer, inflammation, and the like. Inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility The present invention is useful in the treatment or prevention of diseases such as pulmonary embolism, pulmonary graft rejection, pulmonary graft rejection, and lung injury, particularly in the treatment of such diseases. could be.

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

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

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

[0180] In some embodiments, inhibition of PRMT5 is directed against the following non-limiting list of cancers: breast cancer, lung cancer Cancer, esophageal cancer, bladder cancer, hematopoietic organ cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, stomach cancer, pancreatic cancer , liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumor, hepatocellular carcinoma, renal cell carcinoma, melatonin for the treatment or prevention, especially for the treatment of ovarian clear cell carcinoma, oligodendroglioma, ovarian clear cell carcinoma and ovarian serous cystadenoma It can be useful.

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

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

[0183] Examples of cancers that may be treated or prevented, particularly those that may be treated, include acoustic neuroma, adenocarcinoma, adrenal carcinoma, Anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangiosarcoma, and angiosarcoma), appendix cancer, Monoclonal gammopathy, biliary tract cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., , breast cancer, papillary carcinoma, breast cancer, medullary breast carcinoma), brain tumors (e.g., meningiomas; gliomas, e.g., , astrocytoma, oligodendroglioma; medulloblastoma), bronchial cancer, carcinoid tumor, cervical cancer (e.g. , cervical adenocarcinoma), chordoma, choriocarcinoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcomas) tumor), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's disease adenocarcinoma), Ewing's sarcoma, eye cancer (e.g., intraocular melanoma, retinoblastoma), familial hypereosinophilia hyperplasia, 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., (e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), hematopoietic organ cancer (e.g., acute lymphocytic cancer) 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 CL leukemias such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell lymphoma (e.g., diffuse large cell lymphoma (DLH)) and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLH)) CL) (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's lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macrophage") globulinemia), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B Lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and precursor T lymphoblasts Cytic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma) (CTCL), etc. (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma tumor, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous fat pancreatitis-like T lymphomas such as T-cell NHL (e.g., anaplastic large cell lymphoma, anaplastic large cell lymphoma); one or more of the above mixed leukemia / lymphoma; 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 liver cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchial carcinoma, non-small cell lung cancer) Cellular lung cancer (NSCLC), squamous cell lung cancer (SLC), lung adenocarcinoma, Lewis lung cancer, pulmonary neuroendocrine Tumors: typical carcinoid, atypical carcinoid, small cell lung cancer (SCLC), and large cell lung cancer endocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndromes Myeloproliferative disorders (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., polycythemia vera) (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM) (also known as myelofibrosis) Myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilic leukemia Neoplastic lymphoma (CNL), hypereosinophilic syndrome (HES), neuroblastoma, neurofibroma (e.g., Neurofibromatosis (NF) type 1 or 2, schwannoma), neuroendocrine carcinoma (e.g., gastroenteropancreatic Transendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cysts adenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous pancreatic islet cell tumors (IPMN), penile cancer (e.g., Paget's disease of the penis and scrotum) ), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), Bowel cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthocytoma ( KA), melanoma, basal cell carcinoma (BCC), small intestine cancer (e.g., appendiceal cancer), soft tissue sarcoma (e.g., For example, malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), carcinoma osteosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovial tumors, testicular cancer (e.g., seminoma) , testicular embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid gland, papillary thyroid carcinoma (PTC), thyroid medullary carcinoma), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva) However, the present invention is not limited to these.

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

[0185] Examples of cardiovascular diseases that may be treated or prevented, particularly those that may be treated, include cardiac These include, but are not limited to, pancreatic enlargement, restenosis, atherosclerosis, and glomerulonephritis. Not determined.

[0186] Examples of inflammatory diseases that may be treated or prevented, particularly inflammatory diseases that may be treated, include acne. Associated inflammation, 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 disease, ankylosing spondylitis, amylosis, muscle atrophy Lateral sclerosis, autoimmune diseases, allergies and allergic reactions, atherosclerosis , bronchitis, bursitis, 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), Rash, hypersensitivity reactions, burns, dermatitis, pruritus (itching), endometriosis, Guillain-Barré syndrome , infections, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraines) , tension headache), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic hemorrhage Thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., peptic ulcer) , regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal diseases (e.g., eosinophilic esophagitis, eosinophilic gastrointestinal disorders) eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GOR) D or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, Enteritis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's colitis Inflammatory Bowel Syndrome (IBS), lupus, Localized scleroderma, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris Acne, pernicious anemia, peptic ulcer, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain diseases (e.g. For example, Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, cranial radiation injury injury-related chronic inflammation, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic erythematosus tematodes, scleroderma, scleroderma , sarcoidosis, spondyloarthropathy, Sjögren's syndrome, thyroiditis, transplant rejection, tendonitis , trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injuries), blood These include, but are not limited to, vitiligo, vitiligo, and Wegener's granulomatosis.

[0187] In particular, the inflammatory disease is an acute inflammatory disease (e.g., inflammation resulting from, for example, an infection). In particular, inflammatory diseases include chronic inflammatory diseases (e.g., 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 erythema) Degenerative joint diseases such as rheumatoid arthritis, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, and basilar arthritis Chet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute shoulder pain, psoriasis and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchial inflammation, tendonitis, bursitis, skin conditions (e.g., psoriasis, eczema, hypersensitivity eczema, burns, dermatitis, pruritus (itching), enuresis, eosinophilic disorders, gastrointestinal disorders (e.g., peptic ulcer, localized enteritis) , diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis ...trointestinal disorders, eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastrointestinal disorders, eosinophilic Acidophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GO RD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, Colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Beche colitis inflammatory bowel syndrome (IBS) and gastroprokinetic drugs Disorders that improve with administration of steroids (e.g., ileus, postoperative ileus, and ileus during sepsis; gastroesophageal reflux) esophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, e.g., diabetic gastroparesis gastrointestinal disorders such as food intolerance and food allergies as well as non-ulcer dyspepsia (NUD) and Other functional bowel disorders, such as noncardiac chest pain (NCCP, including costochondritis), Not limited to these.

[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 used alone or in combination. It may be administered in combination with the above additional therapeutic agents.

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

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

[0193] Preparation method In this section, as in all other sections, unless the context indicates otherwise: 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 invention is described below and in specific examples. The compounds are generally commercially available or are commonly used by those skilled in the art. They can be prepared by standard synthetic processes as described in the specific examples. The following schemes are intended to illustrate examples of the present invention. It is merely an indication and is not intended to limit the invention in any way.

[0195] Alternatively, the compounds of the present invention may also be synthesized using methods commonly used by those skilled in the art of organic chemistry. Reaction processes similar to those described in the general scheme below, combined with standard synthetic methods, are also possible. It can be prepared by tocolysis.

[0196] All variables are used unless otherwise indicated or clear from the context. and is defined as set forth herein above.

[0197] Those skilled in the art will appreciate that reactive functional groups, e.g., hydroxy, a If amino or carboxy groups are desired in the final product, their unwanted participation in the reaction can be avoided. It will be appreciated that it may be necessary to protect them to avoid this. Conventional protecting groups can be used according to the art, as illustrated in the specific examples. .

[0198] In the reaction shown in the scheme, when NaH is used in the reaction, for example, N2 It may be desirable or necessary to carry out the reaction under an inert atmosphere, such as a gas atmosphere. Those skilled in the art will understand that.

[0199] Post-reaction treatment (e.g., quenching, column chromatography, extraction, etc.) The need to cool the reaction mixture before It will be clear to one skilled in the art that this is possible.

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

[0201] Alternative sequences of chemical reactions shown in the following schemes may also provide desired compounds of the invention. Those skilled in the art will understand that this may be possible.

[0202] The intermediates and compounds shown in the scheme below can be further functionalized according to methods well known to those skilled in the art. Those skilled in the art will understand that, for example, in the formula R 3a or nucleic acid base or nucleus Compounds in which any other substituent on the acid-base derivative represents Cl exhibit a hydroxyl group at a typical temperature of about 100°C. In typical solvents such as dioxane, the reaction with NH3 (e.g., 25% in water) By the reaction, in the formula, R 3a (or any other Cl substituent) represents NH2 It is possible.

[0203] Many more compounds of the present invention can be synthesized using similar synthetic protocols as described in the following schemes: Those skilled in the art will understand that the compound can be prepared using

[0204] If one of the starting materials is available in salt form, the salt may first be converted into a salt, e.g., N,N- Treatment with a base such as diisopropylethylamine (DIPEA) may be necessary. , as one skilled in the art will understand.

[0205] All variables are used unless otherwise indicated or clear from the context. and is defined as set forth herein above.

[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 Reach BiR 6 is a diol protecting group; or together R 4 and R 5 is a diol protecting group Those skilled in the art will appreciate that protecting groups may be utilized in the following schemes as needed, and that any protecting groups may be utilized. It will be appreciated that the protecting group may then be removed to provide a deprotected compound. For example, when the compounds referred to in the following schemes contain a nucleobase or a nucleobase derivative, The nucleobases may be utilized in a protected form, e.g., the NH2 or OH on the nucleobase may be protected by Each can be protected with an amino or hydroxyl protecting group, or the NH2 nucleus on the nucleobase The acid salt groups may be substituted with halo (eg, 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 TA R 5 and R 6 forms a diol protecting group.

[0209] In General Scheme 1, the following reaction conditions typically apply: 1: (I) is (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (T In the presence of EMPO), in a suitable solvent mixture, for example acetonitrile and water, Phenyliodine(III) diacetate in a suitable temperature range, such as room temperature to 50°C. Reacts with oxidizing agents such as (PIDA); 2: (I) can be prepared by the reaction of (I) with a suitable solvent, such as THF, at a suitable temperature range, such as room temperature. Reacts with PPh3, iodine, and bases such as imidazole in the range 3: (III) can be prepared by subjecting (III) to a suitable reaction in a suitable solvent such as THF at a temperature of, for example, 60°C to 90°C. It reacts with bases such as DBU in the appropriate temperature range.

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

[0211] In General Scheme 2, the following reaction conditions typically apply: 1: (V) is (2,2,6,6-tetramethyl-piperidin-1-yl)oxyl (T in the presence of EMPO) in a suitable solvent mixture, e.g., acetonitrile and water, at room temperature, e.g. At a suitable temperature range, such as ~50°C, phenyliodine(III) diacetate (P Reacts with oxidizing agents such as IDA; 2: (V) can be prepared by the reaction of (V) with a suitable solvent, such as THF, at a suitable temperature range, such as room temperature. reacts with PPh3, iodine, and bases such as imidazole; 3: (VII) can be reacted in a suitable solvent such as THF at a temperature of, for example, 60°C to 90°C. It reacts with bases such as DBU in the appropriate temperature range.

[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, -O -C 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 It is alkyl. If a protecting group was initially present, after the deprotection step, R 1’ and R 2’ is protected You will understand that this is not the case.

[0213] General Scheme 3 shows the synthesis of nucleoside analogs (i.e., OR 4 R 10 is replaced by It will be understood that this may also be performed in other cases.

[0214] In general scheme 3, the following reaction conditions typically apply: 1: (IX) can be prepared by reacting (IX) with (IX) in a suitable solvent such as DCM, optionally in the presence of a catalytic amount of DMF. Reacts with oxalyl chloride in a suitable temperature range, e.g., 0°C to room temperature; in a suitable solvent such as tolyl or toluene at a suitable temperature range, e.g., 80°C to 130°C In the method, an acid chloride intermediate is reacted with a base such as triethylamine and an alkene (RHC=C HR 2’ Instead of activation with an acid chloride, a suitable solvent such as acetonitrile is used. (IX) is reacted with 2-chloro- Alternative methods such as reaction with 2-methylpyridinium iodide can be used. This reaction is carried out in the presence of a base such as diisopropylethylamine and an alkene (R 1’ HC=CH R 2’ ) can be carried out in the presence of; 2: When R1' or R2' is a silyl group: (X) is a protic solvent such as HOAc and In the presence of an aprotic solvent such as THF, at a suitable temperature range, for example, 0°C to 60°C, and reacting with a fluoride source such as TBAF; an alternative procedure is to use a suitable solvent such as DCM. In a temperature range of 0°C to 50°C, for example, at room temperature, (X) is added to trimethylsilyl triflate If R1' or R2' is PhS, the rate is (TMS-OTf). : In the presence of a reducing agent such as Raney nickel, optionally in the presence of hydrogen, ethanol or T Deprotection may be carried out in a solvent such as HF at a temperature range of 60°C to 120°C. 3: (XI) can be prepared by subjecting (XI) to a suitable reaction in a suitable solvent, such as methanol, at a temperature of, for example, -78°C to 0°C. At temperatures below this temperature, it reacts with reducing agents such as sodium borohydride.

[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 group. 1~6 Alkyl, -O -C 1~6 Alkyl, or C(O)R a and R a is hydrogen or C 1~6 Alkyl Those skilled in the art will appreciate that if a protecting group was initially present, after the deprotection step, R1’ 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 is replaced by It will be understood that this may also be performed in other cases.

[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 is, each each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or R 4 and R 5 is a diol protecting group.

[0219] In general scheme 5a, the following reaction conditions typically apply: 1: (XVI) can be prepared 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, for example, room temperature to 50°C, In the temperature range, it reacts with a zinc source such as zinc dust or a zinc-copper couple. II) may either be isolated or converted via step 2 in the same pot. 2: (XVII) can be reacted with an aprotic solvent such as THF in the presence of a protic solvent such as HOAc. It reacts with zinc powder in the presence of an organic solvent at a suitable temperature range, for example, from room temperature to 70°C. ru; 3: (XVIII) can be prepared by subjecting (XVIII) to a reaction in a suitable solvent, such as methanol, at a temperature of, for example, -78°C to 0°C. The protecting group reacts with a reducing agent such as sodium borohydride at a suitable temperature. Depending on the above, either (XIXa) or (XIXb) or a mixture thereof can be obtained. There is a possibility that this may occur.

[0220] General Scheme 5b: Preparation of 1,2-cyclobutanol and 1,2-cyclobutanone intermediates Made [ka] In general scheme 5b, the following reaction conditions typically apply: 1: (XVII) can be prepared by the reaction of (XVII) with a suitable solvent such as THF at a suitable temperature, for example, between 0° C. and room temperature. At this temperature, the resulting intermediate is reacted with a reducing agent such as sodium borohydride. , 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, for example 0° C. The resulting intermediate is reacted with zinc powder in the presence of a protic solvent such as HOAc in methanol and at a suitable temperature, for example 60°C. 2: (LXI) is reacted with an oxidizing agent such as m-CPBA to form a methyl methyl ketone. The treatment is carried out in a suitable solvent at a suitable temperature range, for example, from room temperature to 40°C. 3: (LXII) can be prepared by subjecting it to room temperature to room temperature in an alcohol solvent such as isopropyl alcohol. At a suitable temperature range, such as 60° C., sodium cyanoborohydride or sodium cyanoborohydride may be used. It reacts with reducing agents such as lithium boron. 4: (LXIII) can be reacted with, for example, Dess-Martin periodinane (DMP) with an oxidizing agent in a suitable solvent, such as dichloromethane, at a suitable temperature, such as room temperature. and process it accordingly.

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

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

[0223] When a carboxylic acid-substituted cyclobutyl is prepared, it can be further derivatized by esterification. It will be understood that it can be embodied.

[0224] In general scheme 6a, the following reaction conditions typically apply: 1: For example, a reagent such as methyltriphenylphosphonium bromide (MePPh3+Br-) In the presence of a drug, for example, 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 Alternatively, toluene and THF were used with bis(cyclopentadienyl)dimethyltitanium. in a suitable solvent system such as, for example, at a suitable temperature range, for example, 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, the reaction is carried out under a nitrogen atmosphere at room temperature to reflux temperature. in the presence of an aqueous base such as HCl, in the presence of an oxidizing agent such as H2O2, typically at temperatures between 0°C and rt At temperatures of .; 3: Using oxidation conditions well known to those skilled in the art: typically in a suitable solvent such as dichloromethane At temperatures between 0°C and room temperature, for example, Dess-Martin periodinane (aldehyde In the case of R aa is H). Or, (2,2,6,6-tetramethyl-pyridyl For example, acetonitrile and water in the presence of tetrahydrofuran (tetrahydrofuran-1-yl)oxyl (TEMPO) In a suitable solvent mixture, at a suitable temperature range, for example, room temperature to 50°C, Using an oxidizing agent such as phenylalanine(III) diacetate (PIDA) (in the case of carboxylic acids, That is, 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, for example, a metal complex such as methylaluminoxane. In a suitable solvent, such as DCM, at a suitable temperature, such as 0° C. to rt, Reacts with unsaturated reagents such as methyl ropiolate; 2: (LXIX) is reacted in a suitable solvent such as ethyl acetate under a hydrogen atmosphere at room temperature to 50°C. At temperature, the product is treated with a hydrogenation catalyst such as Pt / C. 3: (LXX) is obtained by the reaction of lithium hydroxide in an aqueous solvent mixture, for example aqueous methanol in water. The resulting mixture is stirred for a suitable period of time, e.g., 3 hours, e.g., with a base such as ammonium hydroxide. The reaction takes place at a controlled temperature, such as 0°C to rt. 4: (LXX) can be prepared by the reaction of a suitable solvent such as THF at a temperature of, for example, −78° C. to room temperature. At a suitable temperature, it reacts with a reducing agent such as lithium borohydride.

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

[0228] In general scheme 7, the following reaction conditions typically apply: 1: (XXIV) can be reacted with a non-proton source such as THF in the presence of 1 equivalent of a proton source such as HOAc. in an ionic solvent at a suitable temperature of 0° C. using a short reaction time, e.g., 20 minutes. , reacts with zinc powder; 2: (XXV) can be prepared by the reaction of (XXV) with a suitable solvent such as THF at a suitable temperature, for example, between −0° C. and room temperature. The mixture is then heated to room temperature and then cooled to room temperature. Treat with aqueous base such as NaOH (1M) at a preferred temperature range of 50°C.

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

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

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

[0232] In general scheme 9a, the following reaction conditions typically apply: 1: (XXX) is brominated in a two-phase solvent system consisting of DCM and water under an inert atmosphere. The reaction is carried out in a suitable solvent at a suitable temperature, such as room temperature, by the addition of benzoyl methyl ... a phase transfer catalyst such as triethylammonium chloride and a base such as sodium hydroxide requires. 2: (XXXI) can be prepared by reacting in a suitable solvent such as THF at temperatures ranging from -0°C to low temperatures, for example React with a strong base such as nBuLi under an inert atmosphere at a suitable temperature such as -100°C The resulting mixture is then treated with a borane, such as catecholborane, at the same temperature and Upon heating to 50°C, (XXXII) is formed in situ. 2a: (XXXII) can be reacted with a strong base such as nBuLi in an inert atmosphere in a suitable solvent. It is reacted at room temperature under atmospheric pressure with a mixture of aqueous hydrogen peroxide and a base such as sodium hydroxide.

[0233] General Scheme 9b: Alternative preparation of cyclopropanol (via cyclopropyl ester) Made [ka] In General Scheme 9b, -C(O)R bb is -C(O)C 1~6 Alkyl or phenyl and hydroxyl protecting groups 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, e.g. in a suitable anhydrous solvent, such as acetonitrile, at a suitable temperature, such as room temperature to 60°C. It reacts with anhydrides such as benzoic anhydride. 2: (LXVI) is reacted with an anhydrous solvent, such as 1,2-dichloroethane, under an inert atmosphere. The mixture is treated with diiodomethane and diethyl zinc at a suitable temperature, for example, between room temperature and 50°C. Understand. 3: (LXVII) can be prepared by the reaction of carbon dioxide with carboxylate in an aqueous solvent mixture, for example, aqueous methanol in water. The resulting mixture is then allowed to stand at 0° C. for a suitable period of time, e.g., 3 hours. The reaction occurs at a controlled temperature such as

[0235] General Scheme 10: Preparation of Nucleoside Analogues [ka] In General Scheme 10, R 1 , R 2 , R 10 , and n are as defined herein. R 4is 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 are typically applied: 1: The intermediate of formula (XXXIV) can be reacted with a suitable nucleobase, such as 6-chloropurine, typically can be prepared using reagents such as bis-(trimethylsilyl)acetamide (BSA), e.g., trimethylsilyl In the presence of a reagent such as anhydrous CH3CN, In a solvent; 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. The scheme is 5 or R 6 Deprotection of and / or conversion of nucleobase precursors to nucleobases For example, after coupling, 6-chloropurine may be optionally added. 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 are as defined herein. R 4 is a protecting group, e.g., a silyl group, and together R 5 and R 6 is Geo It is a diamine protecting group.

[0239] In general scheme 11, the following reaction conditions typically apply: 1. In the presence of a reagent such as tetrabutylammonium fluoride (TBAF); e.g. In a suitable solvent, such as THF; at a suitable temperature, such as rt deprotection; 2. For example, TfO (triflic anhydride or trifluoromethanesulfonic anhydride) with any suitable reagent in a suitable solvent, such as dichloromethane (DCM), e.g. Reaction at a suitable temperature such as 0°C; 3. 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. reaction;

[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 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 R who joined together 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) can typically be prepared by the reaction of 1:(XL) in a suitable solvent such as DCM in the presence of a suitable base such as pyridine. Typically, it reacts with an activator such as mesyl chloride at temperatures between 0°C and 40°C; 2: (XLI) is the presence of a catalyst such as tert-butylammonium iodide (TBAI). in a suitable solvent such as DMF or DMA at temperatures typically ranging from 0°C to 120°C reacts with azides such as sodium azide; 3: (XLII) in a suitable protic solvent such as methanol under a hydrogen atmosphere at room temperature Treatment with a hydrogenation catalyst such as Pd / C at a temperature of ∼50°C. 4: (XLIII) is dissolved in a suitable solvent such as dichloromethane and an appropriate aldehyde or ketone. After equilibration at a suitable temperature, such as room temperature, the mixture is treated with acetic acid in a solvent. In the presence of a suitable reducing agent such as sodium borohydride (NaBH(OAc)3), the reaction is carried out at 0°C to room temperature. The reduction is carried out at a suitable temperature range.

[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 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 R who joined together 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) at a suitable temperature range of 50°C to 120°C using an additional solvent. Instead, the compound is treated with a suitable amine.

[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 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 R who joined together 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 reacted with a suitable base such as sodium hydride in DMF or NMP. In any aprotic polar solvent, in the preferred temperature range of 20°C to 120°C, Process with oars. 2: (XXLVII) is dissolved in a suitable solvent system such as acetone and water at a suitable temperature of 20°C to 60°C. The resulting mixture is treated with a suitable oxidizing agent, such as hydrogen peroxide, at a temperature within the range of 3: (XLVII) is dissolved in a suitable solvent such as dichloromethane at a suitable temperature of 0°C to 30°C. The resulting product is treated with a suitable oxidizing agent such as mCPBA at a temperature in the range of 100°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 dissolved in a solvent such as dichloromethane using Dess-Martin periodinane. In a solvent at temperatures ranging from 0°C to room temperature, it is oxidized to the corresponding ketone. 2: Next, in a solvent such as methanol or ethanol, the and by using a reagent such as NaBH4 or in a solvent such as dichloromethane at temperatures between -78°C and 0°C. By using DIBAL (diisobutylaluminum hydride) in the temperature range of ℃ Therefore, (LI) can be reduced.

[0247] Those skilled in the art will recognize that Scheme 15 is a useful analogue for other 1,3-cyclobutane nucleoside analogues, as well as Also applies to 1,2-cyclobutane or cyclopropyl spiro bicyclic nucleoside analogues For example, it will be appreciated that General Scheme 15 can also be used: [ka] where n, R 1 , and R 2 is as defined herein The typical reaction conditions described here for (L) and (LI) are (L'), respectively. ) and (LI').

[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 Archi the other is a silyl group, a C optionally substituted with a silyl group 1~6 Alkyl, - O.C. 1~6 Alkyl, -SC 1~6 Alkyl, -S-aryl, or -O-aryl is.

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

[0250] General Scheme 17: Formation of aminocyclopropanes [ka] In General Scheme 17, R4 , R 5 , and R 6 is, each each independently a hydroxyl protecting group; or together R 5 and R 6 is a diol protecting group; or R 4 and R 5 is a diol protecting group.

[0251] In general scheme 17, the following reaction conditions typically apply: 1: (LV) is dissolved in an aqueous solvent system such as methanol or THF in the presence of LiOH or the like. In the presence of HCl, hydrolysis occurs at temperatures ranging from 0 to 20°C. The resulting carboxylic acid is converted to HA. In the presence of an activating agent such as TU, in a solvent such as DMF or DCM at a temperature between 20°C and 50°C In the range, it can be converted to a carboxamide using ammonia or ammonium chloride, etc. Finally, in the presence of NaOCl or NaOBr, optionally in the presence of sodium hydroxide, The rearrangement occurs in the presence of an aqueous solvent in the 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 a suitable hydroxyl protecting group, as defined herein. is defined, and PG is as defined herein.

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

[0254] Those skilled in the art will appreciate that Scheme 18 can be used to synthesize other 1,3-cyclobutanes or 1,2-cyclobutanes. Butane spiro bicyclic nucleoside analogues or cyclopropyl spiro bicyclic nucleosides It will be understood that this also applies to analogs.

[0255] In all of these preparations, the reaction product may, and if necessary, be isolated from the reaction medium. For example, extraction, crystallization, trituration, or the like may be performed using methods commonly known in the art. The product may be further purified by purification, chromatography, etc.

[0256] Chirally pure forms of the compounds of formula (I) form a preferred group of compounds. Thus, the chirally pure intermediates and their salt forms are chirally pure compounds of formula (I) The enantiomeric mixture of the intermediate is particularly useful for the preparation of the corresponding compound. These compounds are useful for preparing compounds of formula (I) having the following structure: [Example]

[0257] Hereinafter, the terms "rt" or "rt" mean room temperature; "RT" or "R t "teeth , means retention time; f " means retention factor; "Me" means methyl; " "MeOH" means methanol; "MeOD" means monodeuterated methanol; "Et " means ethyl; "EtOH" means ethanol; "EA" or "EtOA" means "c" means ethyl acetate; "Ac" means acetyl; "Ac2O" means acetic acid free "AcOH" means acetic acid; "Et2O" means diethyl ether "Int." means intermediate; "DMF" means N,N-dimethylformamide "THF" means tetrahydrofuran; "LC" means liquid chromatography. "Celite®" means diatomaceous earth; "LCMS" or "LC-MS" means liquid chromatography / mass spectrometry; "GCMS" or "GCMS" means liquid chromatography / mass spectrometry; "C-MS" stands for "gas chromatography / mass spectrometry"; "CV" stands for column volume "HPLC" means high performance liquid chromatography; "TFA" means trifluoroacetic acid; "h" means time; "Me2S" means dimethyl sulfide. "DMSO" means dimethyl sulfoxide; "DMSO-d6" means deuterated diisopropyl ether "DIPE" means diisopropyl ether; "D "CM" means dichloromethane; "PPh3" means triphenylphosphine; "TBAF" means tetrabutylammonium fluoride; "DBU" means 1,8-dibutylammonium fluoride; azabicyclo[5.4.0]undecene-7; "eq." or "equiv" "KOtBu" means potassium tert-butoxide; "TBD" means potassium tert-butoxide. "MSCl" means tert-butyldimethylsilyl chloride; "Bn" means benzoyl "9-BBN" means 9-borabicyclo[3.3.1]nonane; "T "f2O" means triflic anhydride; "TBDMS" means tert-butyldimethyl "aq." means aqueous; "Ts " or "Tos" means tosyl (p-toluenesulfonyl); "DEAD" means diene "Bz" means benzoyl; "BnBr" means benzoyl azodicarboxylate; means benzyl bromide; "Bn" means benzyl; "anhyd." means anhydrous "p-TsOH" means 4-methylbenzenesulfonic acid; "(R)-Mo noPhos is (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F] "BSA" means N,O-bis[1,3,2]dioxaphosphepin-4-amine; (trimethylsilyl)acetamide; "TMSOTf" means trimethylsilyl "Boc" means tert-butyloxycarbonyl "Prep SFC" means preparative supercritical fluid chromatography; "Piv" means pivaloyl; "PivCl" means pivaloyl chloride; "Me PPh3 + Br - " means methyltriphenylphosphonium bromide; "iPrNH2" means isopropylamine; "iPrOH" means isopropyl alcohol; "n-PrNH2" means propylamine; "sat." means saturated; "DM "A" means dimethylacetamide; "NMR" means nuclear magnetic resonance; "Chlo "chloroform-d" means deuterated chloroform; "DIPEA" means diisopropyl "TLC" means thin layer chromatography; "brsm" means 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 " means diisopropyl azodicarboxylate; "methanol-d4" means heavy "TBDPS" means tert-butyldiphenylsilyl; "HMDS" means hexamethyldisilazane; "DMAP" means 4-dimethylaminopyridine "ESI" means electrospray ionization; "ACN" means acetone "TBAI" means tetrabutylammonium iodide; "HA" means tetrabutylammonium iodide; TU" is N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pi Lysin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; "brsm" means based on recovered starting material; "H "MPA" 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; "MAO" means methylaluminoxane do.

[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] CAS 54622-95-6 (200 mg, 0.92 mmol) in DCM (2 mL) To a stirred solution of 1 eq) and 1 drop of DMF was added oxalyl chloride (0.12 mL, 1.37 m mol, 1.5 eq) was added, and the resulting reaction mixture was then stirred at room temperature for 4 hours. The excess solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0260] To the acid chloride obtained above in toluene (2 mL) in a sealed tube, Run (1.35 mL, 9.16 mmol, 10 eq), followed by EtN (0.15 mL, 1.10 mmol, 1.2 eq) was added and the resulting reaction mixture was heated at 120°C overnight (16 h) heated and then quenched with HCl (1M, 10.00 mL). The aqueous phase was diluted with EtOAc. c (20 × 2 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (petroleum ethanol). Purification with ether / EtOAc 90:10, Rf=0.5 gave compound 1 (198m g, 0.66 mmol, 72%) as a colorless oil, which was identified by NMR spectroscopy (It is a mixture of diastereomers as suggested).

[0261] Data for the major isomers: 1 H NMR (400 MHz, 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,-2.31ppm. GC-MS: [M-86] 214, 13.67 min (Method 4) (Molecular ion peak not found) figure)

[0262] Preparation of Compound 2 [ka] Compound 1 (250 mg, 0.83 mmol, 1 eq) was dissolved in dry THF (4 mL) with stirring. The solution was added with acetic acid (0.05 mL, 0.83 mmol, 1 eq) and TBAF (1.66 mL, The resulting reaction mixture was heated at 50° C. for 1 hour. 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 / Et0Ac). 90:10, R f =0.2) to give compound 2 (28 mg, 0.12 mmol, 15%) as a colorless oil (which, as suggested by NMR spectroscopy, was the product of two (81:19) mixture of diastereomers). This experiment was repeated three more times. 30mg, 13%), (50mg, 13%), (125mg, 14%, 20%(brsm )) were obtained, and all of these were combined to obtain Compound 2 (232 mg).

[0263] Data for the major isomers: 1 H NMR (300 MHz, 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=10.0,4.2H z,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] Compound 1 (113 mg, 0.38 mmol, 1 eq) at room temperature (cyclobutane of compound 1) The wavy bond in the figure refers to the mixture of multiple isomers obtained previously) in dry DCM (1.5 mL) To the stirred solution, TMSOTf (0.06 mL, 0.34 mmol, 0.9 eq) was added. The resulting reaction mixture was stirred at the same temperature for 16 hours. ) was carefully added and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was concentrated at rt to give a crude product consisting of starting material and product (TLC). Silica gel column chromatography (petroleum ether / EtOAc 90:10, R f 0 Compound 1a (40 mg, 0.13 mmol) was purified by HPLC using HPLC with HPLC. , as suggested by NMR spectroscopy, four (51:20:19:10) diastereoisomers Compound 3 (31 mg, 0.14 mmol, 36% (65%)) was isolated as a mixture of 3-(2-amino-2-methyl-2-propanol (2-amino-2-methyl-2-propanol) and 2-(2-amino-2-methyl-2-propanol (2-amino-2-methyl-2-propanol)). % brsm)) as colorless crystals (which, as suggested by NMR spectroscopy, consisted of a single as diastereomers).

[0265] Data for the major isomer of compound 1a: 1 H NMR (400 MHz, chloroform) Lum-d)δ 4.89(s,1H),4.64(d,J=5.7Hz,1H),4.6 0(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,3 H),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),1.4 9(s,3H), 1.30 ppm(s,3H).

[0267] Preparation of Compounds 4 and 5 [ka] Compound 2 (205 mg, 0.90 mmol, 1.00 eq) in MeOH (2 mL) Then, NaBH4 (44 mg, 1.17 mmol, 1.30 eq) was added at -78 °C. The resulting reaction mixture was stirred at -78 °C for 1 h. The reaction was then diluted with saturated NH4Cl (10 mL The mixture was quenched by adding ethyl acetate (30 mL) and extracted with ethyl acetate (30 mL). Dry over sodium sulfate, filter, concentrate in vacuo and carry on to the next step.

[0268] To the above obtained alcohol in DCM (2 mL) was added EtN (0.26 mL, 1.8 0 mmol, 2 eq), benzoyl chloride (0.16 mL, 1.35 mmol, 1.5 eq ) was added at 0° C. and the resulting reaction mixture was stirred at rt overnight. The reaction was then diluted with saturated Na Quench by adding HCO3 (20 mL) and extract with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was 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 mmHg). ol, 37%, and as suggested by NMR spectroscopy, two (62:38) diastereoisomers as a mixture of stereomers) as a colorless oil, and compound 5 (100 mg, 0.43 mmol, 48%, and as suggested by NMR spectroscopy, two (62:38) as a mixture of diastereomers).

[0269] For compound 4, Prep SFC (stationary phase: Chiralcel Diacel Purification was carried out using a 20×250 mm OJ column (mobile phase: CO2, iPrOH). 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: 1 H NMR (300 MHz, chloroform) Mu-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), 1.16 ppm (d, J = 0.7 Hz, 3H).

[0273] Data for the major isomer of compound 5: 1 H NMR (300 MHz, chloroform) Mu-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,1) H),3.32(s,3H),2.68-2.53(m,1H),2.29-2.20( 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 .33 ppm (d, J = 0.7 Hz, 3H).

[0274] Substitutional preparation of compound 1 (large scale) [ka] CAS 54622-95-6 (64.00g, 293.58mmol, 1eq) To a solution in toluene (640 mL) was added 1 drop of DMF followed by oxalyl chloride (55.92 g, 440.37 mmol, 1.5 eq) was added, and the resulting reaction mixture was then stirred at room temperature for 1 h. The mixture was stirred and the excess solvent and oxalyl chloride were removed using a vacuum pump for 1 h. The acid chloride obtained above in toluene (600 mL) in a tube was added with vinyltrimethoxysilane. N (293.61 g, 2935.80 mmol, 10 eq), followed by EtN (35.5 8g, 352.296mmol, 1.2eq) was added, and the resulting reaction mixture was heated at 120°C. The mixture was heated at rt overnight (16 h) and then quenched with HCl (1 Maq, 800.00 mL). The aqueous phase was extracted with EtOAc (2 x 600 mL) and the combined organic layers were washed with Na2SO4 The residue was then purified by silica gel column chromatography. Purification by HPLC (petroleum ether / EtOAc 90:10, Rf=0.5) Compound 1 was obtained.

[0275] 26% (23g, 76.33mmol, crude) yellow oil. LCMS(ESI+)m / z :C 14 H 24 Calculated value for O5Si [M+H2O]+ = 318.14, found value 318 .20, RT: 1.678 minutes, Method 1.

[0276] Substitutional preparation of compound 5 (large scale) [ka] Compound 1 (23 g, 76.33 mmol, 1.00 eq) in dry THF (230 mL) ) with acetic acid (4.57 g, 76.33 mmol, 1.00 eq) and TBAF (152. The resulting reaction mixture was heated to 50°C. After completion of the starting material (TLC), MeOH (200 mL) was added and Na BH4 (2.9 g, 76.33 mmol, 2.00 eq) was added at 0°C. The reaction mixture was stirred at 0 °C for 2 h. The reaction was then added saturated NH4Cl (200 mL) The mixture was quenched by stirring and extracted with ethyl acetate (300 mL). The residue was then dried over sodium, filtered, and concentrated in vacuo. Chromatography (petroleum ether / EtOAc 90:10, R f =0.2) The front peak is compound 5a', and the back peak is compound 5b' (compound 5b' and The compound was obtained as a mixture of compounds 95a and 95b described below.

[0277] 3.3% yield (580 mg, 2.52 mmol, crude) of compound 5a' as a yellow oil. GC MS(ESI+)m / z:C 11 H 18 Calculated value for O5 [M-Me]-=215.0 9, Actual 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, actual value 215.09, RT: 6.377 minutes, Method 1.

[0279] Preparation of Compound 4a' [ka] Compound 5a' (1.03g, 4.47mmol, 1.00eq), DMAP (272. 67 mg, 2.23 mmol, 0.50 eq) was dissolved in pyridine (10 mL), Benzoyl chloride (1.25 g, 8.94 mmol, 2.00 eq) was then added dropwise at 0°C. The resulting solution was stirred at 0° C. for 1 h. The reaction was then treated with HCl (1 M, aqueous, 20 mL ) was added until a pH < 7 was reached. The product was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The column was a C18 column (mobile phase A: water (0.1 mmol / L NH4HCO3), mobile phase B: A CN; 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 (300 M z, 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),4.66-4.58(m,1H),3.36(s,3 H),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 165.92,132.62,130.56,1 29.90, 128.06, 112.68, 108.27, 87.81, 85.43, 8 3.93, 70.89, 55.04, 27.78, 26.04, 25.09, 21.67 ppm.LCMS(ESI+)m / z:C 18 H 22 Calculated value for O6 [M+H]+= 335.14, measured value 335.14, RT: 1.811 min, Method 1.

[0281] Preparation of Compound 138a [ka] Compound 4a' (430 mg, 1.28 mmol, 1.00 eq) in HO (5 mL) 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, β anomer predominant) The product was dissolved in dry pyridine (5 mL) and stirred for 30 minutes. (195.84 mg, 1.92 mmol, 1.50 eq) was added at 0°C and stirred at room temperature. The mixture was stirred at room temperature for 3 hours. Then, the mixture was diluted with ice-cold water (10 mL) and The crude mixture was extracted with CH2Cl2 (3 x 10 mL) and stirred at room temperature for 30 min. The combined organic layers were washed with brine (3 x 10 mL), dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE The product was purified by ethanol / EA 100:1 to 10:1. The fractions containing the product were combined and the solvent Evaporation gave compound 138a.

[0283] 80% yield over two steps (420 mg, 1.03 mmol, crude; mixture of α and β anomers) (β anomer is the major product), colorless oil. LCMS (ESI+) m / z: C2 0H 22 Calculated value for O9 [M+H2O]+ = 424.13, Found value 424.13, R T:1.523 minutes, method 1.

[0284] Preparation of Compound 139a [ka] 6-Chloropurine (121.79 mg, 0.81 mmol, 1.10 eq) in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (150. The mixture was heated to 80°C for 16 hours. The mixture was cooled to room temperature and then a solution of compound 138a ( 300 mg, 0.74 mmol, 1.00 eq), followed by trimethylsilyltrifluoro Methanesulfonate (194.94 mg, 0.88 mmol, 1.20 eq) was added, The mixture was heated to 80° C. for 2 h. The mixture was cooled to room temperature and diluted with EtOAc (20 mL). Dilute with saturated NaHCO3 (3 x 20 mL) and saturated aq. NaCl (3 x 20 mL). The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using PE / EtOAc (gradient elution: P The product was purified by elution with hexane (99:1 to 4:1 EtOAc). The fractions containing the product 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, experimental Value 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-dioxa- The mixture was dissolved in ethanol (2.4 mL) and NH3 (aq. 0.6 mL) was added. The mixture was heated to 10° C. for 16 hours. After the mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was , silica gel column chromatography using dichloromethane / methanol (gradient elution The product was purified by distillation with DCM / MeOH 99:1 to 5:1. The fractions containing the product were collected. 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=3.9 Hz,1H),4.40-4.31(m,1H),2.17-2.00(m,2H),1 .78-1.59 ppm(m,2H). 13 C NMR (75MHz, MeOD) δ 1 55.90,152.43,149.60,140.12,119.31,88.43, 87.24,76.52,73.87,25.86,22.51ppm.LCMS(ES I+)m / z:C 12 H 15 Calculated value for N5O4 [M+H]+ = 294.11, experimental Value 294.11, RT: 0.446 min, Method 1.

[0288] Preparation of Compound 4b' [ka] Compound 5b' (2.6 g) as the mixture obtained by the above procedure in "Alternative preparation of compound 5" The compound was used and contained 30% pure compound 5b', 800 mg, 3.47 mmol, 1.00 eq. DMAP (211.67 mg, 1.73 mmol, 0.50 eq) was added to pyridine. The solution was dissolved in 10 mL of benzoyl chloride (971.60 mg, 6.94 mL) and then (mmol, 2.00 eq) was added dropwise at 0°C, and the resulting solution was stirred at 0°C for 1 hour. To the reaction was added HCl (1 M, aqueous, 20 mL) until a pH of <7 was reached. was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried (Na2SO4) The residue was purified by filtration and concentrated in vacuo. The residue was purified by column chromatography (mobile phase A: water (0.1 mmol) / L NH4HCO3), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40 in 30 min The product was purified by HPLC (from 70B to 70B; 210 / 254 nm). The fractions containing the product were collected. The solvent was evaporated to give compound 4b.

[0289] 34% yield (400 mg, 1.19 mmol), colorless oil. 1 H NMR (300 M z, 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),5.0 4(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 (75 MHz, CDCl3) δ 165 .77,132.84,130.41,129.81,128.28,112.84,1 08.18, 89.65, 85.06, 84.26, 70.78, 54.95, 30.6 4,26.22,25.75,25.25ppm.LCMS(ESI+)m / z:C 18 H 22 Calculated value for O6 [M+H]+ = 335.14, Found value 335.14, RT: 1 .675 minutes, method 1.

[0290] Preparation of Compound 138b [ka] Compound 4b' (400 mg, 1.19 mmol, 1.00 eq) in HO (5 mL) The mixture was heated to 35°C for 16 hours. The solution was 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) was obtained.

[0291] Compound 138.1b (420 mg, crude) was dissolved in dry pyridine (5 mL), Stirred for 30 minutes. Acetic anhydride (181.56 mg, 1.78 mmol, 1.50 eq) The mixture was stirred at room temperature for 3 hours. The mixture was poured into ice-cold water (10 mL) and stirred at room temperature for 30 min. The crude mixture was diluted with CH2Cl2 (3 x 10 mL), and the combined organic layers were washed with brine (3 x 10 mL) and dried. The residue was purified by silica gel chromatography. The product was purified by chromatography (gradient elution: PE / EA 100:1 to 10:1). The containing fractions were combined and the solvent 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 is the major product), colorless oil. LCMS (ESI+) m / z: C2 0H 22 Calculated value for O9 [M+H2O]+ = 424.13, Found value 424.13, R T:1.545 minutes, method 1.

[0293] Preparation of Compound 139b [ka] 6-Chloropurine (100.10 mg, 0.65 mmol, 1.10 eq) in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (131. The mixture was heated to 80°C for 16 hours. The mixture was cooled to room temperature and then the compound 138b ( 241 mg, 0.59 mmol, 1.00 eq), followed by trimethylsilyltrifluoro Methanesulfonate (157.21 mg, 0.71 mmol, 1.20 eq) was added, The mixture was heated to 80° C. for 2 h. The mixture was cooled to room temperature and diluted with EtOAc (20 mL). Dilute with saturated NaHCO3 (3 x 20 mL) and saturated aq. NaCl (3 x 20 mL). The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography using PE / EtOAc (gradient elution: P The product was purified by elution with hexane (99:1 to 4:1 EtOAc). The fractions containing the product 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, experimental Value 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-dioxa- The mixture was dissolved in ethanol (3.0 mL) and NH3 (aq. 0.8 mL) was added. The mixture was heated to 10° C. for 16 hours. After the mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was , silica gel column chromatography using dichloromethane / methanol (gradient elution The product was purified by distillation with DCM / MeOH 99:1 to 5:1. The fractions containing the product were collected. 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), 6.0 7(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,2 H), 2.04-1.92 ppm (m, 2H). 13 C NMR (75 MHz, CDCl 3) Waiting for data. 13 C NMR(75MHz,MeOD)δ 155.74,152. 18,149.31,140.06,119.30,90.77,88.47,73.7 5,73.71,67.29,26.56,26.01ppm.LCMS(ESI+)m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294 .11, RT: 0.412 minutes, Method 1.

[0297] Preparation of Compounds 6a and 6b [ka] CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) of acetonitrile To a stirred solution in tolyl (6 mL) was added 2-chloro-1-methylpyridinium iodide (702 mg, 2.75 mmol, 1.5 eq), tert-butyl vinyl ether (2.42 m L, 18.33 mmol, 10 eq), and finally DIPEA (0.96 mL, 5.49 The resulting reaction mixture was then refluxed for 16 hours. The reaction was cooled to room temperature, quenched with HCl (20 mL, 1 M) and extracted with ethyl acetate. 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 compound 6 as a colorless oil. Two isomers were obtained: compound 6a and compound 6b as colorless crystals in pure form.

[0298] Compound 6a (20% yield, 110 mg), R f 0.6 (petroleum ether / EtOAc 8 0:20): 1 H NMR (400 MHz, chloroform-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,1H),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 (101 MHz, chloroform-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 (petroleum ether / EtOAc 8 0:20): 1 H NMR (400 MHz, chloroform-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 (101 MHz, chloroform-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 minutes (method 4).

[0300] Preparation of Compound 7 [ka] CAS 54622-95-6 (2.00 g, 9.16 mmol, 1 eq) in DCM ( To the stirred solution in 1.8 mL of 1000 ml ... ol, 1.5 eq) was added, and the resulting reaction mixture was stirred at room temperature for 4 h. The solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0301] To the above obtained carbonyl chloride in DCM (25 mL) was added ethoxyacetylene (18 0.33 mmol, 40% w / w in hexane, 2 eq) was added. The stirred solution was then At t, add triethylamine (1.38 mL, 10.08 mmol, 1.1 eq) dropwise. After 30 minutes, the suspension was heated to reflux and stirred for an additional 16 hours. After cooling, the triethylammonium chloride was removed by filtration and the filtrate was concentrated in vacuo. The residue was then purified by silica gel column chromatography (petroleum ethanol). Purification with ethanol / EtOAc 70:30 gave compound 7 (1.32 g, 4.88 m mol, 53%) as a brown oil (as suggested by NMR spectroscopy). , a mixture of two (74:26) diastereomers).

[0302] Data for the major isomers: 1 H NMR (400 MHz, 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=5.8,0.8 Hz,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,3 H). 13 C NMR (101 MHz, chloroform-d) δ 186.52, 182.08 113.98,113.40,106.51,101.02,84.32,79.97, 69.94,54.84,25.88,24.91,14.00ppm.

[0303] Preparation of Compound 8 [ka] CAS 54622-95-6 (200 mg, 0.92 mmol, 1 eq) in DCM ( To a stirred solution of 1000 ml ... 1, 1.5 eq) was added, and the resulting reaction mixture was stirred at room temperature for 4 hours. The solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0304] To the acid chloride obtained above in toluene (2 mL) in a sealed tube, add 1-(trimethylsilyl) (1.03 mL, 9.16 mmol, 10 eq) propyne, followed by EtN (0.1 5 mL, 1.10 mmol, 1.2 eq) was added, and the resulting reaction mixture was heated at 120 °C for 1 hour. Heated overnight (16 h) and then quenched with HCl (1 M, 10.00 mL). was extracted with EtOAc (20×2 mL) and the combined organic layers were dried over Na2SO4, Concentration under reduced pressure gave the crude product, and 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%) was obtained as a colorless oil (as indicated by NMR spectroscopy). As shown, it is a mixture of two (82:18) diastereomers.

[0305] Data for the major isomers: 1 H NMR (400 MHz, chloroform-d) δ 4.89(s,1H),4.62(d,J=6.0Hz,1H),4.59(d,J= 6.0Hz,1H),3.28(s,3H),1.87(s,3H),1.50(s,3 H), 1.26(s,3H), 0.28ppm(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,-1.09ppm. LCMS: (ESI + ):[M+1] + =313.3, RT 1.23 minutes (Method 10)

[0306] Preparation of Compound 9 [ka] CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) of toluene To a stirred solution in (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 hours. The reaction was then cooled to room temperature. The mixture was cooled, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics were The crude product was then purified by silica gel chromatography. Compound 9 (140%) was obtained by chromatography (petroleum ether / EtOAc 90:10). mg, 0.42 mmol, 23%) as a pale yellow oil, which was identified by NMR spectroscopy. As suggested, it is a mixture of two (82:18) diastereomers).

[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=6.1Hz,1H),3.39(d,J=8.5Hz,1H),3.3 6(d,J=4.8Hz,1H),3.33(s,3H),1.39ppm(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, 107.4 3, 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] CAS 39682-04-7 (3.10 g, 10.53 mmol, 1 eq) DCM To a stirred solution of 15 mL of DMF, 1 drop of oxalyl chloride (1.35 mL, 15.80 mmol, 1.5 eq) was added and the resulting reaction mixture was then stirred at room temperature for 4 hours. Excess solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0309] EtN (2.28 mL, 15.80 mmol, 1.5 eq) and vinyltrimethylsilyl Dissolve methoxysilane (12.42 mL, 84.29 mmol, 8 eq) in toluene (20 mL The acid chloride obtained above in toluene (10 mL) was added to the stirred solution in toluene (10 mL) by syringe pump. The reaction mixture was then refluxed at 120° C. overnight (16 hours), after which The mixture was quenched with HCl (1M, 40.00 mL). The aqueous phase was washed with EtOAc (40×2 mL). The extracted and 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 / Et0Ac). 90:10) to give compound 10 (2.40 g, 6.37 mmol, 60%). It was obtained as a colorless oil, which, as suggested by NMR spectroscopy, was a mixture of four (56:2 4:11:9) mixture of diastereomers).

[0310] Compound 10 was analyzed by prep HPLC (stationary phase: RP XBridge Prep C18 OBD-10μm, 50×150mm, Mobile phase: 0.25%NH4HCO in water 3 solution, CH3CN) to obtain compound 10a (11.5 mg, 0.03 mmol). Compound 10b (11, 5% yield) (50.6 mg, 0.13 mmol, 20% yield) and compound 10b (1 Two fractions of 2 mg, 0.03 mmol, 5% yield were obtained.

[0311] compound 10a 1 H NMR (400 MHz, chloroform-d): δ 7.31-7.49 (m, 5H ),5.89(d,J=4.0Hz,1H),4.59-4.72(m,3H),4.1 2(s,1H),3.02(dd,J=16.3,11.9Hz,1H),2.65(d d,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 (101 MHz, chloroform-d: δ 202.8, 137.8, 12 9.7, 129.4, 129.3, 114.2, 105.9, 104.9, 84.2, 8 2.9,73.1,44.6,27.4,26.9,25.0,0.0ppm. 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),4.7 3(d,J=11.4Hz,1H),4.57(d,J=11.4Hz,1H),4.3 1(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 205.7,136.6,12 8.3,127.7,127.0,115.3,103.8,100.3,85.2,8 5.1,71.8,43.1,28.2,27.4,22.8,-2.0ppm. LCMS: (ESI + ):[M+18] + =394.3, RT1.35 points (Method 10)

[0313] Modulation of Compound 11

change

[0314] Data for the major isomer of compound 11: 1 H NMR (chloroform-d,60 0MHz):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),2.14-2.2 2(m,1H),1.50(s,3H),1.34ppm(s,3H). 13 C NMR (Chloroform-d, 151MHz): δ = 203.1, 136.8, 128.6, 12 8.2, 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] Compound 11 (350 mg, 1.15 mmol, 1.00 eq) in MeOH (4 mL) (The wavy bond in cyclobutane in compound 11 refers to a mixture of multiple isomers obtained previously. ) was added NaBH4 (57 mg, 1.50 mmol, 1.30 eq) at -78 °C, The resulting reaction mixture was stirred at -78 °C for 1 h. The reaction was then diluted with saturated NH4Cl (10 The mixture was quenched by adding 1 mL of ethyl acetate (20 mL) and extracted with ethyl acetate (30 mL). Drying over anhydrous sodium sulfate, filtering, and concentrating in vacuo gave crude compound 12. The crude product (TLC) consisting of three isomers was purified by silica gel column chromatography. (petroleum ether / EtOAc 90:10 to 80:20) to give a colorless oil. Compound 12a (Rf 0.4, 165 mg, 2 as suggested by NMR spectroscopy) Compound 1 as a colorless oil (47%) as a mixture of two diastereomers (91:9) 2b (Rf 0.3, 80 mg, NMR spectroscopy suggested three diastereomeric 23%) as a mixture of mers (68:26:6), and compound 12c ( Rf 0.2, 80 mg, 2 as a single pure isomer as suggested by NMR spectroscopy Three isomers were obtained, each with a 3% yield of 3%.

[0316] Compound 12a was purified by Prep HPLC (stationary phase: RP XBridge Pre p C18 OBD-10μm, 50×150mm, Mobile phase: 0.25%NH4HC in water O3 solution in MeOH) to give 86 mg, 0.28 mmol, 53% yield.

[0317] Data for compound 12a 1 H NMR (300 MHz, 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, chloro Form-d) δ 7.52-7.35 (m, 5H), 5.93 (d, J = 3.4 Hz, 1 H),4.88-4.81(m,1H),4.71(d,J=3.8Hz,1H),4. 48(s,1H),4.44-4.37(m,1H),4.33(dd,J=8.9,7 .8Hz,1H),3.04(d,J=1.1Hz,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 1 H NMR (300 MHz, 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 ), 1.25 ppm (d, J = 0.7 Hz, 3H). LCMS: (ESI + ):[M+18] + =324.4, RT0.94 minutes (method 10)

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

[0321] 1 H NMR (400 MHz, chloroform-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,1 H),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), 1.18 ppm (s, 9H). 13 C NMR (101 MHz, chloroform-d) δ 205.64, 137.11 128.34, 127.78, 127.76, 114.63, 105.73, 101.5 5, 85.76, 81.73, 74.70, 72.33, 63.74, 50.16, 28 .21, 27.86, 27.44 ppm

[0322] Preparation of Compound 14 [ka] 1-O-Methoxy-β-D-ribofuranose (25.3 g, 154 mmol, 1.00 eq) was dissolved in pyridine (253 mL) and triphenylphosphine (44.4 g, The solution was cooled to 0°C and iodine ( 42.9 g, 169 mmol, 1.10 eq) was added in small portions over a period of 40 minutes. After the addition of the reagents, the solution was cooled to 0°C for an additional 20 minutes and then stirred at room temperature for 24 hours. After this, the reaction mixture was cooled to 0°C and pivaloyl chloride (43.5 mL, 354 mmol, 2.30 eq) was added dropwise to the stirred mixture over 1.5 hours via a pressure equalizing dropping funnel. After the drug was added, the mixture was warmed to room temperature and stirred for 22 hours. The resulting brown slurry was concentrated to 1000 ml and co-evaporated with toluene (2 x 300 mL). n-Heptane (1 L) was added to the mixture, and then triphenylphosphine oxide was The mixture was sonicated for 1 hour, and the solid material was filtered and washed with n-heptane (300 mL). The filtrate was concentrated in vacuo to a minimum volume to give a yellow syrup. The powder was redissolved in 500 mL of EtOAc and added sodium thiosulfate (aq. sat. 1 The organic phase was dried (M gSO4), filtered, and the filtrate was concentrated in vacuo to give compound 14 (49.0 g, 72% crude yield) ) was obtained, which solidified when left at room temperature.

[0323] 1 H NMR (400 MHz, chloroform-d δ 5.27 (d, J = 4.8 Hz, 1H),5.20(dd,J=6.3,4.8Hz,1H),4.85(s,1H),4 .24(q,J=6.6Hz,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, 10 6.1, 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) in DMF (500 mL) DBU (17.8 mL, 119 mmol, 1.10 eq) was added in one go and stirred. The mixture was added to the mixture, which was heated to 90°C for 18 hours. The mixture was cooled to room temperature and evaporated in vacuo to about The brown solution was then diluted with n-heptane (1.5 L) and The resulting organic phase was dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient). Purification was carried out by gradient elution (n-heptane / EtOAc 99:1 to 9:1). The corresponding fractions were collected and the solvent was evaporated to give the desired compound 15 (30.2 mg, 96.1 mmol). l, yield 89%) was obtained as a colorless liquid.

[0325] 1 H NMR (360 MHz, 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),3.4 6(s,3H),1.23(s,9H),1.21ppm(s,9H) 13 C NMR (101 MHz, chloroform-d) δ 177.3, 177.2, 15 7.2,106.2,84.6,73.2,69.7,56.3,39.1,39.0, 27.4, 27.3 ppm

[0326] Preparation of Compound 16 [ka] Zinc powder (25.0 g, 0.38 mol, 1.00 eq) was dissolved in demineralized water (100 mL). The solution was degassed with nitrogen for 15 minutes. Then, copper(II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was added and the mixture was stirred. The solution was degassed and stirred for 45 minutes. The mixture was filtered and the black solid was removed by degassing. The zinc-copper couple was washed with degassed water (250 mL) and degassed acetone (250 mL). The mixture was dried in air for 12 hours. Compound 15 (10.0 g, 31.8 mmol, 1.00 eq) was obtained. ) was weighed into an oven-dried flask and anhydrous diethyl ether (300 mL, 4 Å molecular weight) was added. The solution was then dissolved in zinc-copper couple (14.6 g, 2 23 mmol, 7.00 eq) was added in one portion to a stirred solution in diethyl ether. Fit a pressure-equalizing dropping funnel dried in a pan and add anhydrous diethyl ether (100 mL) and Trichloroacetyl chloride (6.10 mL, 54.1 mmol, 1.70 eq) was charged The reagents were added dropwise over 2.5 hours, carefully monitoring the temperature to ensure it did not exceed 25°C. Then, the zinc-copper couple was decanted and washed with diethyl ether (100 mL). Rinse and dilute the organic layer with n-heptane (500 mL), followed by NaHCO Wash with 3 (aq. sat. 3 x 300 mL) and brine (2 x 250 mL). The phase was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo at 40°C to give compound 16 (13 0.2g, crude).

[0327] 1H NMR (360 MHz, chloroform-d) δ 5.84 (d, J = 4.0 Hz, 1H),5.35(d,J=4.4Hz,1H),4.98(s,1H),3.92(d ,J=18.7Hz,1H),3.51(s,1H),3.40(d,J=18.7Hz ,1H),1.19ppm(s,18H) 13 C NMR (91 MHz, chloroform-d) δ 191.0, 176.3, 175 .4,106.0,91.4,83.2,74.6,71.2,55.9,52.0,3 8.5, 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. Then, zinc powder (4.06 g, 62.1 mmol, 10.0 eq) was added little by little and mixed. The mixture was heated to 50° C. for 5 hours, after which the solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to a minimum volume and redissolved in EtOAc (200 mL). Wash with brine (2 x 75 mL), dry (MgSO4), filter and concentrate in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / E The product was purified by toluene (99:1 to 1:1) and the fractions containing the product were collected and the solvent was removed. Evaporation afforded the desired compound 17 (1.48 mg, 4.16 mmol, 67% yield) as a colorless oil. was obtained as.

[0329] 1H NMR (360 MHz, chloroform-d) δ 5.56 (d, J = 4.4 Hz, 1H),5.26(dd,J=4.4,0.7Hz,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),1.21ppm(s,9 H) 13 C NMR (101 MHz, chloroform-d) δ 203.2, 177.2, 17 6.8,105.7,75.7,75.1,74.0,58.3,55.7,55.5, 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) in MeOH (5 mL) Dissolve NaBH4 (64.0 mg, 1.68 mmol, 1.20 equiv) in -7 The resulting solution was stirred at -78°C for 30 minutes. The reaction mixture was quenched by adding 20 mL of saturated aqueous NH4Cl. The mixture was extracted with 2 x 20 mL of ethyl acetate and the organic layers were combined. The residue was extracted with ethyl acetate / petroleum ether (gradient elution: PE / The product was then loaded onto a silica gel column with EtOAc (99:1 to 4:1). The 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. 1H NMR (400MH z, chloroform-d) δ 5.27 (d, J = 4.5 Hz, 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(E SI + ) m / z:C 18 H 30 Calculated value for O7 [M-CHO] + =327.18, Actual measured value: 327.14, RT: 9.317 min (Method 1).

[0332] Preparation of Compound 19a and Compound 19b [ka] Compound 18a (mixed with compound 18b) (7.00 g, 19.5 mmol, 1.0 eq ), TEA (3.94 g, 39.1 mmol, 2.0 equiv) in DCM (70 mL) and then benzoyl chloride (5.47 g, 39.1 mmol, 2.0 equiv. v) was added dropwise at 0° C. and the resulting solution was stirred at 0° C. for 1 h. The reaction was then diluted with 1M H The mixture was quenched with aqueous Cl until pH < 7. To the resulting solution was added 130 mL of DCM. The mixture was extracted with 1×200 mL of H2O and the organic layers were combined. The residue was extracted with ethyl acetate / petroleum ether (gradient elution: PE / The product was then loaded onto a silica gel column with EtOAc (99:1 to 20:1). The fractions containing 19a were collected and the solvent was evaporated to give compound 19a (mixture with 13% compound 19b). Got it.

[0333] 87% yield (7.90 g, 17.10 mmol), colorless oil. 1 H NMR (400M Hz, 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),2.4 4(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+N H4] + = 480.26, actual value 480.25, RT: 2.151 min (Method 1).

[0334] Preparation of Compound 19b [ka] Compound 18 (2.28g, 6.36mmol, 1.00eq) in THF (60mL) 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) was added. The mixture was cooled to 0 °C and diethyl azodicarboxylate (1.15 mL, 7.31 m mol, 1.20 eq) was added. After the addition, the mixture was allowed to warm to room temperature and stirred for 16 hours. , followed by the addition of pentane (120 mL) to precipitate triphenylphosphine oxide. The solid was filtered and rinsed with heptane (30 mL). The filtrate was added brine (50 mL). The mixture was added and the product was extracted into heptane (1 x 150 mL, 2 x 100 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. Column chromatography (gradient elution: n-heptane / EtOAc 99:1) The fractions containing intermediate 30 were collected and the solvent was evaporated to give compound 30. 19b (1.79 mg, 3.88 mmol, 61% yield) was obtained as a colorless oil.

[0335] 1 H NMR (400 MHz, 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=4.4,1.5 Hz,1H),4.88(d,J=1.5Hz,1H),3.42(s,3H),2.8 1(ddd,J=13.4,7.5,4.4Hz,1H),2.62-2.72(m,2 H),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, 16 6.1, 133.0, 130.0, 129.6, 128.4, 105.7, 81.1, 7 5.1, 74.3, 65.5, 55.4, 41.3, 39.3, 39.0, 38.8, 2 7.2, 27.1 ppm

[0336] Preparation of Compound 20 [ka] 6-Cl Purine CAS 87-42-3 (1.69g, 10.9mmol, 1.1e (quiv) was dissolved in MeCN (37 mL) and N,O-bis(trimethylsilyl) aryl Cetamide (2.02 g, 9.95 mmol, 1 equiv) was added dropwise. The mixture was stirred for 80 The mixture was cooled and then heated to °C overnight. After cooling, compound 19a (1 mL) in MeCN (31 mL) was added. 3% Compound 19b) (4.6 g, 9.95 mmol, 1.00 equiv) Trimethylsilyl trifluoromethanesulfonate (2.65 g, 11.94 m mol, 1.2 equiv) was added and the mixture was heated to 80°C for 2 hours. The mixture was then washed with EtOAc, twice with saturated NaHCO3, and once with saturated aq. NaCl. The organic layer was dried over Na2SO4. The solvent was removed in vacuo. The residue was with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 30:1) The fractions containing the product were collected and the solvent was evaporated to give compound 1. 20 was obtained in 86% yield (5.00 g, 8.56 mmol), a 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 minutes (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 dissolved in sodium methoxide (0.37 g, 6.84 mmol, 1.00 eq The reaction was stirred at rt for 30 min, then washed with H-exchange resin and adjusted to pH=7. The mixture was stirred until the mixture was dissolved in water. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane / methyl The silica gel column was then loaded with ethanol (gradient elution: DCM / MeOH 99:1 to 90:10). The fractions containing the product 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 (400M Hz,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), 2.29-2.22 ppm (m,1H).13 C NMR (101 MHz ,DMSO)δ 156.06,153.09,150.02,140.48,119. 36, 86.86, 78.91, 75.14, 73.28, 57.38, 45.97, 4 1.03 ppm. 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) was added at 0° C. The reaction was stirred at rt for 1 h. The reaction was then diluted to pH=7. Add 1M aqueous NaOH, followed by 50 mL of DCM, and add 60 mL of 1M aqueous NaOH. The mixture was extracted with H2O and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was extracted with dichloromethane / methanol (gradient elution: DCM / MeOH 99 The product was collected and the fractions were then run on a silica gel column. The solvent was evaporated to give compound 22.

[0340] 77% yield (1.58 g, 4.50 mmol), pale yellow oil. 1 H NMR (400M Hz,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 (101 MHz, DMSO) δ 156.04,153.16,149.37,140.31,118.89,112. 93,88.54,84.95,83.96,80.02,57.56,48.94,4 5.32, 26.62, 25.34 ppm. LCMS (ESI + ) m / z:C 15 H 19 Calculated value for N5O4 [M+H] + =334.14, actual value 334.10, RT:0. 894 minutes (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, 1.5 equiv) was added at 0° C. The reaction was stirred at 40° C. for 3 hours. Then The reaction mixture was poured into 30 mL of ice water, extracted with 30 mL of dichloromethane, and concentrated under reduced pressure. Condensation gave compound 23. 97% yield (1.8 g, 4.38 mmol), pale yellow oil. 1 H NMR (300 MHz, 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=1 2.8,7.3Hz,1H),1.96(dd,J=12.5,7.1Hz,1H),1 .52(s,3H), 1.42 ppm(s,3H). 13 C NMR (75 MHz, meta Nol-d4)δ 155.85, 152.30, 148.83, 140.71, 119 .06, 113.22, 89.77, 85.02, 84.26, 81.16, 66.42 ,43.35,38.31,36.62,25.40,24.05ppm.LCMS(E SI + ) m / z:C 16 H 21 Calculated value for N5O6S [M+H] + =412.12, Actual measured 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 L), tetrabutylammonium iodide (0.16 g, 0.43 mmol) , 0.10 equiv) and NaN3 (2.8 g, 43.8 mmol, 10.00 equiv) iv) was added at 0° C. The reaction was stirred at 110° C. for 3 hours. The reaction mixture was then cooled to ice Poured into 45 mL of water, extracted with 2 x 50 mL of dichloromethane and concentrated under reduced pressure. The mixture was purified by dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10 The fractions containing the product were collected and the solvent was evaporated. Compound 24 was obtained.

[0343] 70% yield (1.10 g, 8.56 mmol), white solid. 1 H NMR (300M Hz, 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 155.79,1 52.55,148.94,140.72,119.00,112.94,89.48, 86.17, 85.95, 84.09, 50.02, 41.14, 36.21, 25.3 6, 24.01 ppm. LCMS (ESI + ) m / z:C 15 H 18 Total for N8O3 Calculated value [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 The reaction mixture was dissolved in 1 mL of ethanol and Pd / C (0.2 g) was added. The reaction was heated under a hydrogen atmosphere for 1 hour. The mixture was stirred at rt overnight. After completion, the solution was then filtered. The filter cake was washed with MeOH and filtered. The solution was concentrated under reduced pressure. The residue was extracted with dichloromethane / methanol (gradient elution: DCM / Me The product-containing fraction was then loaded onto a silica gel column with HCl (99:1 to 80:20). The 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 (300M Hz, methanol-d4) δ 8.23 ​​(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(d d,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 CNM R(101MHz,methanol-d4)δ 156.02,152.54,148.94 ,141.03,119.01,112.86,89.46,86.35,85.82, 84.14,41.40,40.93,36.98,25.35,23.98ppm.L CMS(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] Compound 25 (0.12 g, 0.36 mmol, 1.00 eq) in MeOH (2 mL) To the mixture was added 2M HCl (2 mL) and the mixture was heated to 40°C for 3 hours. The solution was cooled to room temperature and carefully quenched with NaHCO3 until pH = 7. The mixture was diluted with CH2 Extract with Cl2 (3 x 2 mL), dry the combined organic layers (Na2SO4), filter, and The filtrate was concentrated in vacuo, and the residue was purified by pre-HPLC (column: Atlantis Pr ep T3 OBD column, 19 x 250 mm, 10 μl; Mobile phase A: water (10 mM NH 4HCO3), 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. Got it.

[0347] 76% yield (0.08 g, 0.27 mmol), white solid. 1 H NMR (300M Hz, 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),2.6 0(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). 13C NMR(75 MHz,D2O)δ 155.68,152.99,149.17,140.14,11 9.00, 87.04, 85.03, 75.67, 73.84, 42.36, 40.93 , 38.77 ppm. LCMS (ESI + ) m / z:C 12 H 16 Calculation for N6O3 Value [M+H] + = 293.13, actual value 293.2, RT: 1.346 min, (Method 8)

[0348] Preparation of Compound 27 [ka] Compound 25 (0.10 g, 0.30 mmol, 1.00 eq) in DCM (10 mL) To the solution, AcOH (0.5 mL) was added, followed by propanal (0.026 g, 0.44 m mol, 1.50 eq) was added. The reaction was stirred at rt for 30 min. The solution was then cooled to 0°C. The mixture was cooled to rt. Slowly add NaBH(OAc)3 (0.13 g, 0.62 mmol, 2.0 0 eq) was added and the mixture was stirred at rt for 3 h and concentrated in vacuo. with fluoromethane / methanol (gradient elution: DCM / MeOH 99:1 to 90:10) The fractions containing the product were collected and the solvent was evaporated to give compound 2. I got a 7.

[0349] 62% yield (0.07 g, 0.18 mmol), white solid. 1 H NMR (300M Hz,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=1 5.6Hz,4H),1.42(s,3H),0.86ppm(t,J=7.4Hz,3 H). 13 C NMR(101MHz,D2O)δ 155.60,152.93,14 8.72,140.76,114.02,88.29,85.20,85.11,83. 277,47.02,46.58,37.52,33.78,25.23,24.10, 22.71, 19.04, 10.12 ppm. LCMS (ESI + ) m / z:C 18 H2 Calculated value for 6N6O3 [M+H] + =375.21 Actual value 375.10, RT:1 .285 minutes, (method 3).

[0350] Preparation of Compound 28 [ka] Compound 27 (0.10 g, 0.27 mmol, 1.00 eq) in MeOH (2 mL) 2M HCl (2 mL) was added and the mixture was heated to 40° C. for 3 h. The mixture was cooled to room temperature and carefully quenched with NaHCO3 to pH = 7. The mixture was extracted with 12 (3 x 2 mL) and the combined organic layers were dried (Na2SO4), filtered, and The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis Pre p T3 OBD column, 19 x 250 mm, 10 μl; Mobile phase A: water (10 mM NH4 HCO3), 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. Compound 28 was obtained by this reaction.

[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] + =33 5.18, 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 , 33.6mmol, 2.00equiv), benzoic acid (6.20g, 50.4mmol , 3.00 equiv) was added. Next, DIAD (10.0 g, 50.4 mmol, 3.00 equiv) was added slowly at 0° C. The mixture was stirred at rt for 1 h, then Heat to 50°C for 2 hours, followed by an additional 0.5 eq triphenylphosphine and 1 eq DIAD was added at 0°C and then heated to 50°C for 1 hour. The reaction was cooled to RT. The mixture was added to saturated aqueous NaHCO3 (200 mL) and 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 silica gel column chromatography. Column chromatography (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 (300MH z, chloroform-d) 8.03-7.98(m,2H), 7.59-7.53(m,1 H),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),1.21pp m (s, 9H), 1.20 (s, 9H). LCMS (ESI +) m / z:C 25 H 34 O Calculated value for 8 [M+NH4] + =480.26, Actual value 480.25, RT:1.5 57 minutes, method 7.

[0354] Preparation of Compound 30 [ka] 6-Cl Purine CAS 87-42-3 (1.65g, 10.7mmol, 1.1eq) (uiv) was dissolved in MeCN (35 mL) and N,O-bis(trimethylsilyl)acetate was added. To the mixture was added dropwise methyltrimethylsilane (2.02 g, 9.73 mmol, 1.0 equiv). The mixture was cooled to 0° C. overnight. After cooling, compound 29 (4 0.5g, 9.73mmol, 1.00equiv) was added, and trimethylsilyl trifluoride was added. Add 2.59g of methylmethanesulfonate (11.68mmol, 1.2 equiv) The mixture was then heated to 80° C. for 2 h. After cooling to rt, the mixture was washed with EtOAc for 2 h. The organic layer was extracted twice and washed once with saturated NaHCO3 and saturated aq. NaCl. The residue was dried over O4. The solvent was removed in vacuo. The residue was dissolved in dichloromethane / methanol ( Gradient elution: DCM / MeOH 99:1 to 30:1) on a silica gel column The fractions containing the product 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 (300 M z, 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=5.5H z,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 .13 ppm (s, 9H). LCMS (ESI + ) m / z:C 29 H 33 ClN4O7 Calculated value for [M+H] + =585.20, measured 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-dioxo- The mixture was heated to 80°C and dissolved in ethanol (45 mL) and concentrated aqueous NH3 (11 mL). The mixture was heated at rt 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, then H exchange resin and pH The mixture was stirred until the temperature reached 7°C. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in dichloromethane. The silica gel was then washed with ethanol / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 31. Got it.

[0357] 95% yield (2.05 g, 7.00 mmol), white solid. 1H NMR (300M Hz, 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 2,2-dimethoxypropane (1.40 g, 13.6 mmol, 2 mL) 0.00 equiv) and perchloric acid (0.13 g, 1.36 mmol, 0.20 equiv ) was added at 0° C. The reaction was stirred at RT for 1 h. The reaction was then diluted with 1M NaOH The resulting solution was quenched with aqueous solution until pH = 7. 60 mL of DCM was added. The mixture was extracted with 1×60 mL of H2O and the organic layers were combined. The residue was extracted with dichloromethane / methanol (gradient elution: DCM / MeOH 99:1 to 85:15) and then loaded onto a silica gel column. The corresponding 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 (400 MHz, methanol-d4) δ 8.23 ​​(d, J = 5.3 Hz, 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),2.46(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, 148.96,141.07,118.94,89.43,86.57,85.45,8 3.97, 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) was added at 0°C. The reaction was stirred at 40°C for 3 h. The reaction mixture was poured into 30 mL of ice water, extracted with 1 x 20 mL of dichloromethane, and Concentration at rt gave compound 33.

[0361] 81% yield (1.00 g, 2.43 mmol), white solid. 1 H NMR (400M Hz, methanol-d4) δ 8.20 (d, J = 7.4 Hz, 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,1 H),1.50(s,3H),1.42ppm(s,3H).LCMS(ESI + )m / z:C 16 H 21 Calculated value for N5O6S [M+H] + =412.12, measured value 412 .15, RT: 1.190 minutes, 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 0.10 equiv) and NaN3 (474 ​​mg, 7.3 mmol, 10.00 equiv ) was added at 0°C. The reaction was stirred at 110°C for 3 h. The reaction was then diluted with 4 mL of ice water. The mixture was poured into a glass flask, extracted with 2 x 5 mL of dichloromethane, and concentrated under reduced pressure. The silica gel was then washed with ethanol / methanol (gradient elution: DCM / MeOH 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 34. Got it.

[0363] 76% yield (200 mg, 0.56 mmol), white solid. 1 H NMR (300M Hz, methanol-d4) δ 8.20 (d, J = 8.1 Hz, 2H), 6.12 (s, 1H),5.78(dd,J=5.8,1.1Hz,1H),5.07(d,J=5.8 Hz,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,3 H), 1.02 ppm (t, J = 7.3 Hz, 1 H). 13 C NMR (75 MHz, Alcohol-d4) δ 156.01, 152.52, 148.89, 140.57, 11 9.03, 113.13, 89.70, 85.01, 84.15, 81.69, 46.5 2,41.64,36.43,25.39,24.04,12.46ppm.LCMS( ESI + ) 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 then concentrated under reduced pressure. The residue was extracted with dichloromethane / methanol (gradient elution: DCM / MeOH 99 The product was collected and the fractions were then run on a silica gel column. The solvent was evaporated to give compound 35.

[0365] 70% yield (130 mg, 0.39 mmol), white solid. 1 H NMR (300M Hz, methanol-d4) δ 8.20 (d, J = 1.9 Hz, 2H), 6.11 (s, 1H),5.78(dd,J=5.8,1.0Hz,1H),5.03(d,J=5.8 Hz,1H),3.14(p,J=7.9Hz,1H),2.91(dt,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),1.4 2 ppm (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 N6O3 Calculated value for [M+H] + =333.16, actual value 333.05, RT: 0.966 min, Method 3.

[0366] Preparation of Compound 36 [ka] Compound 35 (155 mg, 0.470 mmol, 1.00 eq) in MeOH (2 mL) ) was added 2M HCl (2 mL) and the mixture was heated to 40 °C for 3 h. The solution was cooled to room temperature and carefully quenched with NaHCO3 until pH = 7. Extract with CH2Cl2 (3 x 2 mL), dry the combined organic layers (Na2SO4), and filter. The residue was purified by Pre-HPLC (column: Atlantis Prep T3 OBD column, 19 x 250 mm, 10 μl; Mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B in 7 min The product was purified by elution with 210 / 254 nm elution to 12% B. The fractions containing the product were collected and Evaporation of the solvent gave compound 36.

[0367] 37% yield (50 mg, 0.17 mmol), white solid. 1 H NMR (400MH z,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,2 H),4.98(dd,J=7.1,4.1Hz,1H),3.86(d,J=4.0H z,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 CN MR(101MHz,DMSO)δ 156.50,153.01,150.25,14 0.36, 119.77, 86.96, 79.77, 75.28, 73.34, 49.0 6, 46.93, 41.66 ppm. LCMS (ESI + ) m / z:C 12 H16 NO Calculated value for 3 [M+H] + =293.13, Actual value 293.20, RT: 0.948 minutes, method 2.

[0368] Preparation of Compound 37 [ka] Compound 33 (190 mg, 0.46 mmol, 1.00 eq) was dissolved in n-PrNH2 (2m L) and the mixture was heated to 90°C for 48 hours. After that, the solution was cooled to room temperature. Then, Prep-HPLC (column: Atlantis Prep T3 OBD column, 19×250mm 10u; Mobile phase A: Water (10mM NH4HCO3), Mobile phase B: A CN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm) The fractions containing the product were collected and the solvent was evaporated to give compound 37.

[0369] 68% yield (130 mg, 0.35 mmol), white solid. 1 H NMR (300M Hz, methanol-d4) δ 8.21 (d, J = 2.1 Hz, 2H), 6.14 (s, 1H),5.80(dd,J=5.9,1.0Hz,1H),5.13(d,J=5.8 Hz,1H),2.99(dt,J=13.0,6.3Hz,1H),2.92-2.8 3(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=7.5H z,3H). 13C NMR (75 MHz, methanol-d4) δ 165.19,15 2.54, 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 minutes, Method: 3.

[0370] Preparation of Compound 38 [ka] Compound 37 (130 mg, 0.35 mmol, 1.00 eq) in MeOH (2 mL) 2M HCl (2 mL) was added and the mixture was heated to 40°C for 3 h. It was cooled to room temperature and carefully quenched with NaHCO3 until pH = 7. The mixture was then diluted with CH The combined organic layers were dried (Na2SO4), filtered, and the resulting mixture was extracted with 20 mL of HCl (3 x 2 mL). The filtrate was concentrated in vacuo. The residue was purified by pre-HPLC (column: Atlantis P rep T3 OBD column, 19 x 250 mm, 10 μl; Mobile phase A: water (10 mM N H4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min The product was purified by HPLC (210 / 254 nm). The fractions containing the product were collected and the solvent was removed. Evaporation gave compound 38.

[0371] 34% yield (40 mg, 0.12 mmol), white solid. 1 H NMR (400MH z, methanol-d4) δ 8.22 (d, J = 5.5 Hz, 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,2 H),2.66(dt,J=12.2,6.2Hz,1H),2.51(t,J=7.5 Hz,2H),2.14(dd,J=11.8,7.5Hz,1H),2.05-1.9 0(m,1H),1.52(h,J=7.4Hz,2H),0.95ppm(t,J=7 .4Hz,3H). 13 C NMR (101 MHz, methanol-d4) δ 155.9 1,152.42,149.56,140.10,119.29,88.01,80.7 2, 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 For N6O3 Calculated value [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 placed in a two-mouthed bowl containing demineralized water (100 mL). The solution was degassed with nitrogen for 15 minutes. Then, copper sulfate ( II) (1.85 g, 11.5 mmol) was 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 vacuum for 12 hours. CAS 6991-65- Dissolve 7 (5.00 g, 26.9 mmol, 1.00 eq) in anhydrous EtO (150 mL, 4 Å The solution was dried by passing it over molecular sieves and then flame-dried under an inert argon atmosphere. To the zinc-copper couple (12.2 g, 186 mmol, 7.00 eq) in the flask Then, trichloroacetyl chloride (4.29 mL, 37.7 mmol, 1.40 A solution of 1 eq) in anhydrous EtO (30 mL) was 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. The organic phase was washed with pentane / Et2O (100 mL). Washed with water (3 x 150 mL) and brine (3 x 100 mL), dried (MgSO4), Filtration and concentration of the filtrate in vacuo gave 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),1.34pp m(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 .5,25.5 ppm.

[0374] Preparation of Compound 93 [ka] Compound 67.1 (63 g, 212.83 mmol, 1.00 eq) was dissolved in THF (630 m L), and then NaBH4 (16.2 g, 426 mmol, 2.00 eq) was added. The mixture was stirred at 0° C. for 30 min, then added with saturated aqueous NH4Cl ( The product was extracted with EtOAc (3 x 1000 mL) and combined. The organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by PE Silica gel column with PE / EtOAc (gradient elution: PE / EtOAc 99:1 to 70 The product-containing fractions were collected and the solvent was evaporated to give compound 93. obtained.

[0375] 72% yield (45 g, 151.00 mmol), pale yellow oil. 1 H NMR (300M Hz, chloroform-d) δ 4.99 (d, J = 5.7 Hz, 1H), 4.95 (s, 1H),4.68(d,J=5.8Hz,1H),4.21(dd,J=9.7,8.0 Hz,1H),3.53(s,3H),2.89(dd,J=11.8,8.0Hz,1 H),2.16(dd,J=11.8,9.7Hz,1H),1.44(s,3H),1 .36 ppm(s,3H). 13 C NMR (75 MHz, 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) in CHCl (450 mL) Then pyridine (35.8 g, 453.16 mmol, 3.00 eq) and and TfO (51.1 g, 181 mmol, 1.20 eq) were added at 0 °C. The mixture was stirred at 0°C for 1 hour. The mixture was added to saturated aqueous NaHCO3 solution (500 mL) at 0°C. The organic phase was dried over Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue (45 g, crude) was dissolved in AcOH:MeOH (1 :1, 20V) and dissolved in zinc (136 g, 2092.30 mmol, 20.0 e q) was added. The mixture was stirred at 60 °C for 16 h. The residue was dissolved in saturated NaHCO3 Add to aqueous solution (500 mL), filter off the solid, and extract the aqueous phase with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Column chromatography (gradient elution: PE / EtOAc 99:1 to 20:1) The fractions containing the product were collected and the solvent was evaporated to give compound 94.

[0377] 69% yield (25.5 g, 217 mmol, 2 steps). 1 H NMR (300 MHz, Chloroform-d) δ 6.17 (t, J = 1.1 Hz, 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 133.0,132.3,1 12.5, 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). m-CPBA (52.0 g, 302 mmol, 3.00 eq) was added at 0°C. The mixture was stirred at 40° C. for 16 hours. After the mixture was cooled, the solid was removed by filtration. iPrOH (250 mL), followed by NaBH3CN (12.8 g, 203 mmol, 2. 00 eq) was added at 0° C. The mixture was stirred at 60° C. for 2 hours. The mixture was cooled to room temperature. After that, the residue was added to saturated aqueous NaHCO3 solution and the aqueous layer was extracted with EtOAc (3 x 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 9 The product-containing fractions were collected and the solvent was evaporated. Compound 95a was obtained.

[0379] 52% yield (12.1 g, 52.6 mmol, 2 steps), colorless oil. 1 H NMR(4 00MHz, 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),2.21-2.09(m,2H),1.74(td,J=1 1.3,8.9Hz,1H),1.67-1.56(m,1H),1.43(s,3H) ,1.35ppm(s,3H). 13 C NMR (75 MHz, DMSO) δ 111. 5,107.3,91.0,85.1,78.1,73.9,54.5,26.7,25 .5,23.4,20.0 ppm.

[0380] Preparation of Compound 96 [ka] Compound 95a (300mg, 1.30mmol, 1.00eq) in DCM (3mL) 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 hours. The reaction was diluted with saturated aqueous NaSO (20 mL ) and saturated aqueous NaHCO3 (20 mL), followed by E The organic phase was dried over Na2SO4, filtered, and The solution was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution) with PE / EtOAc. The product-containing fractions were purified by elution with hexane (PE / EtOAc 99:1 to 90:10). After recovery and removal of the solvent in vacuo, compound 96 was obtained.

[0381] 63% yield (187 mg, 0.82 mmol), white solid. 1 H NMR (300M Hz, 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),2.64(ddd,J=12.2,10.6,6.0Hz,1H) ,2.15(dt,J=12.1,10.4Hz,1H),1.37(s,3H),1. 34 ppm (s, 3H). 13 C NMR (75 MHz, CDCl) δ 206.2 113.1, 107.1, 101.6, 85.0, 79.0, 54.9, 39.5, 26 .3,25.4,20.0 ppm.

[0382] Preparation of Compound 97a [ka] Compound 95a (12.0g, 52.2mmol, 1.00eq), DMAP (5.79 g, 26.1 mmol, 0.50 eq) was dissolved in pyridine (120 mL), and then Benzoyl chloride (14.6 g, 104 mmol, 2.00 eq) was added dropwise at 0°C, and the resulting The resulting solution was stirred at 0° C. for 1 h. The reaction was then treated with HCl (1 M, aqueous, 20 mL) and The product was extracted with EtOAc (3 x 200 mL) and combined. The combined organic layer was dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. Silica gel column with PE / EtOAc (gradient elution: PE / EtOAc 99:1-8 The product-containing fractions were collected, the solvent was removed in vacuo, and the product was purified by HPLC. Compound 97a was obtained.

[0383] 79% yield (13.7 g, 41.0 mmol), colorless oil. 1 H NMR (300 M z, 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),5.2 1(d,J=5.8Hz,1H),4.86(s,1H),4.62(d,J=5.9H z,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),1.44 ppm(s,3H). 13 C NMR (75 MHz, CDCl3) δ 165.1,13 0.2, 132.9, 129.5, 128.4, 112.4, 107.7, 89.0, 8 5.2,78.7,74.3,55.0,26.4,25.6,22.0,20.8pp m.

[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 (2M, aq. 70 mL) was added. The mixture was heated to 35°C for 16 minutes. The solution was then cooled to room temperature and concentrated in vacuo to give 12 g The crude compound 98a was obtained.

[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 hours, then poured into ice-cold water (200 mL) and cooled to room temperature. The crude mixture was extracted with CH2Cl2 (3 x 200 mL) and the combined The organic layer was washed with brine (3 x 200 mL), dried (Na2SO4), filtered, and the filtrate The residue was purified by silica gel chromatography (gradient elution: PE / EA). The product-containing fractions were combined and the solvent was removed in vacuo. This was removed to give compound 98a.

[0386] 40% yield (3.10 g, 8.20 mmol, 2 steps), yellow oil. 1 H NMR(3 00MHz, 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. 8,3.0Hz,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 CN MR(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 N,O-bis(trimethylsilyl)acetamide (1.65 g, 8 mL) was dissolved in 10 mL of acetamide. The mixture was heated to 80°C for 16 hours. The mixture was cooled to room temperature and then dissolved in compound 98a (3.10 g, 8. 20 mmol, 1.00 eq), followed by trimethylsilyl trifluoromethanesulfonate Add 2.15 g (9.68 mmol, 1.20 eq) of acetone and heat the mixture to 80 °C for 2 hours. The mixture was cooled to room temperature, diluted with EtOAc (50 mL), and saturated NaHC1 The organic layer was washed with 03 (3 x 50 mL) and saturated aqueous NaCl (3 x 50 mL). The residue was dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. Silica gel column chromatography (gradient elution: PE / EtOAc 99: The product-containing fractions were collected and the solvent was removed in vacuo. Compound 99a was obtained.

[0388] 57% yield (2.30 g, 4.60 mmol), white solid. 1 H NMR (400M Hz, 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=7.7 Hz,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 -1.73 ppm (m, 1H). 13 C NMR (75 MHz, MeOD) δ 170. 2,169.8,165.6,151.3,151.1,150.4,146.6,13 3.3, 132.1, 129.7, 129.5, 128.4, 88.4, 86.4, 73 .9,72.6,70.8,22.0,20.3,19.0,18.8ppm.LCMS (ESI+) m / z: calculated for C23H21ClN4O7 [M+H]+ = 501. 11, Actual value 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 at 80°C. The mixture was cooled to room temperature, and the solvent was removed in vacuo to give the product. 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 The mixture was stirred with cellulose (CAS: 78922-04-0) for 30 minutes until the pH reached 7. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by dichloromethane / methanol Silica gel column chromatography (gradient elution: DCM / MeOH 99:1 to 5: The product-containing fractions were collected and the solvent was removed in vacuo to give compound 1. I got 00a.

[0390] 43% yield (30 mg, 0.10 mmol), white solid. 1 H NMR (400MH z, methanol-d4) δ 8.27(s,1H), 8.22(s,1H), 5.98( d,J=7.1Hz,1H),5.02(dd,J=7.1,4.4Hz,1H),4. 42(d,J=4.4Hz,1H),4.17(t,J=8.7Hz,1H),2.37 -2.29(m,1H),2.10-2.01(m,1H),1.62-1.44(m, 2H). 13 C 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, 20.1 ppm. LCMS (ESI + ) m / z:C 12 H 15 For N5O4 Calculated value [M+H]+ = 294.11, measured value 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) in DCM (50 mL) m-CPBA (10.4 g, 60.5 mmol, 3.00 eq) was then dissolved in 0 The mixture was stirred at 40°C for 16 hours. After the mixture was cooled to room temperature, the solid was removed by filtration and added iPrOH (50 mL) and NaBH3CN (2.6 g, 40.6 3 mmol, 2.00 eq) was added at 0°C. The mixture was stirred at 60°C for 2 hours. After cooling to room temperature, the residue was added to saturated aqueous NaHCO3 solution and the aqueous layer was extracted with EtOAc ( The combined organic fractions were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient). The product was purified by gradient elution (PE / EtOAc 99:1 to 95:5). The fractions were collected, the solvent was removed in vacuo, and Compound 95a and Compound 95b were obtained in an amount of 44 It was obtained as a mixture of 56:

[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) was dissolved in pyridine (20 mL) and then Benzoyl (2.5 mg, 17.9 mmol, 2.00 eq) was added dropwise at 0°C, and the resulting solution The mixture was stirred at 0° C. for 1 hour. Then, HCl (aqueous, 1 M) was added to the reaction mixture until the pH was <7. To the resulting solution was added DCM (200 mL) and H2O (200 mL). The product was extracted with DCM (3 x 200 mL) and the combined organic layers were dried (MgS The residue was purified by Pre-HPLC (column: C18 column). ram, 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 The fractions containing the product were collected and the solvent was evaporated to give compound 97a. and compound 97b was obtained.

[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, 2 H),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 (75 MHz, CDCl3 )δ 166.2,132.8,130.3,129.6,128.2,112.2,1 09.4,92.5,85.4,84.2,72.9,55.8,26.4,25.3, 24.6, 23.8 ppm.

[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) in MeOH (8 mL) The mixture was heated to 35°C for 16 hours. The solution was then cooled to room temperature, and the filtrate was concentrated in vacuo. The residue (700 mg) was The mixture was dissolved in water and pyridine (7 mL) and stirred for 30 minutes. Acetic anhydride (364 mg, 3.5 6 mmol, 1.5 eq) was added to the stirred solution at room temperature. The mixture was stirred at room temperature for 3 hours. The mixture was then poured into ice-cold water (30 mL) and stirred at room temperature for 30 minutes. The extract was extracted with CH2Cl2 (3 × 30 mL) and the combined organic layers were washed with brine (3 × 200 mL ), dried over Na2SO4, concentrated and purified by silica chromatography (gradient elution) The product was purified by PE / EA (100:1 to 10:1). The fractions containing the product were combined. The solvent was then removed in vacuo to give compound 98b.

[0397] 43% yield (2 steps, 390 mg, 1.03 mmol), yellow oil. 1 H NMR(3 00MHz, 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=4.9,2.2 Hz,1H),4.96(d,J=2.2Hz,1H),3.14(s,3H),2.4 3-2.28(m,2H),2.22-2.15(m,2H),2.13(s,3H), 2.06 ppm(s,3H). 13 C NMR (75 MHz, CDCl3) δ 169. 7,169.4,165.8,132.9,130.0,129.7,128.3,10 5.9, 88.9, 75.5, 74.1, 71.5, 55.7, 25.4, 24.1, 2 2.8, 20.5 ppm.

[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 and the mixture was heated to 80° C. for 16 h. After the mixture was cooled, compound 98b (390 mg, 1.03 mL) in MeCN (2.8 mL) was dissolved in mmol, 1.00 eq) was added and trimethylsilyl trifluoromethanesulfonate was added. (272 mg, 1.22 mmol, 1.20 eq) was added and the mixture was heated to 80 °C for 2 h. After cooling to room temperature, the mixture was diluted with EtOAc and saturated NaHCO3 and saturated The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EA 9 The product was purified by ethanol (9:1 to 4:1). The fractions containing the product were collected and the solvent was evaporated to give the desired product. Compound 99b was obtained.

[0399] 57% yield (294 mg, 0.58 mmol), white solid. 1 H NMR (300M Hz, 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=7.7 Hz,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), 2.02 ppm(s,3H). 13 C NMR (101 MHz, CDCl3) δ 169 .7,169.1,166.8,152.2,152.0,151.2,143.6,1 33.7, 131.8, 129.6, 128.7, 128.6, 87.2, 84.2, 7 4.2,73.3,72.1,27.2,21.8,20.6,20.3ppm.LCM S(ESI+)m / z:C 23 H 21 Calculated for ClN4O7 [M+H]+ = 501 .11, actual measured value 501.10, RT: 1.767 minutes (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 0° C. for 16 hours. After cooling to room temperature, the solvent was removed in vacuo. The product was purified by Me OH (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 hydrogen chloride until pH=7. The mixture was stirred with exchange resin (CAS: 78922-04-0) for 30 minutes. The solid was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient elution) The product was purified by distillation with DCM / MeOH 99:1 to 5:1. The fractions containing the product were collected. The solvent was evaporated to give compound 100b.

[0401] 30% yield (23 mg, 0.07 mmol), white solid. 1 H NMR (400MH z, 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=4.1H z,1H),2.39-2.31(m,1H),2.14-2.03(m,2H),1. 94-1.83 ppm (m, 1H). 13 C NMR (101MHz, MeOD) δ 1 56.2, 152.2, 148.7, 140.7, 119.6, 89.6, 89.1, 7 4.6,74.1,72.1,24.4,24.3ppm.LCMS(ESI + ) m / z :C 12 H 15 Calculated value for N5O4 [M+H]+ = 294.11, found value 294.0 0, RT: 0.660 minutes (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) was dissolved in EtOH (625 mL) under a nitrogen atmosphere. The mixture was heated at room temperature The mixture was stirred at RT and flushed with nitrogen gas for 15 minutes. ,6A-Dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4 -one (25.0 g, 162.16 mmol, 1.00 eq) and potassium vinyl triflate Fluoroborate (45.7 g, 324 mmol, 2.00 eq) was added and the reaction mixture was The mixture was stirred and refluxed for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was collected by Cel The filtrate was filtered off on a pad of methylcellulose and washed with ethanol. The filtrate was evaporated and washed with n-heptane. was added to the residue and the resulting suspension was filtered through a pad of Celite and separated with heptane The filtrate was washed with NH4OH (3 x 300 mL) to give a dark brown solid residue. Washed with HCl, washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give compound Product 39 (16.2 g, 51% crude yield) was obtained.

[0403] Preparation of Compound 40 [ka] Compound 39 (16.2 g, 82.6 mmol, 1.00 eq) in THF (200 mL) The solution was heated at −78°C under a nitrogen atmosphere with lithium aluminum hydride (24.8 mL, TH Add dropwise to a stirred solution of 1M in F, 24.8 mmol, 0.30 eq) in THF (400 mL) The reaction mixture was stirred under nitrogen at -78°C for 30 minutes. The reaction mixture was quenched by dropwise addition of ethanol (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 organic layer was separated, washed three times with water, washed with brine, dried (MgS O4), filtered, and the filtrate was evaporated. The residue was purified by column chromatography on silica gel. The product was purified by elution with n-heptane / EtOAc (gradient elution: n-heptane / EtOAc 1:0 to 1:1). The containing fractions were collected and the solvent was evaporated to give the desired compound 40 (10.7 g, 71% yield). obtained.

[0404] Preparation of Compound 41 [ka] Compound 40 (3.10 g, 16.6 mmol, 1.00 eq) was dissolved in pyridine (10.3 m L), and tert-butyldimethylsilyl chloride (2.88 g, 19.1 m mol, 1.15 eq) was added in small portions at room temperature. The mixture was stirred at room temperature for 17 hours, and E The organic layer was washed with brine (4 x 80 mL) and dried. The residue was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The resulting mixture was purified by column chromatography (gradient elution: n-heptane / EtOAc 1:0 to 7:3). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 41 (3. 15 g, 63% yield, was obtained 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 CH₂Cl₂ (40 The mixture was cooled to -78°C. Ozone was generated using an ozone generator (F Generated from oxygen gas using a bischer OZ500 / 5) and passed through a glass pipette After 1.5 hours, a blue color was observed and the solution was left to bubble in the cooled solution for an additional 20 minutes at -78°C. The mixture was then flushed with nitrogen for 5 minutes (the blue color disappeared), and dimethyl sulfoxide was added. The solution was cooled to -78°C and then cooled to -78°C. The gas flow was stopped and the mixture was stirred for 1 hour while the temperature was raised to -40°C. Concentrate in vacuo at 30°C to a small volume and dilute the resulting yellow oil with methanol (220 mL) and The solution was cooled to 0°C and redissolved in water (110 mL). (19.8 g, 526 mmol, 12.0 eq) was added in small portions. After 1.5 hours, ice The bath was removed and stirring was continued at room temperature. After stirring for 4 h, the mixture was diluted with CH2Cl2 (35 The product was diluted in 100 mL of HCl (aq. sat. 150 mL) and NH4Cl (aq. sat. 150 mL) was added. Extracted into H2Cl2 (3 x 350 mL) and the combined organic layers were dried (MgSO4) After filtration, the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel. The product was purified by gradient elution (n-heptane / EtOAc 1:0 to 0:1). The fractions containing 42 were collected and the solvent was evaporated to give the desired compound 42 (8.30 g, 63% yield). Obtained 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 ,8.2Hz,1H),1.86(br s,1H),1.57-1.66(m,1H) ,1.49(s,3H),1.31(s,3H),0.91(s,9H),0.09pp m(d,J=2.9Hz,6H) 13 C 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 0.4,-4.5ppm

[0407] Preparation of compound 43 [ka] Compound 42 [CAS:514206-18-9] (8.30g, 27.4mmol, 1 Imidazole (4.67 g, 68 eq) was dissolved in THF (140 mL). 0.6mmol, 2.50eq) and triphenylphosphine (8.03g, 29.1mmol ol, 1.05 eq) was added, followed by addition of iodine (8.79 g, 34.3 mmol, 1.25 eq) was added in small portions. After 1 h, an additional amount of triphenylphosphine (2. 29g, 8.31mmol, 0.30eq) and iodine (2.46g, 9.60mmol , 0.35 eq) was added. The reaction was allowed to continue for 2 hours, and then the mixture was reduced to a minimum volume in vacuo. The mixture was concentrated to rt and n-heptane (400 mL) was added. The organic layer was separated by filtration and the solid was removed. The filtrate was rinsed with n-heptane (100 mL). 150 mL) was added and the product was extracted into n-heptane (3 x 400 mL). The combined organic fractions were dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give Compound 43 (9.84 g, calculated yield by HNMR: 87%) was obtained as a colorless oil.

[0408] 1 H NMR (400 MHz, 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),2.22-2.38(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) in THF (168 mL) Dissolve 1,8-diazabicyclo[5.4.0]undec-7-ene (5.35m L, 35.8 mmol, 1.50 eq) was added. The mixture was heated to 65°C for 2.5 hours. The precipitated DBU-salt was filtered and rinsed with THF. The mixture was concentrated in vacuo to a minimum volume. Then, n-heptane (400 mL) and brine ( 100 mL) was added and the product was extracted into n-heptane (3 x 400 mL). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was evaporated on silica gel. Column chromatography on gel (gradient elution: n-heptane / EtOAc 1:0 to The fractions containing the product were collected, the solvent was evaporated and the desired compound was obtained. Product 44 (6.00 g, 77% yield over two steps) was obtained as a colorless liquid.

[0410] 1 H NMR (400 MHz, chloroform-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),1.3 5(s,3H),0.92(s,9H),0.11ppm(d,J=2.8Hz,6H) 13 C NMR (101 MHz, chloroform-d): δ = 145.6, 113.6, 1 11.2, 80.8, 80.4, 72.3, 37.5, 26.4, 26.0, 24.7, 18.4,-4.5ppm

[0411] Preparation of Compound 45 [ka] Zinc powder (25.0 g, 0.38 mol, 1.00 eq) was dissolved in demineralized water (100 mL). The solution was degassed with nitrogen for 15 minutes. Then, copper(II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was added and the mixture was stirred. The solution was degassed and stirred for 45 minutes. The mixture was filtered and the black solid was removed by degassing. The zinc-copper couple was washed with degassed water (250 mL) and degassed acetone (250 mL). After drying in air for 12 hours, compound 44 (2.50 g, 8.79 mmol, 1.00 eq) was obtained. ) was dissolved in anhydrous Et2O (70 mL, dried over 4 Å molecular sieves). Then, zinc-copper couple (7.93 g, 61.5 mmol, 7.00 eq) was added. Trichloroacetyl chloride (2.94 mL, 26.4 mmol, 3.00 eq) was placed on a glass silica gel The solution was dissolved in anhydrous Et2O (20 mL) in a syringe and added at a rate of 6.5 mL / h at room temperature. After 3 hours, the zinc-copper couple was removed by decantation and the organic layer was Diluted in Et2O (500 mL), NaHCO3 (aq. sat. 3 × 150 mL) and Wash with water and brine (3 x 150 mL), dry (MgSO4), filter, and evaporate the filtrate in vacuo Concentration in the filtrate gave compound 45 (3.36 g, crude).

[0412] 1 H NMR (400 MHz, 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,6 H) 13 C NMR (101 MHz, chloroform-d): δ = 191.8, 112.3, 8 0.7,80.1,71.5,51.7,26.1,25.9,18.4,-4.6,- 4.9 ppm

[0413] Preparation of Compound 46 [ka] Compound 45 (1.25g, 3.16mmol, 1.00eq) in THF (30mL) Dissolve zinc (2.07 g, 31.6 mmol, 10.0 eq) and acetic acid (1.45 mL, 25.3 mmol, 8.00 eq) was added. The mixture was heated to 70 °C for 6 h. The mixture was filtered through Celite, the solids were rinsed with THF, and the filtered The solution was concentrated in vacuo to a minimum volume. The oil was then redissolved in CH2Cl2 (100 mL). The mixture was dissolved in CH2Cl2 (3 x 100 mL) and brine (50 mL) was added. The combined organic fractions were dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / E The product was purified by distillation of the solvent. Evaporation afforded the desired compound 46 (0.648 g, 63% yield over two steps) as a colorless oil. Got it.

[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=10.9,5.3H z,1H),3.36(ddd,J=18.3,4.1,2.4Hz,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, 8 5.2, 80.2, 72.3, 56.7, 52.8, 41.3, 34.4, 26.0, 2 6.0, 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 as intermediate 44 ) was dissolved in methanol (20.0 mL) and cooled to 0°C. Aluminium (282 mg, 7.35 mmol, 4.00 eq) was added in small portions and the mixture was heated to 0°C. The solution was concentrated in vacuo to a minimum volume and dissolved in CH2Cl2 (100 mL). The product was dissolved in HCl and NH4Cl (sat. aq. 50 mL) was added. (3 x 100 mL), and the combined organic layers were dried (MgSO4), filtered, and The solution was concentrated in vacuo to give compound 47 (515 mg, 85% yield), also labeled as intermediate 45. ) was obtained 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. Cool to rt and add potassium tert-butoxide (3.98 mL, 1 M in THF, 3.98 m mol, 1.30 eq) was added dropwise. The mixture was stirred at 0°C for 20 minutes. Compound 46 (1.00 g, 3.06 mmHg) dissolved in THF (12.0 mL) at 0° C. To the resulting solution (1.00 eq) was added dropwise the freshly prepared Wittig reagent. The mixture was stirred at 0° C. for 1.5 hours and then at room temperature for 1.5 hours. The mixture was concentrated in vacuo to a minimum volume. The mixture was concentrated and redissolved in n-heptane (300 mL). The solution was allowed to settle, the mixture was sonicated for 5 min, filtered, and the filtrate was diluted with NH4Cl (aq. sat. The organic layer was washed with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried (MgSO 4) The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel. The product was purified by filtration (gradient elution: n-heptane / EtOAc 1:0 to 7:3). Fractions containing the compound were collected and the solvent was evaporated to give the desired compound 48 (931 mg, 94% yield). rate).

[0417] 1 H NMR (400 MHz, chloroform-d): δ = 4.81 (quin, J = 2. 4Hz,1H),4.78(quin,J=2.4Hz,1H),4.40(t,J=5 .1Hz,1H),4.26(dd,J=5.5,0.9Hz,1H),3.80(dt ,J=11.2,5.5Hz,1H),2.87(dd,J=16.1,2.2Hz,1 H),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 ), 0.10 ppm (d, J = 2.2 Hz, 6 H) 13 C NMR (101 MHz, chloroform-d): δ = 144.7, 110.4, 1 06.8,85.3,79.9,72.0,42.5,41.2,39.2,36.8, 26.0,26.0,24.5,18.4,-4.4,-4.6ppm

[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 The mixture was stirred at room temperature for 3 hours. Concentrate to a minimum volume in air, dissolve in EtOAc (250 mL), and add NH4Cl(aq The organic layer was dried and washed with HCl (3×50 mL) and brine (3×50 mL). (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel. Purification by chromatography (gradient elution: n-heptane / EtOAc 1:0 to 0:1) The fractions containing the product were collected and the solvent was evaporated to give the desired compound 49 (556 mg). , 92% yield).

[0419] 1 H NMR (400 MHz, 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),2.3 8-2.46(m,2H),2.27-2.38(m,1H),1.97(dd,J=1 2.0,5.9Hz,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, 1 07.2,85.4,78.7,70.8,41.7,41.2,39.5,36.6, 25.9, 24.3 ppm

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

[0421] Compound 49 (647 mg, 3.08 mmol, 1.00 eq) was dissolved in anhydrous CHCl (2 0.0 mL) and dissolved in pyridine (0.62 mL, 7.69 mmol, 2.50 eq The mixture was cooled to 0°C and trifluoromethanesulfonic anhydride (0.5 7 mL, 3.39 mmol, 1.10 eq) was added dropwise. The mixture was stirred at 0°C for 30 min. , diluted in CH2Cl2 (100 mL) and added NaHCO3 (aq. sat. 40 mL) The product was extracted into CH2Cl2 (3 x 100 mL) and the combined organic layers were dried. (MgSO4), filtered, and the filtrate was concentrated in vacuo and used immediately in the procedure.

[0422] Potassium 6-chloro-7-deazapurine (5.90 g, 30.8 mmol, 10.0 e q) was dissolved in anhydrous DMF (35.0 mL) and stirred at 0° C. for 30 minutes. The crude triflate (1.0 mL) was dissolved in anhydrous DMF (8.00 mL) at 4° C. for 15 min. The mixture was stirred at 0°C for 2 hours, and then The mixture was then warmed to room temperature and stirred for an additional 2 hours. The combined organic layers were poured into EtOAc (3×100 mL) and the product was extracted with EtOAc (3×100 mL). Wash with lye (3 x 100 mL), dry (MgSO4), filter, and concentrate in vacuo Concentrated to a minimum volume. To the resulting powder, n-heptane (100 mL) was added and the mixture 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- Purification was carried out with heptane / EtOAc (1:0 to 0:1). The fractions containing the product were collected. The solvent was evaporated to give the desired compound 50 (856 mg, 80% over two steps).

[0423] 1H NMR (400 MHz, 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=18.2,2.4Hz,2H),4.69 (d,J=6.5Hz,1H),3.18(dd,J=15.5,2.4Hz,1H), 2.75(dd,J=15.3,2.6Hz,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, 1 43.4, 127.5, 117.9, 112.7, 107.0, 99.8, 85.7, 8 4.9,61.5,43.0,42.3,42.2,38.3,26.6,24.7pp m

[0424] Preparation of Compound 51 [ka] Compound 50 (850 mg, 2.46 mmol, 1.00 eq) was dissolved in 1,4-dioxane ( 20.0 mL) and NH3 (60.0 mL, 25% in H2O) was added. The mixture was heated to 100°C in a pressure reactor for 24 hours. The mixture was reduced to a minimum volume under vacuum. The mixture was concentrated and coevaporated twice with toluene. The residue was purified by column chromatography on silica gel. Purification was carried out by gradient elution (CH2Cl2 / MeOH 1:0 to 7:3). The corresponding fractions were collected and the solvent was evaporated to give the desired compound 51 (790 mg, 98% yield). Ta.

[0425] 1 H NMR (400 MHz, chloroform-d): δ = 8.33 (s, 1H), 6.8 9(d,J=3.7Hz,1H),6.35(d,J=3.5Hz,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, 1 50.5,143.8,123.0,112.4,106.8,103.5,97.6, 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] Compound 51 (255 mg, 0.78 mmol, 1.00 eq) was reacted with 9-borabicyclo[ 3.3.1] Nonane (7.81 mL, 0.5 M in THF, 3.91 mL, 5.00 eq) was added and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 0°C and added with NaOH (7.8 1 mL of 1 M in HO, 7.81 mmol, 10.0 eq) was added, followed by hydrogen peroxide. (1.99 mL, 30% in H2O, 19.5 mmol, 25.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 h, then diluted in CH2Cl2 (250 mL) and added NaHCO3 The organic layer was washed with aqueous saturated sodium chloride (3 x 50 mL) and brine (1 x 50 mL). The residue was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. Purification by chromatography (gradient elution: CH2Cl2 / MeOH 1:0 to 7:3) The fractions containing the product were collected and the solvent was evaporated to give compound 52 (213 mg, 79 % yield) as a 1:1 mixture of diastereoisomers. SFC (stationary phase: Chiralpak Diacel OJ 20×250mm, moving Purification was carried out using a 2000 ml solution of 100% iPrNH2 (phase: CO2, EtOH + 0.4% iPrNH2) to give compound 52a ( Compound 52b (15 mg) and compound 52b (18 mg) were obtained.

[0427] [ka] 1 H NMR (400 MHz, chloroform-d): δ = 8.31 (s, 1H), 6.8 9(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), 1.33 ppm (s, 3H) 13 C NMR (101 MHz, chloroform-d): δ = 156.7, 151.7, 1 50.4,123.1,112.7,97.7,86.2,84.6,66.9,60. 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) and HCl ( 16.0 mL, 1 M in H2O) was added and the mixture was stirred at room temperature for 2 h. The solution was diluted with water (2 The solid residue was obtained by diluting the solution in 100 mL of ethanol (100 mL), freezing, and lyophilizing the solution. Chiralcel Diacel OJ 20×250mm, Mobile phase: CO2, EtO Purification was carried out using HCl + 0.4% i-PrNH2 to obtain compound 54a (14.5 mg, 0 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),7.3 0(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. 77 ppm (m, 1H). 13 C NMR(101MHz,DMSO-d6):δ=157.4,151.2,14 9.8,144.8,137.8,132.8,126.2,122.3,114.6, 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, RT1.15 minutes (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),1.45-1.56 ppm(m,1H). 13 C NMR (101MHz, DMSO-d6): δ=157.4,151.2,15 0.0,144.9,137.8,132.8,126.2,121.9,114.6, 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, RT 1.13 min (Method 9)

[0434] Modulation of compounds 55a and 55b

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[0435] Compounds 55a and 55b, and compounds 54a and 54b are prepared using されたプロセスと It's like a のプロセスによって modulated された.

[0436] Compound 55a 1 H 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=160.9,157.9,15 1.7,150.4,149.4,136.7,123.1,122.7,121.6, 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 1 H 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=13.6,10.3Hz,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=160.9,157.9,15 1.7, 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,RT1.20min(Method 9)

[0438] Preparation of Compound 56 [ka] Compound 17 (2.00 g, 5.50 mmol, 1.00 eq) was heated at 27°C for 1 hour at 47°C with a reflux condenser, a thermometer, and a The substrate was weighed into a 100 mL three-neck flask equipped with a CaCl2 tube. (Cyclopentadienyl)dimethyltitanium (39.4 mL, 7.97 mmol, 1. A solution of 45 eq, CAS: 1271-66-5) (5 wt % in toluene) was added. The flask was covered with aluminum foil to block light and heated to 70°C. [Note: After heating, the active pen When the stasis reagent is produced, one equivalent of methane gas is liberated relative to the titanocene. For reaction setup in glassware, closed systems must be avoided. In addition, the reaction in a metal pressure reactor is slow because the titanocene reagent adheres to the reactor wall. Only conversions are shown.] The reaction was stirred for 17 hours, after which complete conversion was observed. The mixture was concentrated in vacuo to a minimum volume, and n-heptane (100 mL) was added to the residue. The solids were sonicated for 5 minutes and removed by filtration through Celite (n-hexane). The organic layer was concentrated in vacuo to a minimum volume. The residue was filtered and washed with silica gel. Column chromatography on gel (gradient elution: n-heptane / EtOAc 15 columns) The product was purified by distillation in a 1:0 to 3:7 mixture (volume ratio of 1:0 to 3:7). The fractions containing the product were collected and the solvent was evaporated. Evaporation gave the desired compound 56 (58% yield, 1.14 g; 3.19 mmol, colorless oil). Ta.

[0439] 1 H NMR (500 MHz, chloroform-d): δ 5.42 (d, J = 4.5 Hz ,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, 1 39.7, 107.6, 105.7, 80.6, 75.6, 74.5, 55.6, 44. 8,41.5,39.2,39.0,27.4,27.3ppm.

[0440] Preparation of Compound 57 [ka] CAS 176098-48-9 (1.8 g, 6.87 mmol, 1 eq) in EtO (18 mL) and zinc (0.89 g, 13.7 mmol, 2.00 eq) was added. This was followed by the addition of trichloroacetyl chloride (1.6 g, A solution of 8.9 mmol, 1.3 eq) in EtO (6 mL) was added dropwise. The mixture was stirred at rt for 2 h. Then, zinc (4.47 g, 68.7 mmol, 1 0.0 eq), AcOH (1.8 mL) was added and the mixture was stirred at rt for 3 h. was added to saturated aqueous NaHCO3 (50 mL) at 0 °C, the solid was filtered off, and the aqueous phase was 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 The product-containing fractions were collected, the solvent was evaporated, and the target compound was purified. The title compound 57 was obtained.

[0441] 55% yield (2.0 g, 7.63 mmol), yellow oil. 1 H NMR (400 MHz) Chloroform-d) δ 7.39-7.31 (m, 5H), 5.99 (d, J = 4.0 Hz,1H),4.79-4.73(m,2H),4.56(d,J=11.8Hz,1 H),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(1 01MHz, chloroform-d) δ 204.58, 136.96, 128.69, 12 8.26, 127.83, 111.90, 105.70, 85.25, 82.92, 78 .60,71.91,59.13,54.53,26.26,25.75ppm.LCM S(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). Then NaBH4 (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 diluted with saturated aqueous NH4Cl (5 0 mL), then extracted with EA (50 mL) and the organic phase was washed with water over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel ( Purification was carried out by gradient elution (PE / EtOAc 99:1 to 70:30). The corresponding 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 (300 M z, 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=4.0 Hz,1H),4.52(d,J=12.2Hz,1H),3.87-3.74(m,2 H),2.92(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,2 H),1.80(s,1H),1.47(s,3H),1.31ppm(s,3H). 1 3 C NMR (101 MHz, chloroform-d) δ 137.37, 128.58, 1 28.06, 127.80, 111.78, 104.90, 84.72, 83.18, 7 9.04,,71.68,59.85,46.63,40.53,26.52,25.9 4 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). Then, imidazole (267 mg, 3.92 mmol, 2 eq) and TBDPSiCl (5 37 mg, 1.96 mmol, 1 eq) was 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 brine (3×10 mL). The organic phase was dried over MgSO4, filtered and evaporated to a minimum. To remove the remaining DMF, the resulting residue was dissolved in EtOAc (10 mL). After filtration, an additional washing step with brine (5 x 10 mL) was required. Column chromatography on gel (PE / EtOAc 99:1 to 90:10) The fractions containing the product were collected and the solvent was evaporated to give compound 59.

[0445] 56% yield (600 mg, 1.10 mmol), colorless oil. 1 H NMR (400MH z, 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,1H),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. 89,127.74,127.64,127.62,127.59,111.69,10 4.81, 84.56, 83.26, 79.36, 71.55, 60.47, 46.68 ,40.66,26.71,26.59,26.56ppm,LCMS(ESI+)m / z:C 33 H 40 Calculated value for O5Si [M+NH4] + =562.26, actual value 56 2.25, RT:2.657 minutes, Method 1.

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

[0447] 33% yield (150 mg, 0.33 mmol), colorless oil. 1 H NMR (300 M z, chloroform-d) δ 7.64 (dt, J = 7.9, 1.8 Hz, 4H), 7.4 3-7.34(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, 12 9.69,127.68,127.66,111.73,104.45,85.99,7 9.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69 ,26.31,25.78,18.95ppm.LCMS(ESI+)m / z:C 26 H 34 Calculated value for O5Si [M+NH4] + =472.22, actual value 472.25, R T:1.835 minutes, method 1.

[0448] Synthesis of Compound 60.1 [ka] Compound 60 (200 mg, 0.44 mmol, 1 eq) was dissolved in DCM (2 mL). Then DMP (224 mg, 0.52 mmol, 1.2 eq) was added at 0°C. The mixture was stirred at RT for 2 h. 2 mL of saturated aqueous Na2S2O3 and 2 mL of NaH The reaction was quenched by adding saturated aqueous CO3, followed by EtOAc (3x2 The organic phase was dried over Na2SO4. The residue was purified by PE / EA. Silica gel chromatography (gradient elution: PE / EtOAc 99:1 to 90:10) The fractions containing the product were collected and the solvent was evaporated to give compound 60.1. Ta.

[0449] 75% yield (150 mg, 0.33 mmol), pale yellow oil. 1 H NMR (300M Hz, chloroform-d) δ 7.64-7.62 (m, 4H), 7.44-7.36 ( m,6H),5.96(d,J=4.4Hz,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 211.71,135.42,13 3.70,133.64,129.72,127.68,114.02,102.18, 76.21, 75.97, 59.28, 47.73, 44.56, 27.31, 26.7 2, 22.69, 18.94, LCMS (ESI+) m / z: C 26H 32 Against O5Si Calculated value [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) in EtOH (1.3 mL) Then NaBH4 (20 mg, 0.56 mmol, 2 eq) was added at 0 °C. The mixture was stirred at 0°C for 30 minutes. The mixture was added with saturated aqueous NH4Cl (30 mL) at 0°C. The mixture was added to HCl (200 ml) and then extracted with EtOAc (3 x 30 mL). The organic phase was dried over Na2SO4. The residue was purified by silica gel chromatography using PE / EA (gradient elution: PE The product was purified by elution with hexane / Et0Ac 99:1 to 80:20. The fractions containing the product were collected. The solvent was evaporated to give compound 60.2.

[0451] 69% yield (90 mg, 0.19 mmol), pale yellow oil. 1 H NMR (300 M z, 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 .14,134.06,129.55,127.57,112.41,103.70,7 8.80, 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 O Calculated value for 5Si [M+NH4] + =472.22, Actual value 472.20, RT:2 .062 minutes, method 1.

[0452] Preparation of Compound 61 [ka] CAS 6983-40-0 (2.00g, 11.6mmol, 1.0eq) was added to pyridine The solution was dissolved in 20 mL of ethanol, cooled to 0 °C, and added to PivCl (1.81 g, 15.08 m The mixture was stirred at 0°C to rt for 17 h, after which the mixture was The mixture was slowly poured into ice-cold NH4Cl (aq. 30 mL) and the product was dissolved in n-heptane ( The combined organic layers were washed with brine and dried (MgSO4 ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient: The product was purified by elution with PE / EtOAc (99:1 to 90:10). The mixture was 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=3.7Hz,1H),4.34( d,J=2.0Hz,1H),1.48(s,3H),1.39-1.41(m,3H) ,1.19-1.21ppm(m,9H). 13 C NMR (101 MHz, chloroform) Mu-d):δ 176.9,158.5,114.1,106.4,88.8,83.0 ,75.3,38.6,28.0,27.2,26.9ppm.LCMS(ESI+)m / z:C 13 H 20 Calculated value for O5 [M+H] + =257.13, actual value 257.1 0, RT: 1.113 minutes, Method 6.

[0454] Preparation of Compound 62 [ka]

[0455] Compound 61 (2.2 g, 8.5 mmol, 1.0 eq) was dissolved in Et2O (22 mL). The mixture was dissolved and Zn(Cu) (10.1 g, 59.5 mmol, 7.0 eq) was added. followed by adding trichloroacetyl chloride (4.4 g, 24.5 mmHg) with stirring at 0°C. A solution of 2.8 eq) of ethanol in 6 mL of EtO was added dropwise. The mixture was stirred for 2 hours, and then zinc (5.58 g, 85 mmol, 10.00 eq) was added at 0°C. AcOH (2.2 mL) was added and the mixture was stirred at rt for 3 h. The residue was dissolved in water at 0° C. The solid was filtered off and the aqueous phase was diluted with EA (50 mL). After extraction, the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Gel column chromatography (gradient elution: PE / EtOAc 99:1 to 80:20 The fractions containing the product were collected and the solvent was evaporated to give compound 62. .

[0456] 60% yield (1.5 g, 5.03 mmol). 1 H NMR (400 MHz, chloroform) Lum-d)δ 5.99(d,J=3.9Hz,1H),5.35(s,1H),4.6 0(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) Mu-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 Calculations for O6 Value [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). Then NaBH4 (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 a saturated aqueous solution of NH4Cl ( The mixture was added to a solution of 50 mL of EA, and then extracted with EA (50 mL). The organic phase was evaporated over anhydrous sodium sulfate. The residue was purified by column chromatography on silica gel (gradient). The product was purified by gradient elution (PE / EtOAc 99:1 to 70:30). The fractions were collected and the solvent was evaporated to give compound 63.

[0458] 52% yield (780 mg, 2.6 mmol). 1 H NMR (400 MHz, chloroform) Lum-d)δ 5.84(d,J=3.9Hz,1H),5.13(s,1H),4.4 8(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, 10 4.66, 84.38, 79.04, 78.60, 59.54, 46.10, 40.32 ,38.95,27.12,26.40,25.85ppm.LCMS(ESI+)m / z:C 15 H 24 Calculated value for O6 [M+NH4] + =318.20, actual value 318. 16, RT: 1.228 minutes, Method 1.

[0459] Preparation of Compound 64 [ka] Compound 63 (750 mg, 2.50 mmol, 1.0 eq) was dissolved in DMF (8 mL). The mixture was dissolved in imidazole (340 mg, 5.00 mmol, 2.0 eq) and TBDPS ( 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 brine (3 The organic phase was dried over MgSO4, filtered, and evaporated to a minimum. The resulting residue was dissolved in EtOAc (15 mL) and the remaining DMF was removed. An additional washing step with brine (5 x 15 mL) was required to remove the residue. Column chromatography on silica gel (PE / EtOAc 99:1 to 95:5) The fractions containing the product were collected and the solvent was evaporated to give compound 64.

[0460] 52% yield (700 mg, 1.30 mmol), white solid. 1 H NMR (300M Hz, chloroform-d) δ 7.62 (ddd, J = 7.8, 2.8, 1.7 Hz, 4 H),7.36(qt,J=8.7,2.7Hz,6H),5.78(d,J=3.9H z,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, 12 9.63,129.61,127.61,127.59,112.03,104.54, 84.38, 79.02, 78.77, 65.54, 60.25, 46.30, 40.5 6,38.82,30.58,27.02,26.72,26.43,25.88ppm ,LCMS(ESI+)m / z:C 31 H 42Calculated 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). Sodium methoxide (74.0 mg, 1.37 mmol, 1.00 equiv) The reaction was stirred at RT for 30 min, then H-exchange resin and stirred until pH=7. The mixture was stirred for 1 hour, then filtered, and the filtrate was concentrated under reduced pressure. The residue was extracted with PE / EtOAc (gradient elution) PE / EtOAc 99:1 to 80:20) was applied to a silica gel column. The fractions containing the product were collected and the solvent was evaporated to give compound 60.

[0462] 36% yield (230 mg, 0.50 mmol), colorless oil. 1 H NMR (300 M z, chloroform-d) δ 7.64 (dt, J = 7.9, 1.8 Hz, 4H), 7.4 3-7.34(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, 12 9.69,127.68,127.66,111.73,104.45,85.99,7 9.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69 ,26.31,25.78,18.95ppm.LCMS(ESI+)m / z:C 26 H 34 Calculated value for O5Si [M+NH4] + =472.22, actual value 472.25, R T: 1.835 minutes, 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-(naphthalene-2-ylmethyl) (2,3-d)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanol (4.71g, 14.3mmol, 1.00eq, 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) was added, followed by the addition of iodine (8.80 g, 34.6 mmol, 2.4 eq) in small portions. The reaction mixture was stirred at reflux under nitrogen for 2 hours. The reaction mixture was then diluted with EtOAc (4×100 ml). The combined organic layer was extracted with saturated aqueous Na2SO3 (1 x 200 mL), NaHC Wash with saturated aqueous O3 (1 x 200 mL) and brine (1 x 200 mL), then It was dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. n-Heptane was added to the residue. The mixture was stirred for 5 minutes. The solid was removed by filtration and rinsed with n-heptane. The residue was purified by silica gel column chromatography (n-heptane / Et The product was purified by a gradient of 95:5 to 80:20 OAc. and concentrated in vacuo to give compound 66.1.

[0465] 87% yield (26.3 g, 12.4 mmol), white solid. 1 H NMR (400M Hz, chloroform-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=11.22,4.40H z,1H),1.62(s,3H),1.38ppm(s,3H). 13 C NMR(1 00MHz, chloroform-d): δ 134.72, 133.23, 133.20, 1 28.49, 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-heptane / EtOAc; 1:1) = 0.77 LCMS:[M+1] + =458.0[M+1]+,2.29 minutes (method 13)

[0466] Preparation of Compound 66.2 [ka] Compound 66.1 (9.35 g, 19.3 mmol, 1.00 eq) was dissolved in DMF (71 mL ) and sodium iodide (17.4 g, 115.8 mmol, 6.00 eq) The reaction mixture was stirred at 80-85°C for 2 hours and then diluted with DBU (3.46 mL, 23. 2 mmol, 1.2 eq) was added. The reaction mixture was stirred at 85°C for 1.5 hours. Add the second portion of U (0.87 mL, 5.80 mmol, 0.3 eq) and heat at 85 °C for 1. The reaction mixture was stirred for 5 hours, then cooled to room temperature and diluted with EtOAc and deionized water. The aqueous layer was separated and extracted with EtOAc (1x), and then the combined organic layers were washed with citric acid / water. The organic layer was washed with sodium hydroxide (pH=4) buffer (3x) and brine (1x). It was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography. by chromatography (n-heptane / EtOAc gradient 90:10 to 80:20). The fractions containing the product were combined and the solvent removed in vacuo to give compound 66.2. Ta.

[0467] 65% yield (3.94 g, 12.5 mmol), white solid. 1 H NMR (400M Hz, 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),4.88(d ,J=12.42Hz,1H),4.59(m,1H),4.52(m,1H),4.3 6(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 ,27.28ppm.R f (n-heptane / EtOAc; 1:1) = 0.77.MP:1 02.01°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 Activated zinc dissolved in 1 mL * (5.69g, 87.0mmol, 7.00eq)- The following trichloroisothiazolinone was dissolved in anhydrous THF (16 mL). A solution of acetyl chloride (2.28 mL, 20.2 mmol, 1.80 eq) was The solution was added dropwise over 1 hour, after which the zinc salts were removed by filtration through Celite®. 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 was obtained as an orange viscous oil. The product was used directly in the next step. I used it immediately.

[0469] (5.85g, crude), 1 H NMR (400 MHz, chloroform-d): δ 7.9 2-7.80(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=1 1.66Hz,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, 13 3.25,133.11,128.24,127.94,127.77,127.02, 126.34, 126.27, 125.91, 120.23, 113.94, 104.2 8, 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 The suspension was stirred and bubbled for 45 minutes, then filtered. The zinc powder was dissolved in degassed deionized water (1.25 L) and degassed acetone (550 mL). The resulting black powder (100 g) was rinsed with both HCl and HCl (mL) and then dried overnight in vacuo. 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 mixture was cooled to 0 °C and glacial acetic acid (3.56 mL, 62.1 mmol, 5.00 eq) was added. The reaction mixture was stirred at room temperature for 20 hours and filtered through Celite®. The zinc was removed by rinsing...

Claims

1. Formula (A) [Case 1] [In the formula, Y is -O- or -CH ２ - and n is 0 or 1; When n is 1, R １ is hydrogen, R ２ is -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(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 , Silyl group, C substituted with silyl group １～６ Alkyl, ═O, or ═CR ａ ２ Is it or When n is 1, R ２ is hydrogen, R １ 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) N.R. 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 Alkyl, -O-aryl ═O or ═CR ａ ２ and When 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 [Case 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 Alkyl or -O-aryl In some cases, 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 taken together to 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 Or together R ４ and R ５ is a diol protecting group. Although it is a compound of however, (a) the compound has the formula [C3] [In the formula, Y is —O— or —CH ２ - and R ４ is hydrogen or hydroxyl Protective groups, e.g., C １～４ Alkyl, t-butyldimethylsilyl, C １～４ Alkyl-O- C １～４ Alkyl, tetrahydropyranyl, allyl, t-butyldiphenylsilyl, phenyl Zirconium, -C(=O)-C １～４ alkyl, or —C(═O)-phenyl; R ２ is -OH, =O, -CH ２ -OH or =CH ２ and R ５ and R ６ Each Then, -C(=O)-C １～４ Alkyl, benzoyl, benzyl, or -CH ２ - Naphthyl (wherein benzyl, -CH ２ -Naphthyl and benzoyl are -CH ３ and- OCH ３ and optionally substituted with one or two substituents each independently selected from or together with R ５ and R ６ is -C(C １～４ Alkyl) ２ -; or in which Y is -O- or -CH ２ and R ４ is methyl, R ２ is ═O or ═CH ２ and R ５ and R ６ Each independently represents hydrogen or -C (=O)-C １～４ is alkyl] rather than a compound of; (b) the compound has the formula [C4] [In the formula, R ｖ is ═O, —OH, or ═CH ２ is] rather than a compound of; (c) the compound has the formula [C5] [In the formula, R ｗ is methyl or H. rather than a compound of; (d) the compound has the formula [C6] [In the formula, R is CO ２ Et or CH ２ OH] or any stereoisomer thereof, The compound, or a salt or solvate thereof.

2. The compound has the formula (A-1a), (A-3a), (A-1b), or (A-3b): [C7] or a salt or solvate thereof.

3. The hydroxyl protecting group is a silyl group, C １～４ Alkyl, C １～４ Alkyl-O-C １～４ Alkyl, tetrahydropyranyl, allyl, benzyl, -CH ２ -Naphthyl, if Benzoyl, -C(=O)-C １～４ Alkyl, or -C(=O)-phenyl wherein benzyl, -CH ２ -Naphthyl and benzoyl are -CH ３ and -OCH ３ and optionally substituted with one or two substituents each independently selected from and / or the diol protecting group is C(C １～４ Alkyl) ２ - is a claim 3. The compound according to claim 1 or 2.

4. The compound according to any one of claims 1 to 3, wherein Y is O.

5. Y is CH ２ The compound according to any one of claims 1 to 3,

6. The compound according to any one of claims 1 to 5, wherein n is 1.

7. R １ is hydrogen, R ２ But -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(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 S (O) ｘ R ｃ , a silyl group, a C substituted with a silyl group １～６ Alkyl, =O or =CR ａ ２ or R ２ is hydrogen, R １ But -(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 S (O) ｘ R ｃ , silyl group, silyl-substituted C １～６ Alkyl, -O-aryl, =O, or =CR ａ ２ In claim 6, The compound described.

8. The compound according to any one of claims 1 to 5, wherein n is 0.

9. 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 9. The compound of claim 8, wherein

10. The compound is [C8] [C9] [C10] [C11] 2. The compound according to claim 1, which is selected from the group consisting of:

11. Formula (B) [C12] [In the formula, Y is -O- or -CH ２ - and 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.

12. The compound is [C13] 12. The compound of claim 11, which is selected from:

13. Formula (C) [C14] [In the formula, Y is -O- or -CH ２ - and R ４ , R ５ , and R ６ are each independently hydrogen or a hydroxyl protecting group; or teeth R who joined us ４ and R ５ is a diol protecting group; or R who joined us ５ and R ６ is a diol protecting group. Although it is a compound of However, the compound is [C15] isn't it, The compound.

14. The compound is [C16] 14. The compound of claim 13, which is a compound selected from:

15. Formula (D): [C17] [In the formula, Y is -O- or -CH ２ - and Where: [C18] is a single bond or a double bond; [C19] 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, —O—C １～６ Alkyl, -B(OR ｂ ) ２ -S-C １～６ Alkyl, -S-aryl, -O-aryl Reel, or C(O)R ａ and [C20] is a double bond, R １’ and R ２’ One of the groups is hydrogen or C １～６ With alkyl and the other is a silyl group, a C optionally substituted with a silyl group. １～６ Alkyl, -O- C 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 taken together to form a boronic acid protecting group; R ３ is OR ４ Or R １０ and R １０ is a nucleobase or a nucleobase derivative; R ４ , R ５ , and R ６ are each independently hydrogen or a hydroxyl protecting group; or teeth R who joined us ４ and R ５ is a diol protecting group; or R who joined us ５ and R ６ is a diol protecting group. or a salt or solvate thereof.

16. R ３ OR ４ 16. The compound of claim 15,

17. The compound is [C21] 16. The compound of claim 15, which is a compound selected from:

18. Formula (E) [C22] [In the formula, Y is -O- or -CH ２ - and n is 0 or 1; When n is 1, R １ is hydrogen, R ２ is -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(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 , Silyl group, C substituted with silyl group １～６ Alkyl, ═O, or ═CR ａ ２ Is it or When n is 1, R ２ is hydrogen, R １ is -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(CH ２ ) ｍ OPG, -(CH ２ ) ｍC(O)OR ａ , -(CH ２ ) ｍ C ( O) N.R. 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 Alkyl, -O-aryl ═O or ═CR ａ ２ and When 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 [C23] 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 Alkyl, or -O-aryl is a single bond, or R １ Or R ２ , =O, =CH ２ , or = C R ａ ２ 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 death; 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 a hydrogen or a hydroxyl protecting group; or together Became R ５ and R ６ is a diol protecting group; R １０ is a nucleobase or a nucleobase derivative; PG is a hydroxyl protecting group. Although it is a compound of Provided that the compound is: [C24] [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 ５ and R ６ is -C(CH ３ ) ２ - and Y is -O- or -CH ２ - and R １０ teeth, [C25] 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, 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 is hydrogen, halo, -NR ７ａ R ７ｂ , C １～４ Alkyl, C ２～４ Alkenyl, C ３～６ Cycloalkyl, —OH, or —O—C １～４ represents alkyl; R ７ａ is hydrogen; R ７ｂ is hydrogen, C ３～６ Cycloalkyl, or C １～４ is alkyl; R ４ａ is hydrogen, halo, -NR ８ａ R ８ｂ , or C １～４ is alkyl; R ｘ teeth, [C26] is] or a salt or solvate thereof, The compound, or a salt or solvate thereof.

19. The compound has the formula (G-1a) or (G-1b): [C27] or a salt or solvate thereof.

20. 20. The compound of claim 18 or 19, wherein n is 1.

21. R １ is hydrogen, R ２ But -(CH ２ ) ｍ N.R. ａ ２ , -(CH ２ ) ｍ OR ａ , -(C H ２ ) ｍ C(O)OR ａ , -(CH ２ ) ｍ C(O)NR ａ ２ , -(CH ２ ) ｍ C(O)R ａ , -(CH ２ ) ｍ S (O) ｘ R ｃ , a silyl group, a C substituted with a silyl group １～６ Alkyl , =O, or =CR ａ ２ or R ２ is hydrogen, R １ But -(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 S (O) ｘ R ｃ , silyl group, silyl-substituted C １～６ Alkyl, -O-aryl, =O, or =CR ａ ２ 20. The compound according to claim 20, The compound according to claim 1,

22. 20. The compound of claim 18 or 19, wherein n is 0.

23. 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 or =CH ２ 21. The compound of claim 20,

24. The compound is [C28] [C29] 19. The compound of claim 18, which is a compound selected from:

25. The compound is [C30] 25. The compound of claim 24, which is a compound selected from:

26. The compound is [C31] [C32] 19. The compound of claim 18, which is a compound selected from:

27. Formula (H): [C33] [In the formula, R ５ and R ６ are each independently a hydrogen or a hydroxyl protecting group; or together Became R ５ and R ６ is a diol protecting group; R １０ is a nucleobase or a nucleobase derivative. or a salt or solvate thereof.

28. If present, R １０ is cytosine, thymine, uracil, or modified forms thereof, or or in a protected form, or (a-1), (a-2), (a-3), (a-4), and (a -5): [C34] is 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 Each independently represents hydrogen, halo, - N.R. ７ａ R ７ｂ , C １～４ Alkyl, C ２～４ Alkenyl, C ３～６ Cycloalkyl, —OH, or —O— C １～４ and R ７ａ is hydrogen, -C(O)O-C １～４ Alkyl, or [C35] and R ７ｂ is hydrogen, C ３～６ Cycloalkyl, C １～４ Alkyl, or -C(O)O-C 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 represents 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 However; However, Q ３ and Q. ４ 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; Q ７ 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であり； 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 ６ ｊ are each independently hydrogen, halogen, C １～４ Alkyl, -NR ９ａ R ９ｂ , or 1 , C substituted with 2 or 3 halo atoms １～４ is alkyl; R ９ａ and R ９ｂ are each independently hydrogen or C １～４ is alkyl, A compound according to any one of claims 15 to 27.

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