Novel spirobicyclic intermediate

Abstract

The present invention relates to novel spiro bicyclic intermediates that can be used to synthesize spiro bicyclic nucleoside analogs.

Description

Technical Field

[0001] The present invention relates to novel spiro bicyclic intermediates that can be used to synthesize spiro bicyclic nucleoside analogs. Background Art

[0002] PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen or Dart5, is one of the major methyltransferases responsible for monomethylation and symmetric dimethylation of arginine. Post-translational arginine methylation on histones and non-histones appears to be crucial for a variety of biological processes (such as genome organization, transcription, differentiation, spliceosome function, signal transduction, and regulation of cell cycle progression, stem cell and T cell fate) [Stopa, N. et al., Cell Mol Life Sci [Cell and Molecular Life Sciences], 2015.72(11): p. 2041-59] [Geoghegan, V. et al., Nat Commun [Nature Communication], 2015.6: p. 6758]. Metazoan PRMT5 forms a functional complex with methylosome protein 50 (MEP50), also known as Wdr77, and the androgen receptor coactivator p44 and Valois. Elevated PRMT5-MEP50 protein levels and cytoplasmic accumulation are associated with cancer tumorigenesis and have recently been linked to poor clinical outcomes [Shilo, K. et al., Diagn Pathol, 2013.8: p. 201]. In addition to comprehensive enzymology studies, cell rescue experiments investigating the catalytic and scaffolding functions of the PRMT5-MEP50 complex have demonstrated an oncogenic link between protein levels, localization, and enzyme function [Gu, Z. et al., Biochem J, 2012. 446(2): 235-41] [Di Lorenzo, A. et al., FEBS Lett, 2011. 585(13): 2024-31] [Chan-Penebre, E. et al., Nat Chem Biol, 2015. 11(6): 432-7]. This association has made PRMT5 a major small molecule drug target for cancer and other diseases [Stopa, N. et al., Cell Mol Life Sci, 2015. 72(11): 2041-59].

[0003] PRMT5 is a member of the type II PRMT subfamily that utilizes S-adenosylmethionine (SAM) to generate symmetrically dimethylated arginine and S-adenosylhomocysteine ​​(SAH) on histone and non-histone substrates. The crystal structure of the human hetero-octamer complex (PRMT5)4 (MEP50)4 co-crystallized with SAH and histone H4 peptide substrates demonstrates the mechanism of methylation and substrate recognition [Antonysamy, S. et al., Proc Natl Acad Sci USA [Proceedings of the National Academy of Sciences of the United States of America], 2012.109(44): p. 17960-5]. Regulation of PRMT5 activity occurs through a number of different binding partners, post-translational modification traffic, miRNAs, and subcellular localization.

[0004] Methylation of histones H2A and H4 at Arg3 and methylation of histone H3 at Arg8 regulate chromatin organization for the specific repression of gene transcripts associated with differentiation, transformation, cell cycle progression, and tumor suppression [Karkhanis, V. et al., Trends Biochem Sci, 2011. 36(12): p. 633-41]. In addition, PRMT5-mediated methylation of histone H4 at Arg3 may recruit the DNA-methyltransferase DNMT3A to couple with histones and methylate DNA, leading to long-term gene silencing [Zhao, Q. et al., Nat Struct Mol Biol, 2009. 16(3): p. 304-11].

[0005] Non-histone methylation can occur in the cytoplasm or the nucleus, depending on the cellular localization of PRMT5. Methylation of Sm proteins D1 and D3 is required for the assembly of the nuclear spliceosome and occurs in the cytoplasm as part of the PRMT5 containing "methyltransferase complex" [Friesen, WJ et al., Mol Cell Biol [Molecular and Cell Biology], 2001.21 (24): p. 8289-300]. Further evidence that PRMT5 is involved in splicing is provided by conditional PRMT5 knockout in mouse neural stem cells. Cells lacking PRMT5 show selective retention of introns and skipping of exons with weak 5' donor sites [Bezzi, M. et al., Genes Dev [Genes and Development], 2013.27 (17): p. 1903-16].

[0006] In addition to its role in splicing, PRMT5 also affects key pathways related to cell fate and homeostasis by directly methylating key signaling nodes, such as p53 [Jansson, M. et al., Nat Cell Biol, 2008. 10(12): p1431-9], EGFR [Hsu, JM et al., Nat Cell Biol, 2011. 13(2): p174-81], CRAF [Andreu-Perez, P. et al., Sci Signal, 2011. 4(190): p1ra58], PI3K / AKT [Wei, TY et al., Cell Signal, 2014. 26(12): p2940-50], NFkB [Wei, H. et al., Proc Natl Acad Sci US A[Proceedings of the National Academy of Sciences of the United States of America], 2013.110(33):pp.13516-21].

[0007] Since PRMT5 is one of the main sym-Arg methyltransferases and is involved in a variety of cellular processes, increased protein expression appears to be an important factor in its tumorigenicity. Interestingly, the translation of PRMT5 in mantle cell lymphoma (MCL) appears to be regulated by miRNA. Although MCL cells show less mRNA and slower PRMT5 transcription rates than normal B lymphocytes, PRMT5 levels and methylation of H3R8 and H4R3 are significantly increased [Pal, S. et al., EMBO J [EMBO magazine], 2007.26 (15): p. 3558-69]. Re-expression of miRNAs in the 3'UTR region of PRMT5 reduces PRMT5 protein levels [Wang, L. et al., Mol Cell Biol [Molecular and Cell Biology], 2008.28 (20): p. 6262-77]. Surprisingly, PRMT5 antisense RNA was found in the human PRMT5 gene, a finding that supports the hypothesis of specific translational regulation rather than high mRNA expression levels [Stopa, N. et al., Cell Mol Life Sci, 2015. 72(11): 2041-59].

[0008] Recently, a novel subnanomolar PRMT5 inhibitor (EP Z015666) with antitumor activity in multiple MCL xenograft models has been described as the first chemical probe suitable for further validating the biological properties and role of PRMT5 in cancer [Chan-Penebre, E. et al., Nat Chem Biol, 2015.11(6):432-7]. WO 2014100695, WO 2014100719, WO 2015200680 and WO 2014100730 disclose compounds that can be used to inhibit PRMT5 activity. Devkota, K. et al., ACS Med Chem Lett, 2014.5:293-297 describe the synthesis of a series of analogs of the natural product sinefungin and their ability to inhibit EHMT1 and EHMT2. WO 2003070739 discloses partial and full agonists of the A1 adenosine receptor, their preparation, and their therapeutic uses. WO 2012082436 discloses compounds and compositions that are histone methyltransferase modulators and are useful for treating diseases affected by modulation of histone methyltransferase activity. WO 03074083 discloses combination therapies that selectively kill cells deficient in methylthioadenosine phosphorylase. Analogs of MTA are referred to herein as antitoxic agents. Kung, P.-P. et al., Bioorg Med Chem Lett [Bioorganic and Medicinal Chemistry Letters], 2005.15: pp. 2829-2833, describe the design, synthesis, and biological evaluation of novel human 5'-deoxy-5'-methylthioadenosine phosphorylase (MTAP) substrates. WO 2012075500 discloses 7-deazapurine modulators of histone methyltransferases. WO 2014035140 discloses compounds and compositions for modulating histone methyltransferase activity. WO 9640686 describes heterocyclic substituted cyclopentane compounds and methods of using such compounds to inhibit adenosine kinase.

[0009] WO 2016135582 and US 20160244475 describe substituted nucleoside derivatives useful as anticancer agents. Boyer et al. describe diaryl-erythro-furanosyl tuberculocidin analogs as adenosine kinase inhibitors.

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

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

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

[0013] It has been determined that spiro bicyclic nucleosides show interesting activity, such as activity against PRMT5. Novel intermediates that can be used to synthesize spiro bicyclic nucleoside analogs have been developed. Specifically, these intermediates contain functional groups that can be diversified to obtain a variety of spiro bicyclic nucleoside analogs, including nucleoside analogs containing cyclopentane. Therefore, disclosed herein are compounds that can be used as intermediates for preparing spiro bicyclic nucleoside analogs that can, for example, have activity against PRMT5. Also disclosed herein are spiro nucleoside compounds that can be used as intermediates for further functionalization to provide spiro bicyclic nucleoside analogs with interesting activity.

[0014] In one aspect, the present invention relates to a compound of formula (A)

[0015]

[0016] or a salt or solvate thereof, wherein:

[0017] Y is -O- or -CH2-;

[0018] n is 0 or 1;

[0019] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NRa 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0020] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0021] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) mC(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0022] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0023] Each R a are independently hydrogen or C 1-6 alkyl;

[0024] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0025] R c C 1-6 alkyl or aryl;

[0026] PG is a hydroxyl protecting group;

[0027] m is 0 or 1;

[0028] x is 0, 1, or 2;

[0029] R 4 、R 5 and R 6are each independently hydrogen or a hydroxy protecting group;

[0030] or R 5 and R 6 Together they form a diol protecting group;

[0031] or R 4 and R 5 Together they form a diol protecting group;

[0032] The conditions are:

[0033] (a) The compound is not a compound of the formula:

[0034] Wherein Y is -O- or -CH2-; R 4 is a hydrogen or hydroxy protecting group, such as C 1-4 Alkyl, tert-butyldimethylsilyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, tert-butyldiphenylsilyl, benzyl, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl; R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 Each is independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form -C(C 1-4 Alkyl) 2-; or wherein Y is -O- or -CH2, R 4 is methyl, R 2 =O or =CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 Alkyl; and

[0035] (b) the compound is not a compound of the formula:

[0036] where R v =O, -OH or =CH2; and

[0037] (c) the compound is not a compound of the formula:

[0038] where R w is methyl or H; and

[0039] (d) the compound is not a compound of the formula:

[0040] wherein R is CO2Et or CH2OH or any stereoisomer thereof.

[0041] In another aspect, the present invention relates to a compound of formula (B):

[0042]

[0043] or a salt or solvate thereof, wherein:

[0044] Y is -O- or -CH2-;

[0045] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0046] or R 5 and R 6 Together they form a diol protecting group;

[0047] or R 4 and R 5 Together they form a diol protecting group.

[0048] In another aspect, the present invention relates to a compound of formula (C):

[0049]

[0050]

[0051] in:

[0052] Y is -O- or -CH2-;

[0053] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or

[0054] R 4 and R 5 taken together to form a diol protecting group; or

[0055] R 5 and R 6 Together they form a diol protecting group;

[0056] Provided that the compound is not:

[0057]

[0058] In another aspect, the present invention relates to a compound of formula (D):

[0059]

[0060] or a salt or solvate thereof, wherein:

[0061] Y is -O- or -CH2-;

[0062] in is a single bond or a double bond; and

[0063] when When it is a single bond, R 1 ' and R 2 One of ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by 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 ;

[0064] when When it is a double bond, R 1 ' and R 2 ' is hydrogen or C1-6 alkyl and the other is a silyl group, a C optionally substituted silyl group 1-6 Alkyl, -OC 1-6 Alkyl or C(O)R a ;

[0065] and

[0066] R a is hydrogen or C 1-6 alkyl;

[0067] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0068] R 3 OR 4 or R 10 ;

[0069] R 10 is a nucleobase or a nucleobase derivative;

[0070] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or

[0071] R 4and R 5 taken together to form a diol protecting group; or

[0072] R 5 and R 6 Together they form a diol protecting group.

[0073] In another aspect, the present invention relates to a compound of formula (E):

[0074]

[0075] or a salt or solvate thereof, wherein:

[0076] Y is -O- or -CH2-;

[0077] n is 0 or 1;

[0078] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0079] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0080] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0081] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a2 is a double bond;

[0082] Each R a are independently hydrogen or C 1-6 alkyl;

[0083] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0084] R c C 1-6 alkyl or aryl;

[0085] x is 0, 1, or 2;

[0086] m is 0 or 1;

[0087] R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or R 5 and R 6 Together they form a diol protecting group;

[0088] R 10 is a nucleobase or a nucleobase derivative;

[0089] Provided that the compound is not any of the following:

[0090]

[0091] in

[0092] R 5 is hydrogen or -C(=O)-C 1-4 alkyl;

[0093] R 6 is hydrogen or -C(=O)-C 1-4 alkyl; or

[0094] R 5 and R 6 Together they form -C(CH3)2-

[0095] Y is -O- or -CH2-;

[0096] R 10 for

[0097]

[0098] Q 1 CR 6a ;

[0099] Q 2 N or CR 6b ;

[0100] R 6a and R 6b Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0101] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0102] R 3a is hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0103] R 7a is hydrogen;

[0104] R 7b For hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0105] R 4a is hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl; and

[0106] R x for

[0107] or a salt or solvate thereof.

[0108] In another aspect, the present invention relates to a compound of formula (H):

[0109]

[0110] or a salt or solvate thereof, wherein:

[0111] R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or R 5 and R 6 taken together is a diol protecting group; and

[0112] R 10 It is a nucleobase or a nucleobase derivative.

[0113] The present invention will now be further described. In the following paragraphs, different aspects of the present invention are defined in more detail. Unless explicitly indicated otherwise, each aspect so defined can be combined with any one or more other aspects. Specifically, any feature that is indicated as preferred or advantageous can be combined with any one or more other features that are indicated as preferred or advantageous. DETAILED DESCRIPTION

[0114] When describing the compounds of the present invention, the terminology used is intended to be understood in accordance with the following definitions, unless the context dictates otherwise.

[0115] When any variable occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence.

[0116] Whenever the term "substituted" is used herein, unless otherwise indicated or clear from the context, it is intended to indicate that one or more hydrogens (specifically 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen) on the atom or group indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the normal valence is not exceeded and that the substitution results in a chemically stable compound (i.e., a compound sufficiently robust to withstand isolation to a useful degree of purity from a reaction mixture and formulation into a therapeutic agent).

[0117] When two or more substituents are present on a moiety, unless otherwise indicated or clear from the context, the substituents may replace a hydrogen on the same atom, or the substituents may replace hydrogen atoms on different atoms in the moiety.

[0118] As used herein, the prefix "C x-y ” (where x and y are integers) refers to the number of carbon atoms in a given group. Thus, C 1-4 Alkyl groups contain 1 to 4 carbon atoms, C 1-3 Alkyl groups contain 1 to 3 carbon atoms, among others.

[0119] Unless otherwise indicated or clear from the context, the term "halogen" as a group or part of a group is generic for fluorine, chlorine, bromine, iodine.

[0120] For example, the term "C 1-6 "Alkyl" refers to a group of formula C n H 2n+1 wherein n is a number ranging from 1 to 6. 1-6 The alkyl group contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms. 1-6 Alkyl, C 1-4Alkyl and C 1-3 Alkyl groups may be straight or branched and may be substituted as indicated herein.When a subscript is used herein after a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.

[0121] C 1-6 Alkyl includes all straight or branched chain alkyl groups having between 1 and 6 carbon atoms and thus includes methyl, ethyl, n-propyl, isopropyl, 2-methyl-ethyl, butyl and its isomers (e.g., n-butyl, isobutyl and tert-butyl), pentyl and its isomers, hexyl and its isomers, and the like.

[0122] The skilled person will recognize that suitable -OC 1-4 Non-limiting examples of alkyl groups include methyloxy (also known as methoxy), ethyloxy (also known as ethoxy), propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, and tert-butyloxy.

[0123] As used herein, the term "C 2-4 "Alkenyl" refers to a straight or branched hydrocarbon group containing 2 to 4 carbon atoms and containing a carbon-carbon double bond, such as but not limited to ethenyl, propenyl, butenyl, 1-propen-2-yl, etc.

[0124] As used herein as a group or part of a group, the term 'C 3-6 The cycloalkyl group represents a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.

[0125] The term "aryl" as used herein as a group or part of a group refers to a monocyclic or bicyclic aromatic ring system having six to fourteen carbon atoms (ie, C 6-14 Aryl). Non-limiting exemplary aryl groups include phenyl, naphthyl, phenanthrenyl, anthracenyl, indenyl, azulenyl, biphenyl, biphenylene and fluorenyl groups. Aryl is preferably selected from phenyl or naphthyl, more preferably phenyl.

[0126] Whenever a substituent is represented by a chemical structure, '---' indicates a bond to the rest of the molecule.

[0127] Some compounds of the present invention can exist in tautomeric forms. The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also referred to as prototropic tautomers) include interconversions produced via prototropic isomerization, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions produced by the reorganization of some bonding electrons.

[0128] Such forms, to the extent they may exist, although not explicitly indicated in the formulae herein, are intended to be included within the scope of the present invention.

[0129] As used herein, any chemical formula having bonds shown only as solid lines and not as solid or dashed wedges, or otherwise expressed as a formula having a particular configuration (e.g., R, S) around one or more atoms, contemplates every possible stereoisomer, or mixtures of two or more stereoisomers. In the structures shown herein, where the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers are considered and included in the compounds of the present invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.

[0130] The compounds described herein include stereoisomers and tautomeric forms thereof. However, as mentioned in the previous paragraph, where stereochemistry is specified by a bond shown as a solid wedge or a dotted wedge, or otherwise indicated as having a specific configuration (e.g., R, S), then that stereoisomer is specified and defined. Furthermore, when a bond is shown as a wavy bond, unless otherwise specified, this means that the stereochemical configuration at the stereocenter is a mixture of stereoisomers. It will be clear that this also applies to the subgroups having the formulae herein.

[0131] It follows that, where possible, a single compound may exist in stereoisomeric and tautomeric forms.

[0132] The terms "stereoisomer", "stereoisomeric form" or "stereochemically isomeric form" are used interchangeably above and below.

[0133] Enantiomers are stereoisomers that are non-superimposable mirror images of one another. A 1:1 mixture of an enantiomeric pair is a racemate or racemic mixture.

[0134] Atropisomers (or atropoisomers) are stereoisomers with a specific spatial configuration resulting from restricted rotation about a single bond due to large steric hindrance. All atropisomeric forms of the compounds described herein are intended to be included within the scope of the present invention.

[0135] Diastereomers (or diastereomers) are stereoisomers of diastereomers, i.e., they are not mirror images. If the compound contains a double bond, these substituents may be in the E or Z configuration. Substituents on a divalent cyclic (partially) saturated radical may have a cis or trans configuration; for example, if the compound contains a disubstituted cycloalkyl group, these substituents may have a cis or trans configuration. Thus, the present invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers, and mixtures thereof, as far as chemically possible.

[0136] The meaning of all those terms (ie enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof) are known to the skilled person.

[0137] Absolute configuration is assigned according to the Cahn-Ingold-Prelog system. Configuration at asymmetric atoms is designated by R or S. Resolved stereoisomers whose absolute configuration is unknown can be

[0138] They are designated by (+) or (-) depending on the direction they rotate plane polarized light. For example, resolved enantiomers whose absolute configuration is unknown can be designated by (+) or (-) depending on the direction they rotate plane polarized light.

[0139] As an example:

[0140] instruct and mixture.

[0141] It should be understood that unless the context dictates otherwise, for example, formula (A)

[0142] The compound can be alternatively described as

[0143] These structures encompass all possible stereochemical configurations.

[0144] It should be understood that unless the context dictates otherwise, for example, formula (A)

[0145] The compounds covered or a mixture thereof.

[0146] It will be understood by the skilled artisan that, unless the context otherwise provides, this is generally true for any other general formula of the spiro bicyclic nucleoside analogs described in this application (including nucleoside analogs containing cyclopentane). Unless the context otherwise provides, all such forms are encompassed by the general formula wherein describing a possible form. All such forms are intended to be included within the scope of the present invention.

[0147] It is also understood that any compound described herein containing the structure:

[0148] Can have any of the following stereochemistries:

[0149]

[0150] Or it can be a mixture of any one or more of these stereochemistries. 4 This also applies when substituted by a nucleobase or a nucleobase derivative.

[0151] When a specific stereoisomer is identified, it is meant that the stereoisomer is substantially free of other stereoisomers, i.e., associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, particularly less than 2% and most preferably less than 1% of other stereoisomers. Thus, when a compound is, for example, designated as (R), this means that the compound is substantially free of the (S) isomer; when a compound is, for example, designated as E, this means that the compound is substantially free of the Z isomer; when a compound is, for example, designated as cis, this means that the compound is substantially free of the trans isomer. Stereoisomers can be separated using techniques known in the art, such as chromatography. Functionalization, for example, installation of suitable protecting groups such as benzoate (conditions such as BzCl, pyridine, dichloromethane) can facilitate separation of stereoisomers using silica gel chromatography or reverse phase chromatography or supercritical fluid (SFC) chromatography.

[0152] The salts of the compounds described herein and their solvates may be those in which the counterion is pharmaceutically acceptable. Salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of pharmaceutically acceptable compounds. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

[0153] Pharmaceutically acceptable salts include acid addition salts and base addition salts. Such salts can be formed by conventional means, for example, by reacting the free acid or free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent or in a medium in which the salt is insoluble, followed by removal of the solvent or medium using standard techniques (e.g., in a vacuum, by freeze drying or by filtration). Salts can also be prepared by exchanging the counterion of a compound of the invention in salt form with another counterion, for example, using a suitable ion exchange resin.

[0154] The pharmaceutically acceptable addition salts as mentioned above or below are intended to comprise the therapeutically active non-toxic acid addition salt and base addition salt forms that the compounds and their solvates are able to form.

[0155] Suitable acid includes for example, mineral acid, such as hydrohalic acid (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and similar acid; or organic acid, such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid (i.e. oxalic acid), malonic acid, succinic acid (i.e. succinic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-methyl benzenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid and similar acid. On the contrary, the salt form can be converted into the free base form by treating with suitable alkali.

[0156] Compounds containing acidic protons and their solvates can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.

[0157] Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth metal salts such as lithium, sodium, potassium, magnesium, calcium salts, and the like, salts with organic bases (e.g., primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline); benzathine penicillin, N-methyl-D-glucamine, hydrazine salts, and salts with amino acids such as, for example, arginine, lysine, etc. Conversely, the salt form can be converted into the free acid form by treatment with an acid.

[0158] The term solvate comprises the hydrates, as well as the solvent addition forms, which the compounds of the present invention, together with their salts, are able to form. Examples of such forms are, for example, hydrates, alcoholates, and the like.

[0159] The compounds of the present invention prepared as described below can be synthesized as mixtures of enantiomers, particularly racemic mixtures of enantiomers, which can be separated from each other according to resolution procedures known in the art. The method for separating the enantiomeric forms of compounds and their salts and solvates involves liquid chromatography using chiral stationary phases. The pure stereochemical isomeric forms can also be derived from the corresponding pure stereochemical isomeric forms of appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound will be synthesized by stereospecific preparation methods. These methods will advantageously employ enantiomerically pure starting materials.

[0160] The present invention also includes isotopically labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the one most commonly found in nature).

[0161] All isotopes and isotopic mixtures of any particular atom or element as specified herein are considered to be within the scope of the compounds of the invention, whether naturally occurring or synthetically produced, whether with natural abundance or in isotopically enriched form. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 O. 17 O. 18 O. 32 P. 33 P. 35 S. 18 F. 36 Cl, 122 I. 123 I. 125 I. 131 I 、75 Br, 76 Br, 77 Br and 82 Br. Preferably, the radioisotope is selected from the group consisting of: 2 H. 3 H. 11 C and 18 F. More preferably, the radioisotope is 2 H. In particular, deuterated compounds are intended to be included within the scope of the present invention.

[0162] Certain isotopically labeled compounds of the present invention (e.g., 3 H and 14 C-labeled ones) were used in substrate tissue distribution assays. 3 H) and carbon-14( 14 C) isotopes are useful because they are easy to prepare and detect. In addition, heavier isotopes such as deuterium (i.e., 2 H) substitution may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes (e.g. 15 O. 13 N. 11 C and 18 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.

[0163] The protecting groups mentioned herein may be any suitable hydroxy protecting groups. Suitable protecting groups are known in the art, for example from Wuts, PGM and Greene, TW: Protective Groups in Organic Synthesis, 4th edition, Wiley, New York, 2006. For example, the hydroxy protecting group may be a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl or benzoyl, -C(=O)-C 1-4 wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0164] The silyl group mentioned herein may be, for example, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl or triethylsilyl.

[0165] The diol protecting group may be, for example, -C(C 1-4 alkyl) 2- (such as (-C(CH3)2)-. One skilled in the art will understand that when the stereochemistry of the compound is such that -OR 4 AND-OR 5 When it is in cis configuration, R 4 and R 5 can be combined to form a diol protecting group. Similarly, those skilled in the art will understand that when the stereochemistry of the compound is such that -OR 5AND-OR 6 When it is in cis configuration, R 5 and R 6 Can be combined to form a diol protecting group.

[0166] The boronic acid protecting group can be, for example, catechol borane, pinacol borane, N-methyliminodiacetic acid (MIDA) borate, neopentyl glycol borane, pinanediol borane, biscyclohexyl glycol borane, or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol (MPMP-diol) borane.

[0167] The amino protecting group can be, for example, benzoyl (Bz), tert-butyloxycarbonyl (Boc), benzyl (Bn), acetyl (Ac), diphenylcarbamoyl, benzyloxycarbonyl (cbz), fluorenylmethoxycarbonyl (Fmoc), CF3C(O)-, trityl (trt), phthaloyl (phth) or =CHN(CH3)2.

[0168] The nucleobases or nucleobase derivatives mentioned herein encompass pyrimidine and purine nitrogenous bases, including modified and protected forms thereof. For example, the nucleobases mentioned herein include, but are not limited to, adenine, cytosine, guanine, thymine, 6-chloropurine, uracil, adenine, 7-methylguanine, xanthine, hypoxanthine, purine, 2,6-diaminopurine, 5,6-dihydrouracil, 6,8-diaminopurine inosine, 5-methylcytosine, and 5-hydroxymethylcytosine. A modified or protected nucleobase can be, for example, one in which an amino protecting group (e.g., benzoyl (Bz), tert-butyloxycarbonyl (Boc), benzyl (Bn), acetyl (Ac), diphenylcarbamoyl, benzyloxycarbonyl (cbz), fluorenylmethoxycarbonyl (Fmoc), CF3C(O)-, trityl (trt), phthaloyl (phth), =CHN(CH3)2) or an amino (-NH2) group is replaced by a halogen (e.g., chlorine). Such modified or protected nucleobases may also be referred to as nucleobase precursors. For example, the nucleobases or nucleobase derivatives mentioned herein may include any purine or pyrimidine nitrogenous base, such as any of the nucleobases mentioned above, wherein one or more substituents R are present on the heteroaryl core of the nitrogenous base, replacing hydrogen or another substituent moiety, wherein R is selected from, but not limited to, halogen, -NR * R ** , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, C substituted by one, two or three halogen atoms 1-4 Alkyl, where R * For hydrogen, C 1-4 Alkyl or -C(O)OC1-4 Alkyl and R ** For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl.

[0169] “TBDPS” means tert-butyldiphenylsilyl; “Piv” means pivaloyl; “Bn” means benzyl; “Et” means ethyl; “Me” means methyl; “PMB” means p-methoxybenzyl; “TMS” means trimethylsilyl; “tBu-O” means tert-butoxy; and “Pr” means n-propyl.

[0170] In one aspect, the present invention relates to a compound of formula (I)

[0171]

[0172] or a salt or solvate thereof, wherein:

[0173] Y is -O- or -CH2-;

[0174] n is 0 or 1;

[0175] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0176] When n is 1, R 2 is hydrogen and R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) mC(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0177] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0178] Which faces R 1 or R 2 Key When R 1 or R 2 For 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) mS(O) x R c , silyl group, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0179] Each R a are independently hydrogen or C 1-6 alkyl;

[0180] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0181] R c C 1-6 alkyl or aryl;

[0182] PG is a hydroxyl protecting group;

[0183] m is 0 or 1;

[0184] x is 0, 1, or 2;

[0185] R 3 For-OR 4 or R 10 ;

[0186] R 10 It is a nucleobase or a nucleobase derivative.

[0187] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0188] or R 5 and R 6 Together they form a diol protecting group;

[0189] or R 4 and R 5 Together they form a diol protecting group;

[0190] The conditions are:

[0191] (a) The compound is not a compound of the formula:

[0192] Wherein Y is -O- or -CH2-; R 4 is a hydrogen or hydroxyl protecting group, such as C 1-4 Alkyl, tert-butyldimethylsilyl, C 1-4 Alkyl-OC 1-4alkyl, tetrahydropyranyl, allyl, tert-butyldiphenylsilyl, benzyl, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl; R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 Each is independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form -C(C 1-4 Alkyl) 2-; or wherein Y is -O- or -CH2, R 4 is methyl, R 2 =O or =CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 Alkyl; and

[0193] (b) the compound is not a compound of the formula:

[0194] where R v =O, -OH or =CH2; and

[0195] (c) the compound is not a compound of the formula:

[0196] where R w is methyl or H; and

[0197] (d) the compound is not a compound of the formula:

[0198] wherein R is CO2Et or CH2OH or any stereoisomer thereof; and

[0199] (e) The compound is not any of the following:

[0200]

[0201] in

[0202] R 5 is hydrogen or -C(=O)-C 1-4 alkyl;

[0203] R 6 is hydrogen or -C(=O)-C 1-4 Alkyl; or R 5 and R 6Together they form -C(CH3)2-

[0204] Y is -O- or -CH2-;

[0205] R 10 for

[0206]

[0207] Q 1 CR 6a ;

[0208] Q 2 N or CR 6b ;

[0209] R 6a and R 6b Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0210] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0211] R 3a is hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0212] R 7a is hydrogen;

[0213] R 7b For hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0214] R 4a is hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl; and

[0215] R x for

[0216] or a salt or solvate thereof.

[0217] In one aspect, the present invention relates to a compound of formula (A)

[0218]

[0219] or a salt or solvate thereof, wherein:

[0220] Y is -O- or -CH2-;

[0221] n is 0 or 1;

[0222] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0223] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0224] When n is 0, R 1and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0225] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0226] Each R a are independently hydrogen or C 1-6 alkyl;

[0227] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0228] R c C 1-6 alkyl or aryl;

[0229] PG is a hydroxyl protecting group;

[0230] m is 0 or 1;

[0231] x is 0, 1, or 2;

[0232] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0233] or R 5 and R 6 Together they form a diol protecting group;

[0234] or R 4 and R 5 Together they form a diol protecting group;

[0235] The conditions are:

[0236] (a) The compound is not a compound of the formula:

[0237] Wherein Y is -O- or -CH2-; R 4 is a hydrogen or hydroxy protecting group, such as C 1-4 Alkyl, tert-butyldimethylsilyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, tert-butyldiphenylsilyl, benzyl, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl; R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 Each is independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form -C(C 1-4 Alkyl) 2-; or wherein Y is -O- or -CH2, R 4 is methyl, R 2 =O or =CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 Alkyl; and

[0238] (b) the compound is not a compound of the formula:

[0239] where R v =O, -OH or =CH2; and

[0240] (c) the compound is not a compound of the formula: where R w is methyl or H; and

[0241] (d) the compound is not a compound of the formula:

[0242] wherein R is CO2Et or CH2OH or any stereoisomer thereof.

[0243] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof or any subgroup thereof as mentioned in any other embodiment herein, wherein the compound is not a compound of the formula:

[0244] Wherein Y is -O- or -CH2-; R 4 For any chemical moiety, R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 Each is independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form -C(C 1-4 alkyl)2- or wherein R 4 When it is methyl, R 2 =O or =CH2 and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 alkyl.

[0245] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is of the formula:

[0246]

[0247] or a salt or solvate thereof.

[0248] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is of the formula:

[0249]

[0250] or a salt or solvate thereof.

[0251] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is a compound of formula (A-1), (A-2), (A-3), (A-4), (A-5) or (A-6):

[0252]

[0253] or a salt or solvate thereof.

[0254] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is a compound of formula (A-1a), (A-2a), (A-3a), (A-4a), (A-5a) or (A-6a):

[0255]

[0256] or a salt or solvate thereof.

[0257] In one embodiment, the present invention relates to compounds of formula (A) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is a compound of formula (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b):

[0258]

[0259] or a salt or solvate thereof.

[0260] In one embodiment, the present invention relates to compounds of formula (I), and salts and solvates thereof, wherein the compound has the stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0261] In one embodiment, the present invention relates to those compounds of any one of (A-1a), (A-3a), (A-1b) or (A-3b) mentioned in any other embodiment herein and salts and solvates thereof or any subgroup thereof.

[0262] In one embodiment, the present invention relates to those compounds of any one of (A-1a), (A-3a), (A-5a), (A-1b), (A-3b) or (A-5b) mentioned in any other embodiment herein and salts and solvates thereof or any subgroup thereof.

[0263] In one embodiment, the present invention relates to compounds of any of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein:

[0264] Y is -O- or -CH2-;

[0265] n is 0 or 1;

[0266] When n is 1, R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 alkyl; or

[0267] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0268] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0269] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0270] Each R a are independently hydrogen or C 1-6 alkyl;

[0271] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0272] R c C 1-6 alkyl or aryl;

[0273] PG is a hydroxyl protecting group;

[0274] m is 0 or 1;

[0275] x is 0, 1, or 2;

[0276] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0277] or R 5 and R 6 Together they form a diol protecting group;

[0278] or R 4 and R 5 Together they form a diol protecting group;

[0279] Provided that the compound is not a compound of the formula:

[0280] where R w is methyl or H; or

[0281] wherein R is CO2Et or CH2OH or any stereoisomer thereof.

[0282] In one embodiment, the present invention relates to compounds of any of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein:

[0283] Y is -O- or -CH2-;

[0284] n is 0 or 1;

[0285] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0286] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0287] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -OR a 、-OPG、-(CH2)C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0288] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0289] Each R a are independently hydrogen or C 1-6 alkyl;

[0290] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0291] R c C 1-6 alkyl or aryl;

[0292] PG is a hydroxyl protecting group;

[0293] m is 0 or 1;

[0294] x is 0, 1, or 2;

[0295] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0296] or R 5 and R 6 Together they form a diol protecting group;

[0297] or R 4 and R 5 Together they form a diol protecting group;

[0298] The conditions are:

[0299] (a) The compound is not a compound of the formula:

[0300] Wherein Y is -O- or -CH2-; R 4 is a hydrogen or hydroxyl protecting group, such as C 1-4 Alkyl, tert-butyldimethylsilyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, tert-butyldiphenylsilyl, benzyl, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl; R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 are each independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form -C(C 1-4 Alkyl) 2-; or wherein Y is -O- or -CH2, R 4 is methyl, R 2=O or =CH2, and R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 Alkyl; and

[0301] (b) the compound is not a compound of the formula:

[0302] where R v =O, -OH or =CH2.

[0303] In one embodiment, the present invention relates to compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, wherein:

[0304] Y is -O- or -CH2-;

[0305] n is 0 or 1;

[0306] When n is 1, R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 alkyl; or

[0307] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0308] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -OR a 、-OPG、-(CH2)C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0309] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond;

[0310] Each R a are independently hydrogen or C 1-6 alkyl;

[0311] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0312] R c C 1-6 alkyl or aryl;

[0313] PG is a hydroxyl protecting group;

[0314] m is 0 or 1;

[0315] x is 0, 1, or 2; and

[0316] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0317] or R 5 and R 6 Together they form a diol protecting group;

[0318] or R 4 and R 5 Together they form a diol protecting group.

[0319] In one embodiment, the present invention relates to those compounds of any of Formula (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein.

[0320] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1.

[0321] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or R 2 is hydrogen and R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2)m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2.

[0322] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or R 2 is hydrogen and R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -C(O)OR a 、-C(O)NR a 2. -C(O)R a 、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2.

[0323] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -C(O)OR a 、-C(O)NR a 2. -C(O)R a , =O or =CR a 2; and R 2 For hydrogen.

[0324] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is -NH2, -CH2NH2, -OH, -CH2OH, =O or =; and R 2 For hydrogen.

[0325] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is -OH, -CH2OH, =O or =; and R 2 For hydrogen.

[0326] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is hydrogen; and R 2 -(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 2.

[0327] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 2 is -NH2, -CH2NH2, -OH, -CH2OH, =O or =; and R 1 For hydrogen.

[0328] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 2 is -OH, -CH2OH, =O or =; and R 1 For hydrogen.

[0329] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is hydrogen; and R 2 -(CH2) m NR a 2 or -C(O)NR a 2.

[0330] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 2 is -NH2 or -CH2NH2; and R 1 For hydrogen.

[0331] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 and R 2 One of them is 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 2.

[0332] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 and R 2 One of them is hydrogen and the other is -NR a 2. -CH2NR a 2. -OR a 、-CH2OR a 、-C(O)OR a , =O or =CR a 2.

[0333] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 -NR a 2. -CH2NR a 2. -OR a 、-CH2OR a 、-C(O)OR a 、-C(O)R a 、-B(OR b )2、S(O) x R c , =O or =CR a 2; and R 2 For hydrogen.

[0334] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 1, R 1 is hydrogen; R 2 -NR a 2. -CH2NR a 2. -CH2OR a 、-C(O)R a 、-B(OR b )2、S(O) x R c 、-C(O)OR d 、-OR d or =C(R a )(R d );R a is hydrogen or C 1-6 alkyl; and R d C 1-6 alkyl.

[0335] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0.

[0336] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2)m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2 or =CH2.

[0337] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -C(O)OR a 、-C(O)NR a 2 or -B (OR b )2.

[0338] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of them is hydrogen and the other is -CH2NR a 2. -OR a 、-CH2OR a 、-C(O)ORa 、-C(O)R a 、-B(OR b )2 or =CH2.

[0339] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of them is hydrogen and the other is -CH2NR a 2. -OR a 、-CH2OR a 、-C(O)OR a OR-B(OR b )2.

[0340] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of the is hydrogen and the other is -OH, -CH2OH, -CH2NH2, -C(O)OH or C(O)OEt.

[0341] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein n is 0, R 1 and R 2 One of the two is hydrogen and the other is -OH or -CH2NH2.

[0342] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein -(CH2) m NR a When 2 exists, it is -(CH2) m NHC 1-6 Alkyl or -(CH2) m NH2.

[0343] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein when R 1 or R 2 -(CH2) m When OPG is a silyl group, PG is a silyl group, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl.

[0344] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein R a is H, methyl, ethyl or propyl.

[0345] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein -NR a 2 is -NHR when present a .

[0346] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein -NR a 2. -CH2NR a 2. -OR a 、-CH2OR a 、-C(O)OR a 、-C(O)R a 、-S(O) x R c Sum = CR a 2 exists, respectively -NH2, -CH2NH2, -OH, -CH2OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -SR c and =CH2.

[0347] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein Y is O.

[0348] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein Y is CH2.

[0349] In one embodiment, the present invention relates to compounds of any of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein R 4 、R 5 and R 6 are each independently a hydroxy protecting group, or, if R 5 and R 6 In cis orientation, they may optionally be brought together to form a diol protecting group, or if R 4 and R 5 In cis orientation, they may optionally be brought together to form a diol protecting group.

[0350] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b) as mentioned in any other embodiment herein and their salts and solvates or any subgroup thereof, wherein the hydroxy protecting group is selected from a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; and / or the diol protecting group is -C(C 1-4 Alkyl)2-.

[0351] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b), and salts and solvates thereof, such as compounds of any one of Formula (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b), or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 is hydrogen or a hydroxy protecting group such as a silyl group, C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 Alkyl, tetrahydropyranyl, allyl, benzyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl, wherein the benzyl group is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; and R 5 and R 6 Each is independently a hydroxy protecting group, such as -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzoyl, benzyl and -CH2-naphthyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form diol protecting groups such as -C(C 1-4 Alkyl)2-.

[0352] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b), and salts and solvates thereof, such as compounds of any one of Formula (A-1), (A-1a), (A-1b), (A-2), (A-2a), or (A-2b), or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 is a silyl group or C 1-4 alkyl (preferably Me); and R 5 and R 6 -C(=O)-C 1-4 Alkyl (preferably pivaloyl); or R 5 and R6 Together they form the diol protecting group -C(C 1-4 alkyl)2-(preferably -C(CH3)2-).

[0353] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b), and salts and solvates thereof, such as compounds of any one of Formula (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b), or salts or solvates thereof, or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 and R 5 is a hydroxyl protecting group, such as a silyl group, a C 1-4 Alkyl, -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzoyl, benzyl and -CH2-naphthyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 4 and R 5 Together they form diol protecting groups such as -C(C 1-4 alkyl)2; and R 6 is hydrogen or a hydroxy protecting group such as 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, wherein the benzyl group is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0354] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-2), (A-2a), (A-2b), (A-3), (A-3a), (A-3b), (A-5), (A-5a), or (A-5b), and salts and solvates thereof, such as compounds of any one of Formula (A-3), (A-3a), or (A-3b), or salts or solvates thereof, or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 and R 5 is a hydroxyl protecting group, such as -C(=O)-C 1-4alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzoyl, benzyl and -CH2-naphthyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 4 and R 5 Together they form diol protecting groups such as -C(C 1-4 alkyl)2; and R 6 is hydrogen or a hydroxy protecting group such as 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, wherein the benzyl group is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0355] In one embodiment, the present invention relates to compounds of any one of formula (I), (A), (Aa), (Ab), (A-3), (A-3a), (A-3b), and salts and solvates thereof, such as compounds of any one of formula (A-3), (A-3a), or (A-3b), or salts or solvates thereof, or any subgroup thereof mentioned in any other embodiment herein, wherein R 4 and R 5 Together they form the diol protecting group -C(C 1-4 alkyl) 2- (preferably -C(CH3)2-); and R 6 is a silyl group, a benzyl group, a -CH2-naphthyl group or a -C(=O)-C 1-4 Alkyl, wherein the benzyl group is optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0356] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-4), (A-4a), (A-4b), (A-6), (A-6a), or (A-6b), and salts and solvates thereof, such as compounds of any one of Formula (A-4), (A-4a), (A-4b), (A-6), (A-6a), or (A-6b), or salts or solvates thereof, or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 、R 5 and R 6 Each independently is hydrogen or a hydroxy protecting group selected from a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 Alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C1-4 wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3.

[0357] In one embodiment, the present invention relates to compounds of any one of Formula (I), (A), (Aa), (Ab), (A-1), (A-1a), or (A-1b), and salts and solvates thereof, such as compounds of any one of Formula (A-1), (A-1a), or (A-1b), or salts or solvates thereof, or any subgroup thereof as mentioned in any other embodiment herein, wherein R 4 C 1-4 Alkyl groups, such as methyl, and R 5 and R 6 Together they form -C(C 1-4 alkyl)2-, such as -C(CH3)2-.

[0358] In one embodiment, the present invention relates to compounds of any one of formula (I), (A), (Aa), (Ab), (A-3), (A-3a), or (A-3b), and salts and solvates thereof, such as compounds of any one of formula (A-3), (A-3a), or (A-3b), or salts or solvates thereof, or any subgroup thereof as mentioned in any other embodiment herein, wherein R 6 is a silyl group, a benzyl group, a -CH2-naphthyl group, a benzoyl group or a -C(=O)-C 1-4 alkyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3, and R 5 and R 6 Together they form -C(C 1-4 alkyl)2-, such as -C(CH3)2-.

[0359] In one embodiment, the present invention relates to a compound selected from the group consisting of:

[0360]

[0361]

[0362]

[0363]

[0364] or a salt or solvate thereof.

[0365] In another aspect, the present invention relates to a compound of formula (B):

[0366] or a salt or solvate thereof, wherein:

[0367] Y is -O- or -CH2-;

[0368] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group;

[0369] or R 5 and R 6 Together they form a diol protecting group;

[0370] or R 4 and R 5 Together they form a diol protecting group.

[0371] 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 The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0372] In one embodiment, the present invention relates to compounds of formula (B), and salts and solvates thereof, wherein the compound has the stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0373] In one embodiment, the present invention relates to a compound selected from the group consisting of:

[0374]

[0375] or a salt or solvate thereof.

[0376] In another aspect, the present invention relates to a compound of formula (C):

[0377]

[0378] in:

[0379] Y is -O- or -CH2-;

[0380] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or

[0381] R 4 and R 5 taken together to form a diol protecting group; or

[0382] R 5 and R 6 Together they form a diol protecting group;

[0383] Provided that the compound is not:

[0384]

[0385] 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 The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0386] In one embodiment, the present invention relates to compounds of formula (B), and salts and solvates thereof, wherein the compound has the stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0387] In one embodiment, the present invention relates to compounds of formula (C) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the compound is of the formula:

[0388]

[0389] or a salt or solvate thereof.

[0390] In one embodiment, the present invention relates to compounds of formula (C) and salts and solvates thereof, wherein the compound is selected from:

[0391]

[0392]

[0393] or a salt or solvate thereof.

[0394] In another aspect, the present invention relates to a compound of formula (D):

[0395]

[0396] or a salt or solvate thereof, wherein:

[0397] Y is -O- or -CH2-;

[0398] in is a single bond or a double bond; and

[0399] when When it is a single bond, R 1 ' and R 2 One of ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by 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 ;

[0400] when When it is a double bond, R 1 ' and R 2 ' is hydrogen or C1-6 alkyl and the other is a silyl group, a C optionally substituted silyl group 1-6 Alkyl, -OC 1-6 Alkyl or C(O)R a ;

[0401] and

[0402] R a is hydrogen or C 1-6 alkyl;

[0403] Each R b is hydrogen or two R b Together they form a boronic acid protecting group;

[0404] R 3 OR4 or R 10 ;

[0405] R 10 is a nucleobase or a nucleobase derivative;

[0406] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or

[0407] R 4 and R 5 taken together to form a diol protecting group; or

[0408] R 5 and R 6 Together they form a diol protecting group.

[0409] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein:

[0410] Y is -O- or -CH2-;

[0411] in is a single bond or a double bond; and

[0412] when When it is a single bond, R 1 ' and R 2 One of ' is hydrogen or C 1-6 an alkyl group and the other is a silyl group, a C 1-6 Alkyl, -OC 1-6 Alkyl, -B(OR b )2-SC 1-6 Alkyl, -S-aryl, -O-aryl or C(O)R a ;

[0413] when When it is a double bond, R 1 ' and R 2 One of ' is hydrogen or C 1-6 an alkyl group and the other is a silyl group, a C 1-6 Alkyl, -OC 1-6 Alkyl or C(O)R a ;

[0414] and

[0415] R a is hydrogen or C 1-6 alkyl;

[0416] Each R bis hydrogen or two R b Together they form a boronic acid protecting group;

[0417] R 3 OR 4 or R 10 ;

[0418] R 10 is a nucleobase or a nucleobase derivative;

[0419] R 4 、R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or

[0420] R 4 and R 5 taken together to form a diol protecting group; or

[0421] R 5 and R 6 Together they form a diol protecting group.

[0422] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein R 3 OR 4 .

[0423] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment herein, or any subgroup thereof, wherein the silyl group, when present, is trimethylsilyl, triethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl or dimethylphenylsilyl.

[0424] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein For a single bond.

[0425] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein For double bonds.

[0426] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein is a single bond, R 1 ' and R 2 ' one of which is hydrogen and the other is a silyl group, a C1 alkyl group substituted by a silyl group, -OC 1-6 Alkyl or -S-aryl.

[0427] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein is a double bond, R 1 ' and R 2 ' is hydrogen or methyl, and the other is a silyl group, a C1 alkyl group substituted by a silyl group, -OC 1-6 Alkyl or -S-aryl.

[0428] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein R 1 ' and R 2 One of the ' is C 1-6 Alkyl and R 1 ' and R 2 The other one in ' is not C 1-6 Alkyl or hydrogen.

[0429] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein R 1 ' and R 2 One of the ' is hydrogen and R 1 ' and R 2 The other one in ' is not C 1-6 Alkyl or hydrogen.

[0430] 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 The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0431] In one embodiment, the present invention relates to compounds of formula (D), and salts and solvates thereof, wherein the compound has the stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0432] In one embodiment, the present invention relates to compounds of formula (D) and salts and solvates thereof, wherein the compound is selected from:

[0433]

[0434] or a salt or solvate thereof.

[0435] In another aspect, the present invention relates to a compound of formula (E):

[0436]

[0437] or a salt or solvate thereof, wherein:

[0438] Y is -O- or -CH2-;

[0439] n is 0 or 1;

[0440] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0441] When n is 1, R 2 is hydrogen and R 1 -(CH2) mNR 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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0442] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c or =CH2;

[0443] Which faces R 1 or R 2 Key When R 1 or R 2 For hydrogen, -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond

[0444] Each R a are independently hydrogen or C 1-6 alkyl;

[0445] Two R's b Both are hydrogen or two R b Together they form a boronic acid protecting group;

[0446] R c C 1-6 alkyl or aryl;

[0447] x is 0, 1, or 2;

[0448] m is 0 or 1;

[0449] R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or R 5 and R 6 Together they form a diol protecting group;

[0450] R 10 is a nucleobase or a nucleobase derivative;

[0451] PG is a hydroxyl protecting group;

[0452] Provided that the compound is not any of the following:

[0453]

[0454]

[0455] in

[0456] R 5 is hydrogen or -C(=O)-C 1-4 alkyl;

[0457] R 6 is hydrogen or -C(=O)-C 1-4 Alkyl; or R 5and R 6 Together they form -C(CH3)2-

[0458] Y is -O- or -CH2-;

[0459] R 10 for

[0460]

[0461] Q 1 CR 6a ;

[0462] Q 2 N or CR 6b ;

[0463] R 6a and R 6b Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0464] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0465] R 3a is hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0466] R 7a is hydrogen;

[0467] R 7b For hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0468] R 4a is hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl; and

[0469] R x for

[0470] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein:

[0471] Y is -O- or -CH2-;

[0472] n is 0 or 1;

[0473] When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or

[0474] When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2;

[0475] When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a2. -(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;

[0476] Which faces R 1 or R 2 Key When R 1 or R 2 For 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, C substituted by silyl group 1-6 When alkyl or -O-aryl, it is a single bond, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond

[0477] Each R a are independently hydrogen or C 1-6 alkyl;

[0478] Two R's b Together they form a boronic acid protecting group;

[0479] R c C 1-6 alkyl or aryl;

[0480] x is 0, 1, or 2;

[0481] m is 0 or 1;

[0482] R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or R 5 and R 6 Together they form a diol protecting group;

[0483] R 10 is a nucleobase or a nucleobase derivative;

[0484] PG is a hydroxyl protecting group;

[0485] Provided that the compound is not any of the following:

[0486]

[0487]

[0488] in

[0489] R 5 is hydrogen or -C(=O)-C 1-4 alkyl;

[0490] R 6 is hydrogen or -C(=O)-C 1-4 Alkyl; or R 5 and R 6 Together they form -C(CH3)2-

[0491] Y is -O- or -CH2-;

[0492] R 10 for

[0493]

[0494] Q 1 CR 6a ;

[0495] Q 2 N or CR 6b ;

[0496] R 6a and R 6b Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0497] R 9a and R 9bEach independently represents hydrogen or C 1-4 alkyl;

[0498] R 3a is hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0499] R 7a is hydrogen;

[0500] R 7b For hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0501] R 4a is hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl; and

[0502] R x for

[0503] In one embodiment, the present invention relates to compounds of formula (E) as mentioned in any other embodiment, and salts and solvates thereof, or any subgroup thereof, wherein n is 1.

[0504] In one embodiment, the present invention relates to compounds of formula (E) as mentioned in any other embodiment, and salts and solvates thereof, or any subgroup thereof, wherein n is 0.

[0505] In one embodiment, the present invention relates to compounds of formula (E) as mentioned in any other embodiment, and salts and solvates thereof, or any subgroup thereof, wherein Y is O.

[0506] and any other salts and solvates thereof mentioned in any other embodiment or any subgroup thereof, wherein Y is CH2.

[0507] In one embodiment, the present invention relates to compounds of formula (E), and salts and solvates thereof, wherein R 1 and R 2The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0508] In one embodiment, the present invention relates to compounds of formula (E), and salts and solvates thereof, wherein Y, R 4 、R 5 and R 6 The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0509] In one embodiment, the present invention relates to compounds of formula (E), and salts and solvates thereof, wherein the compound has a stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), for example, as depicted in any of the structures below;

[0510]

[0511]

[0512] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof or any subgroup thereof as mentioned in any other embodiment herein, wherein -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 exists, respectively -NH2, -CH2NH2, -OH, -CH2OH, -C(O)OC 1-6 Alkyl, -C(O)-C 1-6 Alkyl, -SR c and =CH2.

[0513] It is understood that Y, n, R, and any of the compounds of formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b), or any subgroup thereof, as defined herein, are the same. 1 、R 2 、R 5 and R 6 All definitions of are applicable to compounds of formula (E) and their salts and solvates. Therefore, in one embodiment, the present invention relates to compounds of formula (E) and their salts and solvates, wherein Y, n, R 1 、R 2 、R 5 and R 6 The same as those compounds of any one of Formula (I), (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0514] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof as mentioned in any other embodiment or any subgroup thereof, wherein R 5 and R 6 are each independently hydrogen or -C(=O)-C 1-4 Alkyl, or R 5 and R 6 Together they form -C(C 1-4 alkyl)2-, such as -C(CH3)2-.

[0515] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is selected from:

[0516]

[0517]

[0518] or a salt or solvate thereof.

[0519] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is selected from:

[0520]

[0521] or a salt or solvate thereof.

[0522] In one embodiment, the present invention relates to compounds of formula (E) and salts and solvates thereof, wherein the compound is selected from:

[0523]

[0524]

[0525] or a salt or solvate thereof.

[0526] In another aspect, the present invention relates to a compound of formula (F):

[0527]

[0528] or a salt or solvate thereof, wherein:

[0529] R 5 and R 6 are each independently hydrogen or a hydroxy protecting group; or R 5 and R 6 taken together is a diol protecting group; and

[0530] R 10 It is a nucleobase or a nucleobase derivative.

[0531] In one embodiment, the present invention relates to compounds of formula (F), and salts and solvates thereof, wherein Y, R 4 、R 5 and R 6 The same as those compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b) or (A-6b), or any subgroup thereof, as defined herein, as any other embodiment.

[0532] In one embodiment, the present invention relates to compounds of formula (F), and salts and solvates thereof, wherein the compound has the stereochemistry as depicted for those compounds of any of formula (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), or (A-6b).

[0533] In one embodiment, the present invention relates to compounds of any one of Formula (A), (Aa), (Ab), (A-1), (A-2), (A-3), (A-4), (A-5), (A-6), (A-1a), (A-2a), (A-3a), (A-4a), (A-5a), (A-6a), (A-1b), (A-2b), (A-3b), (A-4b), (A-5b), (A-6b), (B), (C), (D), (E) and (F), and salts and solvates thereof, or any subgroup thereof, as referred to in any other embodiment herein, wherein the silyl group, if present, is tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, trimethylsilyl or triethylsilyl.

[0534] In one embodiment, the present invention relates to compounds of any of 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), (A-6b), (B), (C), (D), (E) and (F) as referred to in any other embodiment herein, and salts and solvates thereof, or any subgroup thereof, wherein -B(OR b )2, if present, is catechol borane, pinacol borane, N-methyliminodiacetic acid (MIDA) borate, neopentyl glycol borane, pinanediol borane, biscyclohexyl glycol borane, or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol (MPMP-diol) borane.

[0535] In one embodiment, the present invention relates to those compounds of any of formula (D), (E) and (F), wherein R 10 When present, it is cytosine, thymine, uracil, or a modified or protected form thereof, or a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0536]

[0537] R 3a 、R 3b 、R 3c 、R 3d and R 3e are independently hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0538] R 7a Hydrogen, -C(O)OC 1-4 Alkyl or

[0539] R 7b For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl;

[0540] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g are independently hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0541] R 8a and R 8b are each independently hydrogen or C 1-4 alkyl;

[0542] Q 1 N or CR 6a ;

[0543] Q 2 N or CR 6b ;

[0544] Q 3 N or CR 6c ;

[0545] Q 4 N or CR 6d ;

[0546] The condition is Q 3 and Q 4 At most one of them is N;

[0547] Q 8 N or CR 6g ;

[0548] Q 9 N or CR 6h ;

[0549] Q 10 N or CR 6i ;

[0550] Q 11 N or CR 6j ;

[0551] Q 5 CR 3d ;Q 6 is N; and Q 7 CR 4f ;or

[0552] Q 5 CR 3d ;Q 6 CR 4e ; and Q 7 is N; or

[0553] Q 5 N; Q 6 CR 4e ; and Q 7 CR 4f ;or

[0554] Q 5 N; Q 6 CR 4e ; and Q 7 is N; or

[0555] Q 5 N; Q 6 is N; and Q 7 CR 4f ;or

[0556] Q 5 N; Q 6 is N; and Q 7 is N;

[0557] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6jare independently hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b , or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0558] R 9a and R 9b are each independently hydrogen or C 1-4 alkyl.

[0559] In one embodiment, the present invention relates to those compounds of any of formula (D), (E) and (F), wherein R 10 When present, it is cytosine, thymine, uracil, or a modified or protected form thereof, or a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0560]

[0561] where R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0562] R 7a represents hydrogen;

[0563] R 7b Represents hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl;

[0564] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0565] R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl;

[0566] Q 1 Indicates N or CR 6a ;

[0567] Q 2 Indicates N or CR 6b ;

[0568] Q 3 Indicates N or CR 6c ;

[0569] Q 4 Indicates N or CR 6d ;

[0570] The condition is Q 3 and Q 4 At most one of them represents N;

[0571] Q 8 Indicates N or CR 6g ;

[0572] Q 9 Indicates N or CR 6h ;

[0573] Q 10 Indicates N or CR 6i ;

[0574] Q 11 Indicates N or CR 6j ;

[0575] Q 5 Indicates CR 3d ;Q 6 represents N; and Q 7 Indicates CR 4f ;or

[0576] Q 5 Indicates CR 3d ;Q 6 Indicates CR 4e ; and Q 7 represents N; or

[0577] Q 5 Indicates N; Q 6 Indicates CR 4e ; and Q 7 Indicates CR 4f ;or

[0578] Q 5 Indicates N; Q 6 Indicates CR 4e ; and Q 7 represents N; or

[0579] Q 5Indicates N; Q 6 represents N; and Q 7 Indicates CR 4f ;or

[0580] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates N;

[0581] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 Alkyl, –NR 9a R 9b , or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0582] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0583] In one embodiment, the present invention relates to those compounds of any of formula (D), (E) and (F), wherein R 10 When present, it is cytosine, thymine, uracil, or a modified or protected form thereof, or a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4), and (a-5):

[0584]

[0585] where R 3a 、R 3b 、R 3c 、R 3d and R 3e Each independently represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl;

[0586] R 7a represents hydrogen;

[0587] R 7b Represents hydrogen, C3-6 Cycloalkyl or C 1-4 alkyl;

[0588] R 4a 、R 4b 、R 4c 、R 4d 、R 4e 、R 4f and R 4g Each independently represents hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl;

[0589] R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl;

[0590] Q 1 Indicates CR 6a ;

[0591] Q 2 Indicates CR 6b ;

[0592] Q 3 Indicates N or CR 6c ;

[0593] Q 4 Indicates N or CR 6d ;

[0594] The condition is Q 3 and Q 4 At most one of them represents N;

[0595] Q 8 Indicates N or CR 6g ;

[0596] Q 9 Indicates N or CR 6h ;

[0597] Q 10 Indicates N or CR 6i ;

[0598] Q 11 Indicates N or CR 6j ;

[0599] Q 5 Indicates CR 3d ;Q 6 represents N; and Q 7 Indicates CR 4f ;or

[0600] Q 5Indicates CR 3d ;Q 6 Indicates CR 4e ; and Q 7 represents N; or

[0601] Q 5 Indicates N; Q 6 Indicates CR 4e ; and Q 7 Indicates CR 4f ;or

[0602] Q 5 Indicates N; Q 6 Indicates CR 4e ; and Q 7 represents N; or

[0603] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates CR 4f ;or

[0604] Q 5 Indicates N; Q 6 represents N; and Q 7 Indicates N;

[0605] R 6a 、R 6b 、R 6c 、R 6d 、R 6e 、R 6f 、R 6g 、R 6h 、R 6i and R 6j Each independently represents hydrogen, halogen, C 1-4 Alkyl, –NR 9a R 9b , or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0606] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl;

[0607] In one embodiment, the present invention relates to those compounds of any of formula (D), (E) and (F), wherein R 10 When present, it is cytosine, thymine, uracil, or a modified or protected form thereof, or a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2) and (a-3):

[0608]

[0609] where R 3a 、R 3b and R 3c Each independently represents hydrogen, halogen, -NR 7a R 7b 、C 1-4 Alkyl or -OC 1-4 alkyl;

[0610] R 7a represents hydrogen;

[0611] R 7b Represents hydrogen or C 1-4 alkyl;

[0612] R 4a 、R 4b and R 4c Each independently represents hydrogen, halogen, -NR 8a R 8b , or C 1-4 alkyl;

[0613] R 8a and R 8b Each independently represents hydrogen or C 1-4 alkyl;

[0614] Q 1 Indicates N or CR 6a ;

[0615] Q 2 Indicates N or CR 6b ;

[0616] Q 3 Indicates N or CR 6c ;

[0617] Q 4 Indicates N or CR 6d ;

[0618] The condition is Q 3 and Q 4 At most one of them represents N;

[0619] R 6a 、R 6b 、R 6c 、R 6d 、R 6e and R 6f Each independently represents hydrogen, halogen, C 1-4 Alkyl, –NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl;

[0620] R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl.

[0621] In one embodiment, the present invention relates to compounds of any one of formula (D), (E) and (F), wherein R 10 When present, it is a bicyclic aromatic heterocyclic ring system (a-1) wherein R 3a It represents -NH2 or chlorine.

[0622] All possible combinations of the above-indicated embodiments are considered to be encompassed within the scope of the present invention.

[0623] Pharmacology

[0624] It has been determined that spiro bicyclic nucleosides show interesting activity, such as activity against PRMT5. Novel intermediates that can be used to synthesize spiro bicyclic nucleoside analogs have been developed. Specifically, these intermediates contain functional groups that can be diversified to obtain a variety of spiro bicyclic nucleoside analogs. Therefore, disclosed herein are compounds that can be used as intermediates for preparing spiro bicyclic nucleoside analogs that can, for example, have activity against PRMT5. Also disclosed herein are spiro bicyclic nucleoside analogs that themselves can have PRMT5 inhibitory activity or can be used as intermediates for further functionalization to provide spiro bicyclic nucleoside analogs with interesting activity.

[0625] Spirobicyclic nucleoside analogs have been found to inhibit PRMT5 activity.

[0626] Specifically, such compounds can bind to the PRMT5 enzyme and compete with the natural substrate SAM (S-adenosyl-L-methionine) to inhibit this enzyme.

[0627] Such compounds or pharmaceutical compositions thereof can be used for the treatment or prevention, in particular for the treatment of diseases such as blood disorders, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiple organ failure, kidney disease, platelet aggregation, sperm motility, transplant rejection, graft rejection, lung injury, etc.

[0628] Such compounds or pharmaceutical compositions thereof can be used for treatment or prevention, in particular for the treatment of diseases such as allergies, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorders, diabetes, obesity, blood disorders, sickle cell anemia, etc.

[0629] Such compounds or pharmaceutical compositions thereof can be used for treatment or prevention, in particular for the treatment of diseases such as proliferative disorders, eg autoimmune diseases, cancer, benign neoplasms or inflammatory diseases.

[0630] Such compounds or pharmaceutical compositions thereof can be used for the treatment or prevention, in particular for the treatment of the following diseases, such as metabolic disorders, including diabetes, obesity; proliferative disorders, including cancer, hematopoietic system cancer, lung cancer, prostate cancer, melanoma or pancreatic cancer; blood disorders; hemoglobinopathies; sickle cell anemia; β-thalassemia, inflammatory diseases, and autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, etc.

[0631] In some embodiments, inhibition of PRMT5 can be used for treatment or prevention, particularly for the treatment of the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectal adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain cancer, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenocarcinoma.

[0632] Examples of metabolic disorders that may be treated or prevented, in particular treated, include but are not limited to diabetes or obesity.

[0633] Examples of blood disorders that may be treated or prevented, in particular treated, include but are not limited to hemoglobinopathies, such as sickle cell disease or beta-thalassemia.

[0634] Examples of cancers that can be treated or prevented, in particular treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelioma, angiosarcoma), appendix cancer, benign monoclonal gammopathy, bile duct cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., breast adenocarcinoma, breast papillary carcinoma, breast cancer, medullary breast cancer), brain cancer (e.g., meningioma; gliomas, such as astrocytomas, oligodendrocytes), glioma; medulloblastoma), bronchogenic carcinoma, 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 sarcoma, multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarinoma), Ewing sarcoma (e.g., esophageal adenocarcinoma, Barrett's adenocarinoma), sarcoma), eye cancer (e.g., intraocular melanoma, retinoblastoma), common eosinophilia, gallbladder cancer, stomach 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), laryngeal cancer (e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)), hematopoietic cancer (e.g., leukemias such as acute lymphoblastic 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 lymphomas such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma (Burkitt lymphoma), lymphoma), lymphoplasmacytic lymphoma (ie, "Waldenstrom's macroglobulinemia"), immunoblastic large cell lymphoma, hairy cell leukemia (HCL), precursor B lymphoblastic lymphoma, and primary central nervous system (CNS) lymphomas;and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); mixtures of one or more leukemias / lymphomas as described above;and multiple myeloma (MM)), heavy chain diseases (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumor, immune cell amyloidosis, renal cancer (e.g., Wilms' tumor, renal cell carcinoma), lung cancer (e.g., hepatocellular carcinoma (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, non-small cell 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 neuroendocrine carcinoma), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorders (MPD) (e.g., Examples include polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia of unknown etiology (AMM) (also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis), neuroendocrine cancers (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, embryonal carcinoma, adenocarcinoma of the ovary), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor), and penile cancer (e.g., Paget's disease of the penis and scrotum). disease), pinealoma, proneuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small intestine cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland cancer, sweat gland cancer, synovioma, testicular cancer (e.g., seminoma, testicular embryonal carcinoma), thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid cancer), urethral cancer, vaginal cancer, and vulvar cancer (e.g., Paget's disease of the vulva).

[0635] Examples of neurodegenerative diseases that can be treated or prevented, particularly treated, include, but are not limited to, motor neuron disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal muscular atrophy, and cerebellar degeneration.

[0636] Examples of cardiovascular diseases that may be treated or prevented, in particular treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.

[0637] Inflammatory diseases that can be treated or prevented, and in particular treated, include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), rhinitis, asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis, and Reiter's arthritis), upper respiratory tract disease, ankylosing spondylitis, amyloidosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, disease), chronic obstructive pulmonary disease, diverticulitis, dermatomyositis, diabetes (e.g., type 1 diabetes, type 2 diabetes), skin disorders (e.g., psoriasis, eczema, allergic reactions, burns, dermatitis, pruritus (itching)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease disease), glomerulonephritis, gingivitis, hypersensitivity reactions, headaches (e.g., migraines, tension headaches), intestinal obstruction (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorders (e.g., selected from peptic ulcer, Crohn's disease, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis), colitis, Behcet's syndrome, indeterminate colitis, and inflammatory bowel syndrome (IBS), lupus, morphea, myasthenia gravis, myocardial ischemia, multiple sclerosis, nephrotic syndrome, pemphigus vulgaris, pernicious aneaemia, peptic ulcer, polymyositis, primary biliary cirrhosis, neuroinflammatory diseases associated with brain disorders (e.g.,Parkinson's disease, Huntington's disease, and Alzheimer's disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, Crohn's disease, rheumatic fever, systemic lupus erythematosus, scleroderma, scierodoma, sarcoidosis, spondyloarthropathy, Sjogren's syndrome, thyroiditis, transplant rejection, tendinitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scars, burns, physical injuries), vasculitis, vitiligo, and Wegener's granulomatosis.

[0638] Specifically, the inflammatory disease is an acute inflammatory disease (e.g., inflammation caused by infection). Specifically, the inflammatory disease is a chronic inflammatory disease (e.g., conditions caused by asthma, arthritis, and inflammatory bowel disease). Such compounds can also be used to treat inflammation associated with trauma and non-inflammatory myalgia. Such compounds can also be used to treat inflammation associated with cancer.

[0639] Autoimmune diseases that can be treated or prevented, in particular treated, include but are not limited to arthritis (including rheumatoid arthritis, spondyloarthropathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, hemolytic autoimmune anemia, amyotrophic lateral sclerosis, amyloidosis, multiple sclerosis, acute painful shoulder, psoriatic arthritis and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendinitis, bursitis, skin disorders (e.g., psoriasis, eczema, eczematous allergic reactions, burns, dermatitis, pruritus (itching)), enuresis, eosinophilic diseases, gastrointestinal disorders (e.g., selected from peptic ulcer, Crohn's disease, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet's syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)) and disorders ameliorated by gastric motility promoting agents (e.g., ileus, postoperative ileus and ileus during sepsis; gastroesophageal reflux disease (GORD or its synonym GERD); eosinophilic esophagitis, gastroparesis such as diabetic gastroparesis; food intolerances and food allergies and other functional bowel disorders such as non-ulcer dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costochondritis)).

[0640] The effective therapeutic daily amount is from about 0.005 mg / kg to 50 mg / kg.

[0641] Compounds that may be suitable for treating or preventing cancer or cancer-related conditions may be administered alone or in combination with one or more additional therapeutic agents.

[0642] The pharmaceutical composition may comprise a pharmaceutically acceptable carrier and an active ingredient.

[0643] The carrier or diluent must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

[0644] Preparation method

[0645] In this section, as in all other sections, unless the context indicates otherwise, references to a formula also include all other subgroups and instances thereof as defined herein.

[0646] The general preparation of some typical examples of the compounds of the present invention is described below and in the specific examples. The compounds are generally prepared from commercially available starting materials, prepared by standard synthetic methods commonly used by those skilled in the art, or prepared as described in the specific examples. The following schemes are only intended to represent examples of the present invention and are in no way intended to limit the present invention.

[0647] Alternatively, the compounds of the present invention can also be prepared by combining analogous reaction schemes as described in the general schemes below with standard synthetic methods commonly used by those skilled in the art of organic chemistry.

[0648] Unless otherwise indicated or clear from the context, all variables are defined as described above.

[0649] The skilled artisan will recognize that in the reactions described in the schemes, it may be necessary to protect the desired reactive functional groups in the final product, such as hydroxyl, amino or carboxyl groups, to prevent them from participating in undesirable reactions. Conventional protecting groups can be used according to standard practice. This is illustrated in the specific examples.

[0650] The skilled artisan will recognize that in the reactions described in the schemes, it may be desirable or necessary to carry out the reactions under an inert atmosphere, such as under an N2 atmosphere, for example when NaH is used in the reaction.

[0651] It will be clear to the skilled person that it may be necessary to cool the reaction mixture prior to reaction work-up (referring to the series of operations necessary to separate and purify one or more products of a chemical reaction, like for example quenching, column chromatography, extraction).

[0652] The skilled person will recognize that heating the reaction mixture under stirring can increase the reaction yield.In some reactions, microwave heating can be used instead of conventional heating to shorten the overall reaction time.

[0653] The skilled artisan will recognize that an alternative sequence of the chemical reactions shown in the following schemes may also produce the desired compounds of the present invention.

[0654] The skilled artisan will recognize that the intermediates and compounds shown in the following schemes can be further functionalized according to methods well known to the skilled artisan. For example, wherein R 3a Compounds wherein R or any other substituent on the nucleobase or nucleobase derivative represents Cl can be converted to compounds wherein R is R by reaction with NH3 (e.g. 25% in water) in a typical solvent such as dioxane at a typical temperature of about 100°C. 3a (or any other Cl substituent) represents NH 2 of compounds.

[0655] The skilled artisan will recognize that further compounds of the present invention can be prepared by using similar synthetic schemes as described in the schemes below.

[0656] Where one of the starting materials is available as a salt, the skilled person will recognise that it is necessary to first treat the salt with a base such as, for example, N,N-diisopropylethylamine (DIPEA).

[0657] Unless otherwise indicated or clear from the context, all variables are defined as described above.

[0658] In general, the compounds of the present invention can be prepared according to the following general schemes.

[0659] In the following schemes, unless otherwise defined, R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together, they are diol protecting groups as defined herein. The skilled artisan will recognize that protecting groups may be used in the following schemes as needed, and any protecting group may be subsequently removed to provide a deprotected compound. For example, where the compounds mentioned in the following schemes include nucleobases or nucleobase derivatives, the nucleobases may be used in protected form, for example, the NH2 or OH on the nucleobase may be protected with amino or hydroxy protecting groups, respectively, or the NH2 on the nucleobase may be replaced by a halo (e.g., chlorine).

[0660] General Scheme 1: Preparation of cyclopentane spirocyclic precursors

[0661]

[0662] In general scheme 1, R 4 Limited to silyl groups, such as TBDMS, and R 5 and R 6 Together they form a diol protecting group.

[0663] In general scheme 1, the following reaction conditions typically apply:

[0664] 1: reacting (I) with an oxidizing agent such as iodobenzene(III) diacetate (PIDA) in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxy (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50° C.;

[0665] 2: reacting (I) with PPh3, iodine and a base (such as imidazole) in a suitable solvent such as THF at a suitable temperature range such as room temperature;

[0666] 3: React (III) with a base such as DBU in a suitable solvent such as THF at a suitable temperature range such as between 60°C and 90°C.

[0667] General Scheme 2: Preparation of Furanose and Nucleoside Spirocyclic Precursors

[0668]

[0669] In General Scheme 2, R represents R as defined herein 10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0670] In general scheme 2, the following reaction conditions typically apply:

[0671] 1: reacting (V) with an oxidizing agent such as iodobenzene(III) diacetate (PIDA) in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxy (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50°C;

[0672] 2: reacting (V) with PPh3, iodine and a base (such as imidazole) in a suitable solvent such as THF at a suitable temperature range such as room temperature;

[0673] 3: React (VII) with a base such as DBU in a suitable solvent such as THF at a suitable temperature range such as between 60°C and 90°C.

[0674] General Scheme 3: Preparation of 1,2-cyclobutane

[0675]

[0676] In general scheme 3, R 1 ' and R 2 One of ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by a silyl group 1-6 Alkyl, -OC 1-6 Alkyl, -SC1-6 Alkyl, -S-aryl, -O-aryl, B(OR b )2 or C(O)R a , and R a The skilled person will understand that if a protecting group is initially present, then after the deprotection step, R 1 ' and R 2 ' is unprotected.

[0677] It should be understood that General Scheme 3 can also be performed on nucleoside analogs (i.e., where OR 4 R 10 replace).

[0678] In general scheme 3, the following reaction conditions typically apply:

[0679] 1: react (IX) with oxalyl chloride in a suitable solvent (such as DCM), optionally in the presence of a catalytic amount of DMF, at a suitable temperature range (such as 0°C to room temperature); react (IX) with a base (such as triethylamine) and an alkene (R1HC=CHR 2’ ) to treat the acid chloride intermediate. Instead of activating with an acid chloride, alternative methods may be used, such as reacting (IX) with 2-chloro-1-methylpyridinium iodide in a suitable solvent such as acetonitrile at a suitable temperature range such as 80°C to 110°C. The reaction may be carried out in the presence of a base such as diisopropylethylamine and an alkene (R 1’ HC=CHR 2’ ) in the presence of;

[0680] 2: In the case where R1' or R2' is a silyl group: (X) is reacted with a fluorine source (such as TBAF) in the presence of a protic solvent (such as HOAc) and an aprotic solvent (such as THF) at a suitable temperature range (such as between 0°C and 60°C); an alternative procedure is to treat (X) with trimethylsilyl trifluoromethanesulfonate (TMS-OTf) in a suitable solvent (such as DCM) at a temperature range of 0°C to 50°C (e.g., room temperature). In the case where R1' or R2' is PhS: deprotection can be carried out in the presence of a reducing agent (such as Raney nickel), optionally in the presence of hydrogen, in a solvent (such as ethanol or THF, etc.) at a temperature range of 60°C to 120°C.

[0681] 3: React (XI) with a reducing agent (such as sodium borohydride) in a suitable solvent (such as methanol) at a suitable temperature (eg, between -78°C and 0°C).

[0682] General Scheme 4: Alternative Preparation of 1,2-Cyclobutane

[0683]

[0684] In general scheme 4, R 1 ' and R 2 One of ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by a silyl group 1-6 Alkyl, -OC 1-6 Alkyl or C(O)R a , and R a is hydrogen or C 1-6 The skilled person will understand that if a protecting group is initially present, then after the deprotection step, R 1 ' and R 2 ' is unprotected.

[0685] It should be understood that general scheme 4 can also be performed on nucleoside analogs (i.e., where OR 4 R 10 replace).

[0686] In general scheme 4, similar conditions as in general scheme 3 typically apply.

[0687] General Scheme 5a: Preparation of 1,3-cyclobutanol intermediates

[0688]

[0689] In general scheme 5a, R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0690] In general scheme 5a, the following reaction conditions typically apply:

[0691] 1: React compound (XVI) with a zinc source (such as zinc powder or zinc-copper couple) in the presence of a dichloroketone precursor (such as trichloroacetyl chloride) in a suitable solvent (such as diethyl ether or THF) at a suitable temperature range (such as room temperature to 50°C). The resulting compound (XVII) can be isolated or converted in the same pot via step 2;

[0692] 2: reacting (XVII) with zinc powder in the presence of a proton source (such as HOAc) in an aprotic solvent (such as THF) at a suitable temperature range (such as room temperature to 70°C);

[0693] 3: React (XVIII) with a reducing agent (such as sodium borohydride) in a suitable solvent (such as methanol) at a suitable temperature (e.g., between -78°C and 0°C). Depending on the nature of the protecting group, (XIXa) or (XIXb), or a mixture thereof, can be obtained.

[0694] General Scheme 5b: Preparation of 1,2-cyclobutanol and 1,2-cyclobutanone intermediates

[0695] In general scheme 5b, the following reaction conditions typically apply:

[0696] 1: First, (XVII) is reacted with a reducing agent (such as sodium borohydride) in a suitable solvent (such as THF) at a suitable temperature (such as 0° C. to room temperature). The resulting intermediate is treated with a sulfonating agent (such as trifluoromethanesulfonic anhydride) together with a base (such as pyridine) in an anhydrous solvent (such as dichloromethane) at a suitable temperature (e.g., 0° C.). The resulting intermediate is then treated with zinc powder in the presence of a proton source (such as HOAc) in combination with a solvent (such as methanol) at a suitable temperature (such as 60° C.).

[0697] 2: Treatment of (LXI) with an oxidizing agent (such as m-CPBA) in a suitable solvent (eg dichloromethane) at a suitable temperature range (such as between room temperature and 40°C).

[0698] 3: React (LXII) with a reducing agent such as sodium cyanoborohydride or lithium borohydride in an alcohol solvent such as isopropanol at a suitable temperature ranging from room temperature to 60°C.

[0699] 4: Treatment of (LXIII) with an oxidizing agent such as Dess-Martin periodinane (DMP) in a suitable solvent such as dichloromethane at a suitable temperature such as room temperature.

[0700] General Scheme 6a: Preparation of Cyclobutanemethanol

[0701]

[0702] In general scheme 6a, R represents R as defined herein 10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5Taken together are diol protecting groups as defined herein.

[0703] The chemistry is compatible with 1,2-cyclobutanone and 1,3-cyclobutanone.

[0704] It will be appreciated that in the case of preparation of carboxylic acid substituted cyclobutyls, this may be further derivatized by esterification.

[0705] In general scheme 6a, the following reaction conditions typically apply:

[0706] 1: in the presence of a reagent such as methyltriphenylphosphonium bromide (MePPh3+Br-), in the presence of a base such as potassium tert-butoxide (KOtBu), in a solvent such as THF, at a suitable temperature such as between 0°C and room temperature; alternatively, using bis(cyclopentadienyl)dimethyltitanium in a suitable solvent system such as toluene and THF, at a suitable temperature range such as between 50°C and 70°C;

[0707] 2: In the first step, in the presence of the alkene precursor (XXI) and a 9-BBN solution in THF, typically under nitrogen atmosphere, at a temperature between room temperature and reflux temperature.

[0708] In the second step, in the presence of an aqueous base solution such as aqueous NaOH, in the presence of an oxidizing agent such as H2O2, typically at a temperature between 0°C and room temperature;

[0709] 3: using oxidation conditions well known to those skilled in the art; for example, Dess-Martin periodinane in a suitable solvent such as dichloromethane, typically at a temperature between 0°C and room temperature (for aldehydes, i.e., where R aa is H). Alternatively, an oxidizing agent such as iodobenzene(III) diacetate (PIDA) is used in the presence of (2,2,6,6-tetramethyl-piperidin-1-yl)oxy (TEMPO) in a suitable solvent mixture such as acetonitrile and water at a suitable temperature range such as room temperature to 50°C (for carboxylic acids, i.e., where R aa is OH).

[0710] General Scheme 6b: Preparation of 1,2-cyclobutanemethanol

[0711]

[0712] In general scheme 6b, R cc C 1-6 alkyl.

[0713] In general scheme 6b, the following reaction conditions typically apply:

[0714] 1: reacting (XVI) with an unsaturated reagent such as methyl propiolate in the presence of a metal complex such as methylaluminoxane in a suitable solvent such as DCM at a suitable temperature such as 0° C. to room temperature under an inert atmosphere;

[0715] 2: Treatment (LXIX) with a hydrogenation catalyst such as Pt / C in a suitable solvent such as ethyl acetate under a hydrogen atmosphere at a temperature between room temperature and 50 °C.

[0716] 3: React (LXX) with a base such as lithium hydroxide in an aqueous solvent mixture such as aqueous methanol in water. The resulting mixture is reacted at a controlled temperature (such as between 0°C and room temperature) for a suitable time (such as 3 hours).

[0717] 4: React (LXX) with a reducing agent such as lithium borohydride in a suitable solvent such as THF at a suitable temperature, for example -78°C to room temperature.

[0718] General Scheme 7: Preparation of Cyclopropanemethanol

[0719]

[0720] In general scheme 7, R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0721] In general scheme 7, the following reaction conditions typically apply:

[0722] 1: reacting (XXIV) with zinc powder in the presence of a proton source (such as 1 equivalent of HOAc) in an aprotic solvent (such as THF) at a suitable temperature of 0°C using a short reaction time (e.g. 20 minutes);

[0723] 2: Compound (XXV) is reacted with a reducing agent such as sodium borohydride in a suitable solvent such as THF at a suitable temperature, for example -0°C to room temperature. The mixture is then treated with an aqueous base such as NaOH (1 M) at a suitable temperature ranging from room temperature to 50°C.

[0724] General Scheme 8: Alternative Preparation of Cyclopropanemethanol

[0725]

[0726] In general scheme 8, R represents R as defined herein10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0727] In general scheme 8, the following reaction conditions typically apply:

[0728] 1: Under an inert atmosphere, in a suitable solvent such as dichloromethane, (XXVII) is treated with a catalyst such as Rh2(OAc)4 or triphenylacetic acid rhodium (II) dimer with an α-diazo ketone or diazo ester at a suitable temperature range of room temperature to 50°C. The catalyst can be a chiral catalyst such as (S)-Ph-Pheox Ru(II) or (R)-Ph-Pheox Ru(II), so that the synthesis is asymmetric;

[0729] 2: React (XXVIIIa) with a reducing agent such as lithium borohydride in a suitable solvent such as THF at a suitable temperature, for example -0°C to room temperature.

[0730] General Scheme 9a: Preparation of cyclopropanol

[0731]

[0732] In general scheme 9a, R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together, they are a diol protecting group as defined herein. b It is a boronic acid protecting group.

[0733] In general scheme 9a, the following reaction conditions typically apply:

[0734] 1: Under an inert atmosphere, in a two-phase solvent system consisting of DCM and water, (XXX) is treated with bromoform. This reaction requires a phase transfer catalyst (such as benzyltriethylammonium chloride) and a base (such as sodium hydroxide) in a suitable solvent at a suitable temperature (such as room temperature);

[0735] 2: (XXXI) is reacted with a strong base (such as nBuLi) in a suitable solvent (such as THF) under an inert atmosphere at a suitable temperature (e.g., between -0°C and low temperature (such as -100°C). The resulting mixture is then treated with borane (such as catecholborane) at the same temperature and allowed to warm to 50°C, resulting in the in situ formation of (XXXII).

[0736] 2a: (XXXII) is reacted with a mixture of aqueous hydrogen peroxide and a base such as sodium hydroxide at room temperature under an inert atmosphere with a strong base such as nBuLi in a suitable solvent.

[0737] General Scheme 9b: Alternative preparation of cyclopropanols (via cyclopropyl esters)

[0738]

[0739] In general scheme 9b, -C(O)R bb -C(O)C 1-6 Alkyl or hydroxy protecting groups, such as benzoyl.

[0740] In general scheme 9b, the following reaction conditions typically apply:

[0741] 1: (LXV) is treated with a suitable base (such as potassium carbonate etc.) under inert atmosphere and reacted with an anhydride (such as benzoyl anhydride) in a suitable anhydrous solvent (such as acetonitrile) at a suitable temperature (such as room temperature to 60°C).

[0742] 2: Treat (LXVI) with diiodomethane and diethylzinc in an anhydrous solvent such as 1,2-dichloroethane at a suitable temperature (such as between room temperature and 50°C) under an inert atmosphere.

[0743] 3: React (LXVII) with a base such as potassium carbonate in an aqueous solvent mixture such as aqueous methanol in water. The resulting mixture is reacted at a controlled temperature such as 0°C for a suitable time such as 3 hours.

[0744] General Scheme 10: Preparation of Nucleoside Analogs

[0745]

[0746] In general scheme 10, R 1 、R 2 、R 10 and n are as defined herein, R 4 Preferably Me or -C(O)C 1-6 Alkyl and R 5 and R 6 Preferably -C(O)C 1-6In general scheme 10, the following reaction conditions typically apply:

[0747] 1: reacting an intermediate of formula (XXXIV) with a suitable nucleobase precursor, e.g., 6-chloropurine, typically in the presence of a reagent such as bis-(trimethylsilyl)acetamide (BSA), a reagent such as trimethylsilyl trifluoromethanesulfonate (TMSOTf), in a solvent such as anhydrous CH3CN; typically at a temperature between room temperature and 100°C;

[0748] It will be appreciated that the protocol may be carried out with any suitable nucleobase precursor. 5 or R 6 Additional steps of deprotection and / or conversion of the nucleobase precursor to the nucleobase. For example, after coupling, 6-chloropurine can be converted to adenine.

[0749] General Scheme 11: Preparation of Cyclopentane-Containing Nucleoside Analogs

[0750]

[0751] In general scheme 11, R 1 、R 2 、R 10 and n are as defined herein, R 4 is a protecting group, such as a silyl group, and R 5 and R 6 Together they form a diol protecting group.

[0752] In general scheme 11, the following reaction conditions typically apply:

[0753] 1 is typically deprotected in the presence of a reagent such as tetrabutylammonium fluoride (TBAF); in a suitable solvent such as THF; at a suitable temperature (e.g., at rt);

[0754] 2. Reaction with a suitable reagent such as Tf2O (trifluoromethanesulfonic anhydride or trifluoromethanesulfonic anhydride) in a suitable solvent such as dichloromethane (DCM) at a suitable temperature such as 0°C;

[0755] 3. Reaction with a suitable nucleobase intermediate in the presence of a base such as potassium tert-butoxide, in a suitable solvent such as DMF, at a suitable temperature such as between -10°C and 0°C;

[0756] General Scheme 12: Conversion of alcohol-substituted analogs to amine-substituted analogs

[0757]

[0758] In general scheme 12, R a, m and n are as defined herein, and R represents R as defined herein 10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0759] In general scheme 12, the following reaction conditions typically apply:

[0760] 1: reacting (XL) with an activating agent such as methanesulfonyl chloride in the presence of a suitable base such as pyridine in a suitable solvent such as DCM, typically at a temperature range of 0°C to 40°C;

[0761] 2: reacting (XLI) with an azide (such as sodium azide) in the presence of a catalyst such as tert-butylammonium iodide (TBAI) in a suitable solvent such as DMF or DMA, typically at a temperature range of 0°C to 120°C;

[0762] 3: Treatment with a hydrogenation catalyst such as Pd / C in a suitable protic solvent such as methanol etc. under hydrogen atmosphere at a temperature between room temperature and 50°C (XLII).

[0763] 4: Treatment of (XLIII) with acetic acid in a suitable solvent such as dichloromethane and an appropriate aldehyde or ketone. After equilibration at a suitable temperature such as room temperature, reduction is carried out in the presence of a suitable reducing agent such as sodium triacetoxyborohydride (NaBH(OAc) 3 ) at a suitable temperature range of 0° C. to room temperature.

[0764] General Scheme 13: Conversion of alcohol-substituted analogs to amine-substituted analogs

[0765]

[0766] In general scheme 13, R a , m and n are as defined herein, and R represents R as defined herein 10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0767] In general scheme 13, the following reaction conditions typically apply:

[0768] 1: Treatment with a suitable amine (XLI) in the absence of additional solvent at a suitable temperature in the range of 50 to 120°C.

[0769] General Scheme 14: Conversion of alcohol-substituted analogs to thio-substituted analogs

[0770] In general scheme 14, R c , m and n are as defined herein, and R represents R as defined herein 10 OR 4 , R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0771] In general scheme 14, the following reaction conditions typically apply:

[0772] 1: Treatment (XLVI) with a suitable thiol in the presence of a suitable base such as sodium hydride in an aprotic polar solvent such as DMF or NMP etc. at a suitable temperature in the range of 20 to 120 °C.

[0773] 2: Treatment of (XXLVII) with a suitable oxidizing agent such as hydrogen peroxide in a suitable solvent system such as acetone and water at a suitable temperature ranging from 20 to 60 °C.

[0774] 3: Treatment of (XLVII) with a suitable oxidizing agent such as mCPBA in a suitable solvent such as dichloromethane at a suitable temperature ranging from 0°C to 30°C.

[0775] General Scheme 15: Conversion of the 3'β stereocenter to α(xylose-ribose)

[0776] In general scheme 15, the following reaction conditions typically apply:

[0777] 1: Oxidation of (L) to the corresponding ketone using Dess-Martin periodinane in a solvent such as dichloromethane at temperatures ranging from 0°C to room temperature.

[0778] 2: (LI) can then be reduced by a reagent such as NaBH4 in a solvent such as methanol or ethanol at a temperature ranging from 0°C to room temperature, or by using DIBAL (diisobutylaluminum hydride) or the like in a solvent such as dichloromethane at a temperature ranging from -78°C to 0°C.

[0779] The skilled person will appreciate that Scheme 15 may also be applicable to other 1,3-cyclobutane nucleoside analogs, as well as 1,2-cyclobutane or cyclopropyl spirobicyclic nucleoside analogs. For example, General Scheme 15 may also be represented as:

[0780]

[0781] Where n, R 1 and R 2 As defined herein; and wherein typical reaction conditions described for (L) and (LI) apply to (L') and (LI'), respectively.

[0782] General Scheme 16: Reduction of a carbonyl group to a methylene group

[0783]

[0784] In general scheme 16, R 1 ' and R 2 One of ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by a silyl group 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 alkyl, -S-aryl or -O-aryl.

[0785] In general scheme 16, the following reaction conditions typically apply:

[0786] 1: (LIII) is converted in situ to a hydrazone by treatment with hydrazine, optionally in the presence of an acid such as sulfuric acid, in a suitable solvent such as ethanol, at a suitable temperature range of 20° C. to 80° C. The hydrazone can be removed by treatment with a base such as potassium tert-butoxide (KOtBu) or the like in a suitable solvent such as DMSO at a temperature range of 4° C. to 40° C. Alternatively, (LIII) is converted in situ to a tosylhydrazone by reaction with tosyl-NHNH2 in a suitable solvent such as methanol or ethanol at a suitable temperature range of 60° C. to 100° C., followed by reaction with a reducing agent such as sodium borohydride or the like at a suitable temperature range of 20° C. to 70° C.

[0787] General Scheme 17: Formation of Aminocyclopropanes

[0788]

[0789] In general scheme 17, R 4 、R 5 and R 6 are each independently a hydroxyl protecting group; or R 5 and R 6 Together they form a diol protecting group; or R 4 and R 5 Taken together are diol protecting groups as defined herein.

[0790] In general scheme 17, the following reaction conditions typically apply:

[0791] 1: (LV) is hydrolyzed in the presence of LiOH or the like in an aqueous solvent system in the presence of methanol or THF at a temperature range of 0°C to 20°C. The resulting carboxylic acid is converted in a carboxamide using ammonia or ammonium chloride in the presence of an activating agent such as HATU in a solvent such as DMF or DCM at a temperature range of 20°C to 50°C. Finally, rearrangement is carried out in the presence of NaOCl or NaOBr, optionally in the presence of sodium hydroxide, in an aqueous solvent at a temperature range of 0°C to 50°C.

[0792] General Scheme 18: Conversion of the 2'β stereocenter to α(arabinose-ribose)

[0793]

[0794] In general scheme 18, R is defined as a suitable hydroxy protecting group as defined herein and PG is as defined herein.

[0795] In general scheme 18, the following reaction conditions typically apply:

[0796] 1: Oxidation of (LVIII) to the corresponding ketone using Dess-Martin periodinane in a solvent such as dichloromethane at a temperature ranging from 0°C to room temperature.

[0797] 2: (LIX) can then be reduced by a reagent such as NaBH4 in a solvent such as methanol at a temperature ranging from 0°C to room temperature, or by using DIBAL or the like in a solvent such as dichloromethane at a temperature ranging from -78°C to 0°C.

[0798] The skilled artisan will appreciate that Scheme 18 may also be applicable to other 1,3-cyclobutane or 1,2-cyclobutane spirobicyclic nucleoside analogs or cyclopropyl spirobicyclic nucleoside analogs.

[0799] In all of these preparations, the reaction products can be isolated from the reaction medium and, if necessary, further purified according to methods generally known in the art, such as extraction, crystallization, trituration, and chromatography.

[0800] The chirally pure forms of the compounds of formula (I) form a preferred group of compounds. Therefore, the chirally pure forms of these intermediates and their salt forms are particularly useful in preparing chirally pure compounds of formula (I). Enantiomeric mixtures of these intermediates are also useful in preparing compounds of formula (I) having the corresponding configuration.

[0801] Examples

[0802] Hereinafter, the term "rt" or "rt" means room temperature; "RT" or "R t " means retention time; "Rf" means retention factor; "Me" means methyl; "MeOH" means methanol; "MeOD" means monodeuterated methanol; "Et" means ethyl; "EtOH" means ethanol; "EA" or "EtOAc" means ethyl acetate; "Ac" means acetyl; "Ac2O" means acetic anhydride; "AcOH" means acetic acid; "Et2O" means diethyl ether; "Int." means intermediate; "DMF" means N,N-dimethylformamide; "THF" means tetrahydrofuran; "LC" means liquid chromatography; means diatomaceous earth; “LCMS” or “LC-MS” means liquid chromatography / mass spectrometry; “GCMS” or “GC-MS” means gas chromatography / mass spectrometry; “CV” means column volume; “HPLC” means high performance liquid chromatography; “TFA” means trifluoroacetic acid; “h” means hours; “Me2S” means dimethyl sulfide; “DMSO” means dimethyl sulfoxide; “DMSO-d6” means deuterated dimethyl sulfoxide; “DIPE” means diisopropyl ether; “D "CM" means dichloromethane; "PPh3" means triphenylphosphine; "TBAF" means tetrabutylammonium fluoride; "DBU" means 1,8-diazabicyclo[5.4.0]undecene-7; "eq." or "equiv" means equivalent; "KOtBu" means potassium tert-butoxide; "TBDMSCl" means tert-butyldimethylsilyl chloride; "Bn" means benzyl; "9-BBN" means 9-boranobicyclo[3.3.1]nonane; "Tf2O" means trifluoromethane. Sulfonic anhydride; "TBDMS" means tert-butyldimethylsilyl or t-butyldimethylsilyl; "aq." means aqueous; "Ts" or "Tos" means tosyl (p-toluenesulfonyl); "DEAD" means diethyl azodicarboxylate; "Bz" means benzoyl; "BnBr" means benzyl bromide; "Bn" means benzyl; "anhyd" means anhydrous; "p-TsOH" means 4-methylbenzenesulfonic acid; "(R)-MonoPhos" means (R)-N,N-dimethyldinaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphopeptane-4-amine; "BSA" means N,O-bis(trimethylsilyl)acetamide; "TMSOTf" means trimethylsilyl trifluoromethanesulfonate; "Boc" means tert-butyloxycarbonyl; "preparative SFC" means preparative supercritical fluid chromatography; "Piv" means pivaloyl; "PivCl" means pivaloyl chloride; "MePPh3 + Br -" means methyltriphenylphosphonium bromide; "iPrNH2" means isopropylamine; "iPrOH" means isopropyl alcohol; "n-PrNH2" means propylamine; "sat." means saturated; "DMA" means dimethylacetamide; "NMR" means nuclear magnetic resonance; "chloroform-d" means deuterated chloroform; "DIPEA" means diisopropylethylamine; "TLC" means thin layer chromatography; "brsm" means recovered raw material basis; "w / w" means weight / weight; "ppm" means parts per million; "TEA" means triethylamine; "PE" means petroleum ether; "DMP" means Dess-Martin periodinane; "DIAD" means diisopropyl azodicarboxylate; "methanol-d4" means deuterated methanol; "TBDPS" means tert-butyldiphenylsilyl; "HMDS" means hexamethyldisilazane. silazane; “DMAP” means 4-dimethylaminopyridine; “ESI” means electrospray ionization; “ACN” means acetonitrile; “TBAI” means tetrabutylammonium iodide; “HATU” means N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; “brsm” means recycled raw material basis; “HMPA” means hexamethylphosphoramide; “m-CPBA” or “mCPBA” means meta-chloroperbenzoic acid; “nBuLi” means n-butyllithium; “EDA” means ethyl diazoacetate; “tBu” means tert-butyl; “DIBAL” or “DIBAl-H” means diisobutylaluminum hydride; “DCE” means 1,2-dichloroethylene; and “MAO” means methylaluminoxane.

[0803] symbol

[0804] Indicates a mixture of the following substances:

[0805]

[0806] Preparation of intermediates and nucleosides

[0807] Preparation of cyclobutane

[0808] Preparation of compound 1

[0809]

[0810] To a stirred solution of CAS 54622-95-6 (200 mg, 0.92 mmol, 1 eq) in DCM (2 mL) and a drop of DMF was added oxalyl chloride (0.12 mL, 1.37 mmol, 1.5 eq), and the resulting reaction mixture was stirred at room temperature for 4 hours. Excess solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0811] To the acid chloride in the toluene (2mL) in a sealed tube obtained above, vinyltrimethylsilane (1.35mL, 9.16mmol, 10eq) is added, followed by EtN (0.15mL, 1.10mmol, 1.2eq), and the resulting reaction mixture is heated at 120°C overnight (16h), quenched with HCl (1M, 10.00mL) thereafter. The aqueous phase is extracted with EtOAc (20 × 2mL), and the combined organic layers are dried over NaSO and concentrated under reduced pressure to provide a crude product. The residue is then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, Rf=0.5) to give compound 1 (198mg, 0.66mmol, 72%) as a colorless oil (as indicated by NMR spectroscopy, a mixture of diastereomers).

[0812] Data of the main isomers:

[0813] 1 H NMR (400MHz, chloroform d) δ4.91 (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).

[0814] 13 C NMR (101 MHz, chloroform- d ) δ 206.40, 112.65, 106.92, 103.08, 84.66, 79.29, 54.68, 40.91, 26.26, 24.95, 18.64, −2.31 ppm.

[0815] GC-MS: [M-86] 214, 13.67 min (Method 4) (no molecular ion peak was found)

[0816] Preparation of compound 2

[0817]

[0818] To a stirred solution of compound 1 (250 mg, 0.83 mmol, 1 eq) in anhydrous THF (4 mL) was added acetic acid (0.05 mL, 0.83 mmol, 1 eq) and TBAF (1.66 mL, 1.0 M THF solution, 2 eq). The resulting reaction mixture was heated at 50 ° C for 1 hour. After the raw material was completed (TLC), water (20 mL) was added and extracted with EtOAc (30 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide a crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90: 10, R f =0.2) to give compound 2 (28 mg, 0.12 mmol, 15%) as a colorless oil (as indicated by NMR spectroscopy, which was a mixture of two (81:19) diastereomers). The experiment was repeated 3 more times to give (30 mg, 13%), (50 mg, 13%), (125 mg, 14%, 20% (brsm)), all of which were combined to give compound 2 (232 mg).

[0819] Data of the main isomers:

[0820] 1 H NMR (300 MHz, CHLOROFORM-d) δ 5.01 (s, 1H), 4.87 (d, J = 5.7 Hz, 1H), 4.64 (d, J = 5.7 Hz, 1H), 3.35 (s, 3H), 3.03-2.96 (m, 1H), 2.83 (dd, J = 10.0, 4.2 Hz, 1H), 2.20 (td, J = 11.3, 4.2 Hz, 1H), 2.04 (td, J = 11.2, 10.1 Hz, 1H), 1.49 (s, 3H), 1.30 ppm (s, 3H).

[0821] 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.

[0822] GC-MS: [M+1] 229, 13.60 min (Method 4).

[0823] Preparation of compound 3

[0824]

[0825] To a stirred solution of compound 1 (113 mg, 0.38 mmol, 1 eq) (the wavy bond in the cyclobutane of compound 1 refers to a mixture of multiple isomers as previously obtained) in anhydrous DCM (1.5 mL) was added TMSOTf (0.06 mL, 0.34 mmol, 0.9 eq) at room temperature and the resulting reaction mixture was stirred at the same temperature for 16 hours. Saturated NaHCO (5 ml) was carefully added and extracted with EtOAc. The organic layer was dried over NaSO and concentrated under reduced pressure to provide a crude product (TLC) consisting of a starting material and a product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, R f 0.5) was purified to give compound 1a (40 mg, 0.13 mmol) as a colorless oil (which was a mixture of four (51:20:19:10) diastereomers as indicated by NMR spectroscopy) and compound 3 (31 mg, 0.14 mmol, 36% (65% brsm)) as colorless crystals (which was in the form of a single diastereomer as indicated by NMR spectroscopy).

[0826] Data of the main isomer of compound 1a: 1 H NMR (400 MHz, CHLOROFORM-d) δ 4.89 (s, 1H), 4.64 (d, J = 5.7 Hz, 1H), 4.60 (d, J = 5.8 Hz, 1H), 3.31 (s, 3H), 3.21 (dd, J = 17.5, 4.6 Hz, 1H), 2.70 (dd, J = 17.2, 10.1 Hz, 1H), 1.85 (dd, J = 12.9, 10.1 Hz, 1H), 1.47 (d, J = 0.7 Hz, 3H), 1.30 (d, J = 0.7 Hz, 3H), 0.12 ppm (s, 9H).

[0827] Data of compound 3: 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.01 (s, 1H), 4.87 (d, J = 5.7 Hz, 1H), 4.64 (d, J = 5.7 Hz, 1H), 3.35 (s, 3H), 3.07-2.92 (m, 1H), 2.81 (ddd, J = 17.1, 10.0, 4.0 Hz, 1H), 2.20 (td, J = 11.2, 4.0 Hz, 1H), 2.04 (dd, J = 11.5, 10.9 Hz, 1H), 1.49 (s, 3H), 1.30 ppm (s, 3H).

[0828] Preparation of Compound 4 and Compound 5

[0829]

[0830] To compound 2 (205 mg, 0.90 mmol, 1.00 eq) in MeOH (2 mL) was added NaBH (44 mg, 1.17 mmol, 1.30 eq) at -78 ° C and the resulting reaction mixture was stirred at -78 ° C for 1 hour. The reaction was then quenched by adding saturated NH Cl (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated in vacuo and carried to the next step.

[0831] To a solution of the alcohol obtained above in DCM (2 mL) was added EtN (0.26 mL, 1.80 mmol, 2 equiv), benzoyl chloride (0.16 mL, 1.35 mmol, 1.5 equiv) at 0°C and the resulting reaction mixture was stirred at room temperature overnight. The reaction was then quenched by the addition of saturated NaHCO (20 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 80:20, R f =0.6 and R f =0.4) to give compound 4 (110 mg, 0.33 mmol, 37%, as a mixture of two (62:38) diastereomers as indicated by NMR spectroscopy) and compound 5 (100 mg, 0.43 mmol, 48%, as a mixture of two (62:38) diastereomers as indicated by NMR spectroscopy) as colorless oils.

[0832] Compound 4 was purified by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 m, mobile phase: CO 2 , iPrOH) to give compound 4a (63.4 mg, 0.19 mmol, 58% yield, major isomer) and compound 4b (31 mg, 0.09 mmol, 28% yield, minor isomer).

[0833] Data of compound 4a:

[0834] LCMS: (ESI + ):[M+1] + =335.0, RT 2.18 min (Method 11)

[0835] Data of compound 4b:

[0836] LCMS: (ESI + ):[M+1] + =335.1, RT 2.18 min (Method 11)

[0837] Data of the main isomer compound 4a: 1 H NMR (300MHz, chloroform-d) δ8.13-8.05(m,2H),7.58-7.49(m,1H),7.47-7.36(m,2H),5.60(t,J=8.7Hz,1H),4.88(s,1H),4.86(d,J=5.6Hz,1H),4. 61(d,J=5.6Hz,1H),3.35(s,3H),2.42-2.15(m,2H),2.05-1.85(m,1H),1.79-1.65(m,1H),1.20(d,J=0.7Hz,3H),1.16ppm(d,J=0.7Hz,3H).

[0838] Data of the main isomer of compound 5: 1 H NMR (300MHz, chloroform-d) δ4.94(d,J=5.8Hz,1H),4.87(s,1H),4.77-4.70(m,1H),4.64(d,J=5.8Hz,1H),4.40(bs,1H),3.32(s,3H),2.68-2.53(m ,1H),2.29-2.20(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),1.33ppm(d,J=0.7Hz,3H).

[0839] Alternative preparation of compound 1 (larger scale)

[0840]

[0841] To CAS 54622-95-6 (64.00g, 293.58mmol, 1eq) solution in toluene (640mL), add a drop of DMF, add oxalyl chloride (55.92g, 440.37mmol, 1.5eq) subsequently, then gained reaction mixture is stirred at room temperature 1 hour.Use vacuum pump to remove excessive solvent and oxalyl chloride in 1 hour.To the acyl chloride in the toluene (600mL) in sealed tube obtained above, add vinyltrimethylsilane (293.61g, 2935.80mmol, 10eq), add Et subsequently N (35.58g, 352.296mmol, 1.2eq) and gained reaction mixture is heated at 120 ℃ and spends the night (16h), quenched with HCl (1M aqueous solution, 800.00mL) afterwards. The aqueous phase was extracted with EtOAc (2×600 mL), and the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford the crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, Rf=0.5) to afford compound 1.

[0842] 26% (23 g, 76.33 mmol, crude) yellow oil. LCMS (ESI+) m / z: C 14 H 24 Calculated value of O5Si[M+H2O]+=318.14, found 318.20, RT: 1.678 min, Method 1.

[0843] Alternative preparation of compound 5 (larger scale)

[0844]

[0845] To compound 1 (23g, 76.33mmol, 1.00eq) in anhydrous THF (230mL), acetic acid (4.57g, 76.33mmol, 1.00eq) and TBAF (152.66mL, 1.0M THF solution, 2.00eq) were added dropwise. The resulting reaction mixture was heated at 50°C overnight. After the raw material was completed (TLC), MeOH (200mL) was added and NaBH (2.9g, 76.33mmol, 2.00eq) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 2 hours. The reaction was then quenched by adding saturated NH4Cl (200mL) and extracted with ethyl acetate (300mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10, R f =0.2) was purified, the front peak was compound 5a', and the back peak was compound 5b' (obtained as a mixture of compound 5b' and the following compounds 95a and 95b).

[0846] 3.3% yield (580 mg, 2.52 mmol, crude) of compound 5a' as a yellow oil. GCMS (ESI+) m / z: C 11 H 18 Calculated value for O5[M-Me]-=215.09, found 215.09, RT: 6.387 min, Method 1.

[0847] 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 the following compounds 95a and 95b). GCMS (ESI+) m / z: C 11 H 18 Calculated value for O5[M-Me]-=215.09, found 215.09, RT: 6.377 min, Method 1.

[0848] Preparation of compound 4a'

[0849]

[0850] Compound 5a' (1.03 g, 4.47 mmol, 1.00 eq) and DMAP (272.67 mg, 2.23 mmol, 0.50 eq) were dissolved in pyridine (10 mL). Benzoyl chloride (1.25 g, 8.94 mmol, 2.00 eq) was then added dropwise at 0°C and the resulting solution was stirred at 0°C for 1 hour. HCl (1 M, aqueous solution, 20 mL) was then added to the reaction until a pH <7 was reached. The product was extracted with EtOAc (3 x 20 mL), and the combined organic layers were dried (Na2SO4), filtered, and the filtrate concentrated in vacuo. The residue was purified by C18 column (mobile phase A: water (0.1 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40B to 70B over 30 min; 210 / 254 nm). Fractions containing the product were collected and the solvent evaporated to yield compound 4a'.

[0851] 29% yield (430 mg, 1.28 mmol), colorless oil. 1H NMR (300 MHz, 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 = 8.9 Hz, 1H), 4.93-4.83 (m, 2H), 4.66-4.58 (m, 1H), 3.36 (s, 3H), 2.45-2.30 (m, 1H), 2.11-1.85 (m, 2H), 1.80-1.66 (m, 1H), 1.21 (s, 3H), 1.16 ppm (s, 3H). 13 C NMR (75MHz, CDCl3) δ165.92,132.62,130.56,129.90,128.06,112.68,108.27,87.81,85.43,83.93,70.89,55.04,27.78,26.04,25.09,21.67ppm. LCMS(ESI+)m / z:C 18 H 22 Calculated value for O6[M+H]+=335.14, found 335.14, RT: 1.811 min, Method 1.

[0852] Preparation of compound 138a

[0853]

[0854] Compound 4a' (430 mg, 1.28 mmol, 1.00 eq) was dissolved in H2O (5 mL) and formic acid (5 mL) was added. The mixture was heated to 35°C for 16 hours. The solution was then cooled to room temperature and concentrated in vacuo. This gave 440 mg of crude compound 138.1a.

[0855] Compound 138.1 (440 mg, crude; a mixture of α- and β-anomers, with the β-anomer being the major product) was dissolved in anhydrous pyridine (5 mL) and stirred for 30 minutes. Acetic anhydride (195.84 mg, 1.92 mmol, 1.50 eq) was added at 0°C and added to the stirring solution at room temperature. The mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was poured into ice-cold water (10 ml) and stirred at room temperature for 30 minutes. The crude mixture was extracted with CH2Cl2 (3×10 ml) and the combined organic layers were washed with brine (3×10 ml), dried (Na2SO4), filtered, and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA from 100:1 to 10:1). The fractions containing the product were combined and the solvent was removed in vacuo to give compound 138a.

[0856] The yield of 2 steps was 80% (420 mg, 1.03 mmol, crude product; a mixture of α and β anomers, with the β anomer being the major product), colorless oil. LCMS (ESI+) m / z: C 20 H 22 Calculated value for O9[M+H2O]+=424.13, found 424.13, RT: 1.523 min, Method 1.

[0857] Preparation of compound 139a

[0858]

[0859] 6-Chloropurine (121.79 mg, 0.81 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (150.22 mg, 0.74 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80°C for 16 hours. After the mixture was cooled to room temperature, compound 138a (300 mg, 0.74 mmol, 1.00 eq) in MeCN (2.2 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (194.94 mg, 0.88 mmol, 1.20 eq) and the mixture was heated to 80°C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc (20 mL), washed with saturated NaHCO (3×20 mL) and saturated aqueous NaCl (3×20 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 4:1).The fractions containing the product were collected and the solvent was removed in vacuo to give compound 139a.

[0860] 59% yield (220 mg, 0.44 mmol, crude), colorless oil. LCMS (ESI+) m / z: C 23 H 21 Calculated value for ClN4O7[M+H]+=501.11, found 501.11, RT: 1.534 min, Method 1.

[0861] Preparation of compound 140a

[0862]

[0863] Compound 139a (280 mg, 0.56 mmol, 1.00 eq) was dissolved in 1,4-dioxane (2.4 mL) and NH3 (0.6 mL aqueous solution) was added. The mixture was heated to 80 ° C for 16 hours. After the mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography with dichloromethane / methanol (gradient elution: DCM / MeOH from 99: 1 to 5: 1). The fractions containing the product were collected and the solvent was removed in vacuo to obtain compound 140a.

[0864] 44% yield (75 mg, 0.25 mmol), off-white solid. 1 H NMR(300MHz,MeOD)δ8.21(d,J=6.9Hz,2H),6.16(d,J=6.8Hz,1H),5.08-5.01(m,1H) ,4.61(d,J=3.9Hz,1H),4.40-4.31(m,1H),2.17-2.00(m,2H),1.78-1.59ppm(m,2H). 13 C NMR (75MHz, MeOD) δ155.90,152.43,149.60,140.12,119.31,88.43,87.24,76.52,73.87,25.86,22.51ppm. LCMS(ESI+)m / z:C 12 H 15 Calculated value for N5O4[M+H]+=294.11, found 294.11, RT: 0.446 min, Method 1.

[0865] Preparation of compound 4b'

[0866]

[0867] Compound 5b' (2.6 g, used as the mixture obtained in the "Alternative Preparation of Compound 5" procedure above, containing 30% pure compound 5b', 800 mg, 3.47 mmol, 1.00 eq), DMAP (211.67 mg, 1.73 mmol, 0.50 eq) were dissolved in pyridine (10 mL), and then benzoyl chloride (971.60 mg, 6.94 mmol, 2.00 eq) was added dropwise at 0°C and the resulting solution was stirred at 0°C for 1 hour. HCl (1 M, aqueous solution, 20 mL) was then added to the reaction until pH <7 was reached. The product was extracted with EtOAc (3 x 20 mL) and the combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by C18 column (mobile phase A: water (0.1 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 80 mL / min; gradient: 40B to 70B in 30 min; 210 / 254 nm). The fractions containing the product were collected and the solvent was evaporated to give compound 4b'.

[0868] 34% yield (400 mg, 1.19 mmol), colorless oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 8.15-8.06 (m, 2H), 7.59-7.51 (m, 1H), 7.48-7.39 (m, 2H), 5.64-5.52 (m, 1H), 5.04 (s, 1H), 4.63 (d, J = 0.8 Hz, 2H), 3.42 (s, 3H), 2.44-2.17 (m, 3H), 2.05-1.88 (m, 1H), 1.35 (s, 3H), 1.30 ppm (s, 3H). 13 C NMR (75MHz, CDCl3) δ165.77,132.84,130.41,129.81,128.28,112.84,108.18,89.65,85.06,84.26,70.78,54.95,30.64,26.22,25.75,25.25ppm. LCMS(ESI+)m / z:C 18 H 22 Calculated value for O6[M+H]+=335.14, found 335.14, RT: 1.675 min, Method 1.

[0869] Preparation of compound 138b

[0870]

[0871] Compound 4b' (400 mg, 1.19 mmol, 1.00 eq) was dissolved in H2O (5 mL) and formic acid (5 mL) was added. The mixture was heated to 35°C for 16 hours. Subsequently, the solution was cooled to room temperature and concentrated in vacuo. This gave 420 mg of crude compound 138.1b (a mixture of α and β anomers, with the β anomer being the major product).

[0872] Compound 138.1b (420 mg, crude product) was dissolved in anhydrous pyridine (5 mL) and stirred for 30 minutes. Acetic anhydride (181.56 mg, 1.78 mmol, 1.50 eq) was added at 0 ° C and added to the stirring solution at room temperature. The mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was poured into ice-cold water (10 ml) and stirred at room temperature for 30 minutes. The crude mixture was extracted with CH2Cl2 (3×10 ml) and the combined organic layer was washed with brine (3×10 ml), dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA from 100:1 to 10:1). The fractions containing the product were combined and the solvent was removed in vacuo to obtain compound 138b.

[0873] The yield of the two steps was 74% (361 mg, 0.88 mmol, crude product; a mixture of α and β anomers, with the β anomer being the major product), a colorless oil. LCMS (ESI+) m / z: C 20 H 22 Calculated value for O9[M+H2O]+=424.13, found 424.13, RT: 1.545 min, Method 1.

[0874] Preparation of compound 139b

[0875]

[0876] 6-Chloropurine (100.10 mg, 0.65 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (131.95 mg, 0.65 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80°C for 16 hours. After the mixture was cooled to room temperature, compound 138b (241 mg, 0.59 mmol, 1.00 eq) in MeCN (2.2 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (157.21 mg, 0.71 mmol, 1.20 eq) and the mixture was heated to 80°C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc (20 mL), washed with saturated NaHCO (3×20 mL) and saturated aqueous NaCl (3×20 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 4:1).The fractions containing the product were collected and the solvent was removed in vacuo to give compound 139b.

[0877] 71% yield (210 mg, 0.42 mmol, crude), colorless oil. LCMS (ESI+) m / z: C 23 H 21 Calculated value for ClN4O7[M+H]+=501.11, found 501.11, RT: 1.597 min, Method 1.

[0878] Preparation of compound 140b

[0879]

[0880] Compound 139b (295 mg, 0.59 mmol, 1.00 eq) was dissolved in 1,4-dioxane (3.0 mL) and NH3 (0.8 mL aqueous solution) was added. The mixture was heated to 80 ° C for 16 hours. After the mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was purified by silica gel column chromatography with dichloromethane / methanol (gradient elution: DCM / MeOH from 99: 1 to 5: 1). The fractions containing the product were collected and the solvent was removed in vacuo to obtain compound 140b.

[0881] 53% yield (92 mg, 0.31 mmol), off-white solid. 1H NMR (300 MHz, methanol-d4) δ 8.23 ​​(d, J = 9.8 Hz, 2H), 6.07 (d, J = 5.2 Hz, 1H), 4.83-4.77 (m, 1H), 4.52-4.44 (m, 1H), 4.23 (d, J = 5.1 Hz, 1H), 2.21-2.08 (m, 2H), 2.04-1.92 ppm (m, 2H). 13 C NMR (75 MHz, CDCl3) awaiting data. 13 CNMR(75MHz,MeOD)δ155.74,152.18,149.31,140.06,119.30,90.77,88.47,73.75,73.71,67.29,26.56,26.01ppm. LCMS(ESI+)m / z:C 12 H 15 Calculated value for N5O4[M+H]+=294.11, found 294.11, RT: 0.412 min, Method 1.

[0882] Preparation of compounds 6a and 6b

[0883]

[0884] To a stirred solution of CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) in acetonitrile (6 mL) is added 2- chloro-1-methylpyridinium iodide (702 mg, 2.75 mmol, 1.5 eq), tert-butyl vinyl ether (2.42 mL, 18.33 mmol, 10 eq) and finally DIPEA (0.96 mL, 5.49 mmol, 3 eq). The resulting reaction mixture is then refluxed for 16 hours. The reaction is then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics are dried over sodium sulfate, filtered and concentrated to give crude product compound 6. The crude product consisting of 2 isomers is then purified by silica gel column chromatography (petroleum ether / EtOAc 80:20 to give compound 6a as a colorless oil and compound 6b as a pure form of colorless crystals).

[0885] Compound 6a (20% yield, 110 mg), R f 0.6 (petroleum ether / EtOAc 80:20): 1H NMR (400 MHz, CHLOROFORM-d) δ 5.48 (d, J = 5.8 Hz, 1H), 5.02 (s, 1H), 4.55 (d, J = 5.8 Hz, 1H), 4.11 (t, J = 7.9 Hz, 1H), 3.32 (s, 3H), 2.98-2.82 (m, 2H), 1.46 (s, 3H), 1.29 (s, 3H), 1.19 ppm (s, 9H).

[0886] 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, 25.30 ppm.

[0887] Compound 6b (25% yield, 140 mg), R f 0.4 (petroleum ether / EtOAc 80:20): 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.04 (s, 1H), 4.84 (d, J = 5.7 Hz, 1H), 4.60 (d, J = 5.8 Hz, 1H), 4.15 (dd, J = 6.1, 1.8 Hz, 1H), 3.43 (s, 3H), 3.22 (dd, J = 17.4, 6.1 Hz, 1H), 2.65 (dd, J = 17.3, 1.8 Hz, 1H), 1.48 (s, 3H), 1.29 (s, 3H), 1.22 ppm (s, 9H).

[0888] 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, 25.48 ppm.

[0889] GC-MS: [M + ]301,15.14min(Method 4).

[0890] Preparation of compound 7

[0891]

[0892] To a stirred solution of CAS 54622-95-6 (2.00 g, 9.16 mmol, 1 eq) in DCM (8 mL) and one drop of DMF was added oxalyl chloride (1.18 mL, 13.75 mmol, 1.5 eq), and the resulting reaction mixture was 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.

[0893] Ethoxyacetylene (18.33mmol 40%w / w hexane solution, 2eq) is added to the DCM solution (25ml) of the phosgene obtained above. The stirred solution is then treated dropwise with triethylamine (1.38mL, 10.08mmol, 1.1eq) at room temperature. After 30min, the suspension is heated to reflux and stirred for another 16 hours. The gained turbid mixture is cooled, triethylammonium chloride is removed by filtration afterwards and the filtrate is concentrated in vacuo to give a brown oil. The residue is then purified by silica gel column chromatography (petroleum ether / EtOAc 70:30) to obtain compound 7 (1.32g, 4.88mmol, 53%) as a brown oil (as indicated by NMR spectroscopy, it is a mixture of two (74:26) diastereomers).

[0894] Data of the main isomers: 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.35 (d, J = 0.9 Hz, 1H), 5.02 (d, J = 1.2 Hz, 1H), 4.88 (dd, J = 5.8, 1.2 Hz, 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, 1.1 Hz, 3H), 1.30 ppm (s, 3H).

[0895] 13 C NMR (101 MHz, chloroform-d) δ 186.52, 182.08, 113.98, 113.40, 106.51, 101.02, 84.32, 79.97, 69.94, 54.84, 25.88, 24.91, 14.00 ppm.

[0896] Preparation of compound 8

[0897]

[0898] To a stirred solution of CAS 54622-95-6 (200 mg, 0.92 mmol, 1 eq) in DCM (2 mL) and one drop of DMF was added oxalyl chloride (0.12 mL, 1.37 mmol, 1.5 eq), and the resulting reaction mixture was stirred at room temperature for 4 hours. Excess solvent and oxalyl chloride were removed in vacuo for 1 hour and carried on to the next step.

[0899] 1- (trimethylsilyl) propyne (1.03 mL, 9.16 mmol, 10 eq) was added to the acid chloride in toluene (2 mL) obtained above in a sealed tube, followed by EtN (0.15 mL, 1.10 mmol, 1.2 eq) and the resulting reaction mixture was heated at 120 ° C overnight (16 hours), then quenched with HCl (1 M, 10.00 mL). The aqueous phase was extracted with EtOAc (20 × 2 mL), and the combined organic layers were dried over NaSO and concentrated under reduced pressure to provide a crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90: 10) to give compound 8 (146 mg, 0.47 mmol, 51%) as a colorless oil (as indicated by NMR spectroscopy as a mixture of two (82: 18) diastereomers).

[0900] Data of the main isomers: 1 H NMR (400 MHz, chloroform-d) δ 4.89 (s, 1H), 4.62 (d, J = 6.0 Hz, 1H), 4.59 (d, J = 6.0 Hz, 1H), 3.28 (s, 3H), 1.87 (s, 3H), 1.50 (s, 3H), 1.26 (s, 3H), 0.28 ppm (s, 9H).

[0901] 13 C NMR (101 MHz, chloroform- d ) δ 190.85, 179.55, 164.97, 112.15, 107.42, 107.24, 85.15, 80.81, 54.60, 25.55, 23.60, 10.45, −1.09 ppm.

[0902] LCMS: (ESI + ):[M+1] + =313.3, RT 1.23min (Method 10)

[0903] Preparation of compound 9

[0904]

[0905] To a stirred solution of CAS 54622-95-6 (400 mg, 1.83 mmol, 1 eq) in toluene (6 mL) is 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 is then refluxed for 16 hours. The reactant is then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, the combined organic matter is dried over sodium sulfate, filtered and concentrated. The crude product is then subjected to silica gel chromatography (petroleum ether / EtOAc 90: 10) to give compound 9 (140 mg, 0.42 mmol, 23%) as a light yellow oil (as indicated by NMR spectroscopy as a mixture of two (82: 18) diastereomers).

[0906] Data of the main isomers: 1 H NMR (400 MHz, chloroform-d) δ 7.32 (s, 5H), 5.20-5.12 (m, 2H), 5.06 (s, 1H), 4.44 (d, J = 6.1 Hz, 1H), 3.39 (d, J = 8.5 Hz, 1H), 3.36 (d, J = 4.8 Hz, 1H), 3.33 (s, 3H), 1.39 ppm (s, 3H), 1.30 (s, 3H).

[0907] 13 C NMR (101 MHz, chloroform-d) δ 195.94, 158.20, 134.45, 129.25, 129.08, 127.89, 113.36, 107.43, 95.72, 82.32, 77.32, 77.00, 76.68, 76.42, 55.57, 40.93, 26.76, 25.90 ppm.

[0908] Preparation of compound 10

[0909]

[0910] To a stirred solution of CAS 39682-04-7 (3.10 g, 10.53 mmol, 1 eq) in DCM (15 mL) and one drop of DMF was added oxalyl chloride (1.35 mL, 15.80 mmol, 1.5 eq), and the resulting reaction mixture was 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.

[0911] To a stirred solution of EtN (2.28 mL, 15.80 mmol, 1.5 eq) and vinyltrimethylsilane (12.42 mL, 84.29 mmol, 8 eq) in toluene (20 mL) was added a toluene solution (10 mL) of the acid chloride obtained above using a syringe pump at 80 ° C. Over 2 hours. The reaction mixture was then refluxed at 120 ° C. overnight (16 hours) before being quenched with HCl (1 M, 40.00 mL). The aqueous phase was extracted with EtOAc (40 × 2 mL), and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to provide a crude product. The residue was then purified by silica gel column chromatography (petroleum ether / EtOAc 90: 10) to give compound 10 (2.40 g, 6.37 mmol, 60%) as a colorless oil (as indicated by NMR spectroscopy as a mixture of four (56: 24: 11: 9) diastereomers).

[0912] Compound 10 was purified via preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH 4 HCO 3 solution in water, CH 3 CN) to give two fractions of compound 10a (11.5 mg, 0.03 mmol, 5% yield) (50.6 mg, 0.13 mmol, 20% yield) and compound 10b (12 mg, 0.03 mmol, 5% yield).

[0913] Compound 10a

[0914] 1 H NMR (400 MHz, chloroform-d): δ 7.31-7.49 (m, 5H), 5.89 (d, J = 4.0 Hz, 1H), 4.59-4.72 (m, 3H), 4.12 (s, 1H), 3.02 (dd, J = 16.3, 11.9 Hz, 1H), 2.65 (dd, J = 16.1, 12.1 Hz, 1H), 1.69 (s, 3H), 1.61-1.67 (m, 1H), 1.30 (s, 3H), 0.00 ppm (s, 9H).

[0915] 13 C NMR (101 MHz, chloroform-d): δ 202.8, 137.8, 129.7, 129.4, 129.3, 114.2, 105.9, 104.9, 84.2, 82.9, 73.1, 44.6, 27.4, 26.9, 25.0, 0.0 ppm.

[0916] LCMS: (ESI + ):[M+1] +=377.4, RT 1.31 min (Method 10)

[0917] Compound 10b

[0918] 1 H NMR (600MHz, chloroform-d): δ7.33-7.37(m,2H),7.29-7.33(m,1H),7.26-7.29(m,2H),6.12(d,J=4.3Hz,1H),4.75(dd,J=4.3,2.1Hz,1H),4.73(d,J=11.4 Hz,1H),4.57(d,J=11.4Hz,1H),4.31(d,J=2.0Hz,1H),2.79(d,J=12.2Hz ,2H),1.84(t,J=12.2Hz,1H),1.57(s,3H),1.43(s,3H),0.14ppm(s,9H).

[0919] 13 C NMR (151 MHz, chloroform-d): δ 205.7, 136.6, 128.3, 127.7, 127.0, 115.3, 103.8, 100.3, 85.2, 85.1, 71.8, 43.1, 28.2, 27.4, 22.8, -2.0 ppm.

[0920] LCMS: (ESI + ):[M+18] + =394.3, RT 1.35 min (Method 10)

[0921] Preparation of compound 11

[0922]

[0923] To compound 10 (1.60g, 4.25mmol, 1eq) in anhydrous THF (5mL) in the stirred solution, acetic acid (0.24mL, 4.25mmol, 1eq) and TBAF (12.75mL, 1.0M THF solution, 3eq). The gained reaction mixture was stirred at room temperature for 5 hours, quenched by adding water (20mL) and extracted with EtOAc (40mL). The organic layer merged is through Na2SO4 drying and concentrating under reduced pressure provides crude product. Then residue is passed through silica gel column chromatography (petroleum ether / EtOAc 80:20, R f=0.5) to give compound 11 (185 mg, 0.61 mmol, 14% (28% brsm)) as a colorless oil (as indicated by NMR spectroscopy, it is a mixture of two (65:35) diastereomers). The experiment was repeated once more to provide 180 mg, 14% and the two products were combined to give compound 11 (365 mg).

[0924] Data of the main isomer of compound 11: 1 H NMR (chloroform-d, 600MHz): δ = 7.34-7.38 (m, 2H), 7.31-7.33 (m, 1H), 7.30 (br d,J=6.9Hz,2H),6.05(d,J=3.6Hz,1H),4.69(d,J=12.2Hz,1H),4.66(d,J=3.5Hz,1H),4.49(d,J=12.2Hz,1H), 4.20(s,1H),2.64-2.77(m,2H),2.36(td,J=11.3,4.9Hz,1H),2.14-2.22(m,1H),1.50(s,3H),1.34ppm(s,3H). 13 C NMR (chloroform-d, 151 MHz): δ = 203.1, 136.8, 128.6, 128.2, 128.0, 113.4, 106.6, 99.7, 86.6, 83.6, 72.0, 40.7, 27.1, 26.5, 26.0 ppm.

[0925] Preparation of compound 12

[0926]

[0927] To compound 11 (350 mg, 1.15 mmol, 1.00 eq) in MeOH (4 mL) was added NaBH (57 mg, 1.50 mmol, 1.30 eq) at -78 ° C. (the wavy bond in the cyclobutane of compound 11 refers to a mixture of multiple isomers as previously obtained) and the resulting reaction mixture was stirred at -78 ° C. for 1 hour. The reaction was then quenched by adding saturated NH Cl (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give crude compound 12. The crude product consisting of three isomers was then purified by silica gel column chromatography (petroleum ether / EtOAc 90:10 to 80:20) (TLC) to give three isomers, namely compound 12a (Rf 0.4, 165 mg, 47%, as a mixture of two diastereomers (91:9, as indicated by NMR spectroscopy)) as a colorless oil, compound 12b (Rf 0.3, 80 mg, 23%, as a mixture of three diastereomers (68:26:6), as indicated by NMR spectroscopy) as a colorless oil, and compound 12c (Rf 0.2, 80 mg, 23%, as a single pure isomer, as indicated by NMR spectroscopy) as a colorless oil.

[0928] Compound 12a was purified via preparative HPLC (stationary phase: RP XBridge Prep C18 OBD-10 μm, 50×150 mm, mobile phase: 0.25% NH 4 HCO 3 solution in water, MeOH) to give 86 mg, 0.28 mmol, 53% yield.

[0929] Data of compound 12a

[0930] 1 H NMR (300MHz, chloroform-d) δ7.39-7.25(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).

[0931] LCMS: (ESI + ):[M+18] + =324.3, RT 1.01 min (Method 10)

[0932] Data of the main isomer of compound 12b: 1 H NMR (300 MHz, chloroform-d) δ 7.52-7.35 (m, 5H), 5.93 (d, J = 3.4 Hz, 1H), 4.88-4.81 (m, 1H), 4.71 (d, J = 3.8 Hz, 1H), 4.48 (s, 1H), 4.44-4.37 (m, 1H), 4.33 (dd, J = 8.9, 7.8 Hz, 1H), 3.04 (d, J =1.1Hz,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).

[0933] Data of compound 12c

[0934] 1 H NMR (300MHz, chloroform-d) δ7.36-7.20 (m, 5H), 5.91 (d, J = 3.9Hz, 1H), 4.69 (d, J = 12. 1Hz,1H),4.56(dd,J=4.0,0.8Hz,1H),4.46(d,J=12.1Hz,1H),4.35-4.24(m, 1H),3.77(t,J=0.6Hz,1H),2.50(d,J=8.7Hz,1H),2.15-2.00(m,2H),2.00-1 .84(m,1H),1.81-1.68(m,1H),1.45-1.37(m,3H),1.25ppm(d,J=0.7Hz,3H).

[0935] LCMS: (ESI + ):[M+18] + =324.4, RT 0.94 min (Method 10)

[0936] Preparation of compound 13

[0937]

[0938] To a stirred solution of CAS 39682-04-7 (400 mg, 1.36 mmol, 1 eq) in acetonitrile (6 mL) was added 2-chloro-1-methylpyridinium iodide (521 mg, 2.04 mmol, 1.5 eq), tert-butyl vinyl ether (1.79 mL, 13.59 mmol, 10 eq) and finally DIPEA (0.71 mL, 4.08 mmol, 3 eq). The resulting reaction mixture was then refluxed for 16 hours. The reactant was then cooled to room temperature, quenched with HCl (20 mL, 1 M), extracted with ethyl acetate, and the combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was then subjected to silica gel chromatography (petroleum ether / EtOAc 90: 10) to give compound 13 (100 mg, 0.27 mmol, 20% as a single diastereomer, but an unknown diastereomer) as a colorless oil.

[0939] 1 H NMR (400MHz, chloroform-d) δ7.39-7.28(m,5H),6.07(d,J=4.3Hz,1H),4.77(d,J=12.0Hz,1H),4.73(dd,J=4.4,2.1Hz,1H),4.68(d, J=2.2Hz,1H),4.60(d,J=12.0Hz,1H),4.32(t,J=8.3Hz,1H),2.87-2.74(m,2H),1.49(s,3H),1.39(s,3H),1.18ppm(s,9H).

[0940] 13 C NMR (101 MHz, chloroform-d) δ 205.64, 137.11, 128.34, 127.78, 127.76, 114.63, 105.73, 101.55, 85.76, 81.73, 74.70, 72.33, 63.74, 50.16, 28.21, 27.86, 27.44 ppm

[0941] Preparation of compound 14

[0942]

[0943] 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, 169 mmol, 1.10 eq) was added in portions. The solution was cooled to 0 ° C. and iodine (42.9 g, 169 mmol, 1.10 eq) was added in portions over 40 minutes. After the addition of the reagent, the solution was cooled at 0 ° C. for another 20 minutes and then stirred at room temperature for 24 hours. Subsequently, the reaction mixture was cooled to 0 ° C. and pivaloyl chloride (43.5 ml, 354 mmol, 2.30 eq) was added dropwise to the stirring mixture via a pressure-equalizing dropping funnel over 1.5 hours. After the addition of the reagent, the mixture was warmed to room temperature and stirred for 22 hours. The mixture was concentrated in vacuo to a minimum volume and co-evaporated with toluene (2×300 ml) to dryness. In the remaining brown slurries, n-heptane (1L) is added, followed by triphenylphosphine oxide precipitation. The mixture is ultrasonically treated for 1 hour, and the solid material is filtered and washed with n-heptane (300ml). The filtrate is concentrated in vacuo to minimum volume to obtain yellow slurry. Subsequently, the slurry is redissolved in EtOAc (500ml) and washed with sodium thiosulfate solution (saturated aqueous solution 1 × 250ml) and salt solution (1 × 250ml). The organic phase is dried (MgSO ), filtered and the filtrate is concentrated in vacuo to obtain compound 14 (49.0g, 72% crude yield), which solidifies when placed at room temperature.

[0944] 1 H NMR(400MHz, chloroform-dδ5.27(d,J=4.8Hz,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)

[0945] 13 C NMR (101 MHz, chloroform-d δ 177.0, 176.8, 106.1, 80.3, 75.2, 74.9, 55.3, 38.8, 38.6, 27.1, 6.7 ppm

[0946] Preparation of compound 15

[0947]

[0948] Compound 14 (47.8g, 108mmol, 1.00eq) is dissolved in DMF (500ml), and DBU (17.8ml, 119mmol, 1.10eq) is added once to the stirring mixture, and the mixture is heated to 90°C for 18 hours. The mixture is cooled to room temperature and concentrated in vacuo to about 250ml. Subsequently, the brown solution is diluted in n-heptane (1.5l) and washed with brine (3×750ml). The obtained organic phase is dried (MgSO4), filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 99:1 to 9:1). The fractions containing the product are collected, and the solvent is evaporated to obtain the desired compound 15 (30.2g, 96.1mmol, 89% yield) as a colorless liquid.

[0949] 1 H NMR (360MHz, chloroform-d) δ5.76 (dt, J=5.1, 1.9Hz, 1H), 5.16 (d, J=5.1Hz, 1H), 5.02 (s, 1H), 4 .51(t,J=1.8Hz,1H),4.08(t,J=2.0Hz,1H),3.46(s,3H),1.23(s,9H),1.21ppm(s,9H)

[0950] 13 C NMR (101 MHz, chloroform-d) δ 177.3, 177.2, 157.2, 106.2, 84.6, 73.2, 69.7, 56.3, 39.1, 39.0, 27.4, 27.3 ppm

[0951] Preparation of compound 16

[0952]

[0953] Zinc powder (25.0 g, 0.38 mol, 1.00 eq) was added to a two-necked round-bottom flask (500 ml) equipped with softened water (100 ml), and the solution was degassed with nitrogen over a 15-minute period. Subsequently, copper (II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was added, and the stirred solution was degassed and stirred for 45 minutes. The mixture was filtered, and the black solid was washed with degassed water (250 ml) and degassed acetone (250 ml) respectively. The zinc-copper couple was vacuum dried for 12 hours. Compound 15 (10.0 g, 31.8 mmol, 1.00 eq) was weighed in an oven-dried flask and dissolved in anhydrous ether (300 ml, 4% by volume). The mixture was dried over 400 nm (1 / 4-thiazolinone) (5% by weight, 4-nitropropane, 2-naphthene, 1-dextrose ...

[0954] 1 H NMR (360 MHz, chloroform-d) δ 5.84 (d, J = 4.0 Hz, 1H), 5.35 (d, J = 4.4 Hz, 1H), 4.98 (s, 1H), 3.92 (d, J = 18.7 Hz, 1H), 3.51 (s, 1H), 3.40 (d, J = 18.7 Hz, 1H), 1.19 ppm (s, 18H)

[0955] 13 C NMR (91 MHz, chloroform-d) δ 191.0, 176.3, 175.4, 106.0, 91.4, 83.2, 74.6, 71.2, 55.9, 52.0, 38.5, 26.8 ppm

[0956] Preparation of compound 17

[0957]

[0958] Compound 16 (2.64g, 6.21mmol, 1.00eq) is dissolved in THF (45.0ml), and acetic acid (5.33ml, 93.1mmol, 15.0eq) is added, followed by addition of zinc powder (4.06g, 62.1mmol, 10.0eq) in batches and the mixture is heated to 50°C for 5 hours. Subsequently, the solution is cooled to room temperature and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a minimum volume, redissolved in EtOAc (200ml), washed with brine (2 × 75ml), dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 99: 1 to 1: 1). The fractions containing the product are collected, the solvent is evaporated, and the desired compound 17 (1.48g, 4.16mmol, 67% yield) is obtained as a colorless oil.

[0959] 1 H NMR (360 MHz, chloroform-d) δ 5.56 (d, J = 4.4 Hz, 1H), 5.26 (dd, J = 4.4, 0.7 Hz, 1H), 4.91 (s, 1H), 3.43-3.51 (m, 2H), 3.42 (s, 3H), 3.33-3.41 (m, 1H), 3.14-3.25 (m, 1H), 1.22 (s, 9H), 1.21 ppm (s, 9H)

[0960] 13 C NMR (101 MHz, chloroform-d) δ 203.2, 177.2, 176.8, 105.7, 75.7, 75.1, 74.0, 58.3, 55.7, 55.5, 39.0, 38.8, 27.1 ppm

[0961] Preparation of Compound 18a and Compound 18b

[0962]

[0963] Compound 17 (500 mg, 1.40 mmol, 1.0 eq) was dissolved in MeOH (5 mL), and NaBH4 (64.0 mg, 1.68 mmol, 1.20 equiv) was added portionwise at -78 ° C. The resulting solution was stirred at -78 ° C for 30 minutes. The reaction was then quenched by adding 20 mL of saturated NH4Cl aqueous solution. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (gradient elution: PE / EtOAc from 99:1 to 4:1). The fractions containing the product were collected and the solvent was evaporated to give compound 18a (mixed with 14% compound 18b).

[0964] 75% yield (375 mg, 11.4 mmol), colorless oil. 1 H NMR (400 MHz, chloroform-d) δ 5.27 (d, J = 4.5 Hz, 1H), 5.16 (dd, J = 4.6, 1.9 Hz, 1H), 4.83 (d, J = 1.9 Hz, 1H), 3.92 (p, J = 7.1 Hz, 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), 1.20 ppm (s, 9H). GCMS (ESI + )m / z:C 18 H 30 O7[M-CH3O] +Calculated value = 327.18, found 327.14, RT: 9.317 min, (Method 1).

[0965] Preparation of Compound 19a and Compound 19b

[0966]

[0967] Compound 18a (a mixture with compound 18b) (7.00 g, 19.5 mmol, 1.0 eq) and TEA (3.94 g, 39.1 mmol, 2.0 equiv) were dissolved in DCM (70 mL), and benzoyl chloride (5.47 g, 39.1 mmol, 2.0 equiv) was added dropwise at 0°C. The resulting solution was stirred at 0°C for 1 hour. The reaction was then quenched with 1 M aqueous HCl until the pH was <7. 130 mL of DCM was added to the resulting solution, which was extracted with 1 x 200 mL of H2O, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (gradient elution: PE / EtOAc from 99:1 to 20:1). The product-containing fractions were collected and the solvent was evaporated to give compound 19a (a mixture containing 13% of compound 19b).

[0968] 87% yield (7.90 g, 17.10 mmol), colorless oil. 1 H NMR (400MHz, chloroform-d) δ8.07-8.01(m,2H),7.60-7.52(m,1H),7.44(dd,J=8.4 ,7.1Hz,2H),5.38(d,J=4.5Hz,1H),5.21(dd,J=4.5,1.3Hz,1H),4.86-4.78 (m,2H),3.40(s,3H),3.05-3.14(m,1H),2.94-2.84(m,1H),2.73(dd,J=12 .9,7.3Hz,1H),2.44(dd,J=12.9,7.3Hz,1H),1.29(s,9H),1.22ppm(s,9H). LCMS(ESI + )m / z:C 25 H 34 O8[M+NH4] + Calculated = 480.26, found 480.25, RT: 2.151 min (Method 1).

[0969] Preparation of compound 19b

[0970]

[0971] Compound 18 (2.28 g, 6.36 mmol, 1.00 eq) was dissolved in THF (60 ml) and benzoic acid (932 mg, 7.63 mmol, 1.20 eq) was added, followed by triphenylphosphine (2.01 g, 7.63 mmol, 1.20 eq). The mixture was cooled to 0 ° C and diethyl azodicarboxylate (1.15 ml, 7.31 mmol, 1.20 eq) was added. After addition, the mixture was warmed to room temperature and stirred for 16 hours, followed by addition of pentane (120 ml) to precipitate triphenylphosphine oxide. The solid was filtered and rinsed with heptane (30 ml). Salt water (50 ml) was added to the filtrate, and the product was extracted with heptane (1 × 150 ml, 2 × 100 ml). The combined organic layer was dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 99:1 to 4:1). The fractions containing intermediate 30 were collected and the solvent was evaporated to give compound 19b (1.79 g, 3.88 mmol, 61% yield) as a colorless oil.

[0972] 1 H NMR (400MHz, chloroform-d) δ7.98-8.04(m,2H),7.52-7.60(m,1H),7.39-7.47(m,2H),5.44(m,1H),5.37(d,J=4.4Hz,1H),5.18(dd,J=4.4,1.5Hz,1H ),4.88(d,J=1.5Hz,1H),3.42(s,3H),2.81(ddd,J=13.4,7.5,4.4Hz,1H),2.62-2.72(m,2H),2.52-2.62(m,1H),1.21(s,9H),1.20ppm(s,9H)

[0973] 13 C NMR (101 MHz, chloroform-d) δ 177.2, 177.0, 166.1, 133.0, 130.0, 129.6, 128.4, 105.7, 81.1, 75.1, 74.3, 65.5, 55.4, 41.3, 39.3, 39.0, 38.8, 27.2, 27.1 ppm

[0974] Preparation of compound 20

[0975]

[0976] 6-Cl purine CAS 87-42-3 (1.69 g, 10.9 mmol, 1.1 equiv) was dissolved in MeCN (37 mL), and N,O-bis(trimethylsilyl)acetamide (2.02 g, 9.95 mmol, 1 equiv) was added dropwise. The mixture was heated to 80°C overnight. After the mixture cooled, compound 19a (containing a mixture of 13% compound 19b) (4.6 g, 9.95 mmol, 1.00 equiv) in MeCN (31 mL) was added, along with trimethylsilyl trifluoromethanesulfonate (2.65 g, 11.94 mmol, 1.2 equiv), and the mixture was heated to 80°C for 2 hours. After cooling to room temperature, the mixture was extracted twice with saturated NaHCO₃ into EtOAc and once with saturated aqueous NaCl. The organic layer was dried over Na₂SO₄. The solvent was removed in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 30:1). The fractions containing the product were collected and the solvent was evaporated to give compound 20 in 86% yield (5.00 g, 8.56 mmol) as a foamy solid. 1 H NMR (300MHz, chloroform-d) δ8.81(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 ClN4O7[M+H] + Calculated = 585.20, found 585.30, RT: 2.226 min (Method 6).

[0977] Preparation of compound 21

[0978]

[0979] Compound 20 (4.0 g, 6.8 mmol, 1.0 equiv) was dissolved in 1,4-dioxane (40 mL) and aqueous NH3 (10 mL). The mixture was heated to 80°C overnight. After cooling to room temperature, the solvent was removed in vacuo. The product was dissolved in MeOH (40 mL) and sodium methoxide (0.37 g, 6.84 mmol, 1.00 equiv). The reaction was stirred at room temperature for 30 min and then stirred with H exchange resin until pH = 7. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 21.

[0980] 95% yield (1.90 g, 6.48 mmol), white solid. 1 H NMR(400MHz,D2O)δ8.24(s,1H),8.16(s,1H),5.97(d,J=6.6Hz,1H),4.91(dd,J=6.7,4.5Hz, 1H), 4.40 (p, J = 6.5Hz, 1H), 4.28 (d, J = 4.5Hz, 1H), 2.64-2.42 (m, 4H), 2.29-2.22ppm (m, 1H). 13 C NMR (101MHz, DMSO) δ156.06,153.09,150.02,140.48,119.36,86.86,78.91,75.14,73.28,57.38,45.97,41.03ppm. LCMS(ESI + )m / z:C 12 H 15 N5O4[M+H] + Calculated = 294.11, found 294.12, RT: 1.301 min (Method 8).

[0981] Preparation of compound 22

[0982]

[0983] Compound 21 (1.80 g, 6.14 mmol, 1.00 equiv) was dissolved in acetone (18 mL), and 2,2-dimethoxypropane (1.3 g, 12.3 mmol, 2.00 equiv) and perchloric acid (0.12 g, 1.22 mmol, 0.20 equiv) were added at 0°C. The reaction was stirred at room temperature for 1 hour. 1 M aqueous NaOH was then added to the reaction until pH = 7, followed by the addition of 50 mL of DCM, and the mixture was extracted with 1 x 60 mL of H2O, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 85:15). The fractions containing the product were collected and the solvent was evaporated to give compound 22.

[0984] 77% yield (1.58 g, 4.50 mmol), light yellow oil. 1 H NMR (400MHz, DMSO-d6) δ8.00(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),2.5 1(dd,J=12.1,6.1Hz,1H),2.24(dt,J=12.2,6.4Hz,1H),1.85(dd,J=11.9,7.9Hz,1H),1.23(s,3H),1.21-1.16(m,1H),1.13ppm(s,3H). 13 C NMR (101MHz, DMSO) δ156.04,153.16,149.37,140.31,118.89,112.93,88.54,84.95,83.96,80.02,57.56,48.94,45.32,26.62,25.34ppm. LCMS(ESI + )m / z:C 15 H 19 N5O4[M+H] + Calculated value = 334.14, found 334.10, RT: 0.894 min (Method 3).

[0985] Preparation of compound 23

[0986]

[0987] Compound 22 (1.5 g, 4.5 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL), and pyridine (15 mL) and MsCl (0.77 g, 6.75 mmol, 1.5 equiv) were added at 0° C. The reaction was stirred at 40° C. for 3 hours. The reaction mixture was then poured into 30 mL of ice water and extracted with 30 mL of dichloromethane and concentrated under reduced pressure to give compound 23 in 97% yield (1.8 g, 4.38 mmol), a light yellow oil. 1 H NMR (300MHz, methanol-d4) δ8.23 (s, 1H), 8.19 (s, 1H), 6.14 (d, J = 1.1Hz, 1H), 5.77 ( dd,J=5.8,1.1Hz,1H),5.08(d,J=5.8Hz,1H),4.74(q,J=7.1Hz,1H),3.13(dt ,J=12.8,6.4Hz,1H),3.01(s,3H),2.83(dt,J=12.7,6.4Hz,1H),2.54(dd,J= 12.8, 7.3Hz, 1H), 1.96 (dd, J = 12.5, 7.1Hz, 1H), 1.52 (s, 3H), 1.42ppm (s, 3H). 13 CNMR (75 MHz, methanol-d4) δ 155.85, 152.30, 148.83, 140.71, 119.06, 113.22, 89.77, 85.02, 84.26, 81.16, 66.42, 43.35, 38.31, 36.62, 25.40, 24.05 ppm. LCMS (ESI + )m / z:C 16 H 21 N5O6S[M+H] + Calculated value = 412.12, found 412.15, RT: 0.987 min (Method 1).

[0988] Preparation of compound 24

[0989]

[0990] Compound 23 (1.80 g, 4.38 mmol, 1.00 equiv) was dissolved in DMF (30 mL) and tetrabutylammonium iodide (0.16 g, 0.43 mmol, 0.10 equiv) and NaN3 (2.8 g, 43.8 mmol, 10.00 equiv) were added at 0°C. The reaction was stirred at 110°C for 3 hours. The reaction mixture was then poured into 45 mL of ice water, extracted with 2×50 mL of dichloromethane and concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 24.

[0991] 70% yield (1.10 g, 8.56 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.22(s,1H),8.19(s,1H),6.15(s,1H),5.69(dd,J=5.9,0.9Hz,1H),5.18(d,J=5.9Hz,1H),4.04-3.96(m ,1H),2.67-2.49(m,2H),2.26(ddd,J=13.0,5.1,3.2Hz,1H),1.88(ddd,J=13.2,7.8,3.4Hz,1H),1.51(s,3H),1.43ppm(s,3H). 13 C NMR (75 MHz, methanol-d4) δ 155.79, 152.55, 148.94, 140.72, 119.00, 112.94, 89.48, 86.17, 85.95, 84.09, 50.02, 41.14, 36.21, 25.36, 24.01 ppm. LCMS (ESI + )m / z:C 15 H 18 N8O3[M+H] + Calculated = 359.15, found 359.15, RT: 1.216 min (Method 6).

[0992] Preparation of compound 25

[0993]

[0994] Compound 24 (1.0 g, 2.80 mmol, 1.00 equiv) was dissolved in methanol (10 mL) and Pd / C (0.2 g) was added. The reaction was stirred at room temperature overnight under a hydrogen atmosphere. After completion, the solution was filtered. The filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to give compound 25.

[0995] 75% yield (0.75 g, 2.25 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.23(s,1H),8.22(s,1H),6.20(s,1H),5.68(dd,J=5.9,0.8Hz,1H),5.22(d,J=5.9Hz,1H),3.61(t,J=7.9Hz,1H),2.64-2 .57(m,1H),2.52(ddd,J=13.6,8.2,5.0Hz,1H),2.25(dd,J=13.3,7.5Hz,1H),1.80(ddd,J=13.2,8.2,4.9Hz,1H),1.51(s,3H),1.43ppm(s,3H). 13 C NMR (101 MHz, methanol-d4) δ 156.02, 152.54, 148.94, 141.03, 119.01, 112.86, 89.46, 86.35, 85.82, 84.14, 41.40, 40.93, 36.98, 25.35, 23.98 ppm. LCMS (ESI + )m / z:C 15 H 20 N6O3[M+H] + Calculated value = 333.16, found 333.10, RT: 0.902 min (Method 3).

[0996] Preparation of compound 26

[0997]

[0998] To compound 25 (0.12 g, 0.36 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL) and the mixture was heated to 40 ° C for 3 hours. Subsequently, the solution was cooled to room temperature and carefully quenched with NaHCO to pH = 7. The mixture was extracted with CH Cl (3 × 2 mL) and the combined organic layers were dried (Na SO ), filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19*250 mm 10 u; mobile phase A: water (10 mM NH HCO ), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min). The fractions containing the product were collected and the solvent was evaporated to give compound 26.

[0999] 76% yield (0.08 g, 0.27 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.25(s,1H),8.17(s,1H),6.01(d,J=6.4Hz,1H),4.90(dd,J=6.3,4.6Hz,1H),4.27(d,J=4.6Hz,1H),3.56(p,J=7.5Hz, 1H), 2.60(ddd,J=12.9,8.2,4.5Hz,1H), 2.45(ddd,J=12.8,8.1,4.6Hz,1H), 2.31(dd,J=13.5,7.0Hz,1H), 2.13ppm(dd,J=13.1,6.8Hz,1H). 13 C NMR (75MHz, D2O) δ155.68,152.99,149.17,140.14,119.00,87.04,85.03,75.67,73.84,42.36,40.93,38.77ppm. LCMS(ESI + )m / z:C 12 H 16 N6O3[M+H] + Calculated value = 293.13, found 293.2, RT: 1.346 min (Method 8)

[1000] Preparation of compound 27

[1001]

[1002] To compound 25 (0.10 g, 0.30 mmol, 1.00 eq) in DCM (10 mL) was added AcOH (0.5 mL) followed by propionaldehyde (0.026 g, 0.44 mmol, 1.50 eq). The reactant was stirred at room temperature for 30 min and the solution was cooled to 0 ° C. NaBH (OAc) 3 (0.13 g, 0.62 mmol, 2.00 eq) was slowly added and the mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99: 1 to 90: 10). The fractions containing the product were collected and the solvent was evaporated to give compound 27.

[1003] 62% yield (0.07 g, 0.18 mmol), white solid. 1 H NMR(300MHz,D2O)δ8.16(d,J=17.6Hz,2H),6.23(s,1H),5.66(d,J=5.9Hz, 1H),5.22(d,J=5.9Hz,1H),3.84-3.65(m,1H),2.87-2.67(m,3H),2.59(dd, J=13.9,7.0Hz,1H),2.41(dd,J=13.7,8.1Hz,1H),1.89(s,3H),1.75(t,J= 7.1Hz, 1H), 1.53 (d, J = 15.6Hz, 4H), 1.42 (s, 3H), 0.86ppm (t, J = 7.4Hz, 3H). 13 CNMR(101MHz,D2O)δ155.60,152.93,148.72,140.76,114.02,88.29,85.20,85. 11,83.277,47.02,46.58,37.52,33.78,25.23,24.10,22.71,19.04,10.12ppm. LCMS(ESI + )m / z:C 18 H 26 N6O3[M+H] + Calculated value = 375.21, found 375.10, RT: 1.285 min, (Method 3).

[1004] Preparation of compound 28

[1005]

[1006] To compound 27 (0.10 g, 0.27 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL) and the mixture was heated to 40 ° C for 3 hours. Subsequently, the solution was cooled to room temperature and carefully quenched with NaHCO 3 to pH = 7. The mixture was extracted with CH 2 Cl 2 (3×2 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19*250 mm 10 u; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: ACN; 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 28.

[1007] 45% yield (0.040 g, 0.12 mmol), white solid. 1 H NMR(300MHz,DMSO-d6)δ8.25(s,1H),8.13(s,1H),7.22(s,2H),5.85(d,J=5.6Hz,1H) ,5.26(s,1H),4.81(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) δ156.52,153.01,149.98,140.36,119.79,87.94,84.94,75.91,73.70,49.18,47.14,41.00,37.38,23.18,12.33ppm. LCMS(ESI + )m / z:C 15 H 22 N6O3[M+H] + Calculated value = 335.18, found 335.25, RT: 0.908 min, (Method 3).

[1008] Preparation of compound 29

[1009]

[1010] Compound 18a (a mixture with compound 18b) (6.00 g, 16.8 mmol, 1.00 equiv) was dissolved in THF (60 mL), and triphenylphosphine (8.80 g, 33.6 mmol, 2.00 equiv) and benzoic acid (6.20 g, 50.4 mmol, 3.00 equiv) were added. DIAD (10.0 g, 50.4 mmol, 3.00 equiv) was then slowly added at 0°C. The mixture was stirred at room temperature for 1 hour, then heated to 50°C for 2 hours. Subsequently, 0.5 eq of triphenylphosphine and 1 eq of DIAD were added at 0°C, and then heated to 50°C for 1 hour. The reaction was cooled to room temperature and added to saturated aqueous NaHCO3 (200 mL). The aqueous phase was extracted with EA (200 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 from 99:1 to 5:1).The fractions containing the product were collected and the solvent was evaporated to give compound 29.

[1011] 69% yield (12.0 g, 35.92 mmol), yellow oil. 1 HNMR (300MHz, chloroform-d)8.03-7.98(m,2H),7.59-7.53(m,1H),7.43(t,J=7.8Hz,2H),5.47-5.39(m,1H),5.37(d,J=4.5Hz,1H),5.18(dd,J =4.5,1.5Hz,1H),4.88(d,J=1.6Hz,1H),3.42(s,3H),2.81(m,1H),2.71-2.61(m,2H),2.60-2.50(m,1H),1.21ppm(s,9H),1.20(s,9H). LCMS(ESI + )m / z:C 25 H 34 O8[M+NH4] + Calculated value = 480.26, found 480.25, RT: 1.557 min, method 7.

[1012] Preparation of compound 30

[1013]

[1014] 6-Cl purine CAS 87-42-3 (1.65 g, 10.7 mmol, 1.1 equiv) was dissolved in MeCN (35 mL), and N,O-bis(trimethylsilyl)acetamide (2.02 g, 9.73 mmol, 1.0 equiv) was added dropwise. The mixture was heated to 80°C overnight. After the mixture cooled, compound 29 (4.5 g, 9.73 mmol, 1.00 equiv) in MeCN (30 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (2.59 g, 11.68 mmol, 1.2 equiv), and the mixture was heated to 80°C for 2 hours. After cooling to room temperature, the mixture was extracted twice with EtOAc, washed once with saturated NaHCO₃, and once with saturated aqueous NaCl. The organic layer was dried over Na₂SO₄. The solvent was removed in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 30:1). The product-containing fractions were collected and the solvent was evaporated to give compound 30.

[1015] 76% yield (4.30 g, 7.36 mmol), foamy solid. 1 H NMR (300MHz, chloroform-d) δ8.78(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,1 H), 6.06 (d, J = 5.5Hz, 1H), 5.81 (d, J = 4.8Hz, 1H), 5.43-5.32 (m, 1H), 3.02 (m, 1H), 2.86-2.60 (m, 3H), 1.29 (s, 9H), 1.13ppm (s, 9H). LCMS(ESI + )m / z:C 29 H 33 ClN4O7[M+H] + Calculated value = 585.20, found 585.30, RT: 2.227 min, method 5.

[1016] Preparation of compound 31

[1017]

[1018] Compound 30 (4.30 g, 7.35 mmol, 1.00 equiv) was dissolved in 1,4-dioxane (45 mL) and concentrated aqueous NH3 solution (11 mL). The mixture was heated to 80 ° C and kept overnight. After cooling to room temperature, 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 room temperature for 30 min and then stirred with H exchange resin until pH = 7. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 31.

[1019] 95% yield (2.05 g, 7.00 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.24(s,1H),8.16(s,1H),6.00(d,J=6.6Hz,1H),4.93(dd,J=6.7,4.5Hz,1H),4.4 4(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 N5O4[M+H] + Calculated value = 294.11, found 294.20, RT: 1.409 min, Method 8.

[1020] Preparation of compound 32

[1021]

[1022] Compound 31 (2.00 g, 6.82 mmol, 1.00 equiv) was dissolved in acetone (20 mL), and 2,2-dimethoxypropane (1.40 g, 13.6 mmol, 2.00 equiv) and perchloric acid (0.13 g, 1.36 mmol, 0.20 equiv) were added at 0°C. The reaction was stirred at room temperature for 1 h. The reaction was then quenched with 1 M aqueous NaOH until pH = 7. 60 mL of DCM was added to the resulting solution, which was extracted with 1 x 60 mL of H2O, and the organic layers were combined. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 85:15). Fractions containing the product were collected and the solvent was evaporated to yield compound 32.

[1023] 79% yield (1.80 g, 5.40 mmol), white solid. 1 H NMR (400MHz, methanol-d4) δ8.23(d,J=5.3Hz,2H),6.15(s,1H),5.67(dd,J=5.9,0.9Hz,1H),5.13(d,J=5.9Hz,1H),4.26-4.15( m,1H),2.46(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, 83.97, 61.30, 53.40, 44.13, 39.85, 25.40, 24.04 ppm. LCMS (ESI + )m / z:C 15 H 22 N6O3[M+H] + Calculated value = 334.15, found 334.10, RT: 0.903min, method 3.

[1024] Preparation of compound 33

[1025]

[1026] Compound 32 (1.00 g, 3.00 mmol, 1.00 equiv) was dissolved in dichloromethane (10 mL), and pyridine (10 mL) and MsCl (0.51 g, 4.50 mmol, 1.5 equiv) were added at 0° C. The reaction was stirred at 40° C. for 3 h. The reaction was then poured into 30 mL of ice water, extracted with 1×20 mL of dichloromethane, and concentrated under reduced pressure to give compound 33.

[1027] 81% yield (1.00 g, 2.43 mmol), white solid. 1H NMR (400MHz, methanol-d4) δ8.20(d,J=7.4Hz,2H),6.17(s,1H),5.67(d,J=5.9Hz,1H),5.23(d,J=5.9Hz,1H),4.98(p,J=6.3Hz,1H),3.01(s,3H), 2.84(dd,J=11.6,7.4Hz,1H),2.65(dt,J=13.8,6.3Hz,1H),2.51(dd,J=11.4,6.9Hz,1H),2.04-1.93(m,1H),1.50(s,3H),1.42ppm(s,3H). LCMS(ESI + )m / z:C 16 H 21 N5O6S[M+H] + Calculated value = 412.12, found 412.15, RT: 1.190 min, method 3.

[1028] Preparation of compound 34

[1029]

[1030] Compound 33 (300 mg, 0.73 mmol, 1.00 equiv) was dissolved in DMF (3 mL) and tetrabutylammonium iodide (27 mg, 0.07 mmol, 0.10 equiv) and NaN3 (474 ​​mg, 7.3 mmol, 10.00 equiv) were added at 0°C. The reaction was stirred at 110°C for 3 h. The reaction was then poured into 4 mL of ice water, extracted with 2×5 mL of dichloromethane and concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to give compound 34.

[1031] 76% yield (200 mg, 0.56 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.20(d,J=8.1Hz,2H),6.12(s,1H),5.78(dd,J=5.8,1.1Hz,1H),5.07(d,J=5.8Hz,1H),3.65(p,J=7.7Hz,1H),2.64 (dt,J=12.6,6.5Hz,1H),2.27(dd,J=12.4,8.3Hz,1H),1.68(dd,J=12.2,8.0Hz,1H),1.52(s,3H),1.42(s,3H),1.02ppm(t,J=7.3Hz,1H). 13C NMR (75 MHz, methanol-d4) δ 156.01, 152.52, 148.89, 140.57, 119.03, 113.13, 89.70, 85.01, 84.15, 81.69, 46.52, 41.64, 36.43, 25.39, 24.04, 12.46 ppm. LCMS (ESI + )m / z:C 15 H 18 N8O3[M+H] + Calculated value = 359.15, found 359.20, RT: 1.364 min, Method 22.

[1032] Preparation of compound 35

[1033]

[1034] 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 room temperature overnight. After completion, the solution was filtered. The filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: DCM / MeOH from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to give compound 35.

[1035] 70% yield (130 mg, 0.39 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.20(d,J=1.9Hz,2H),6.11(s,1H),5.78(dd,J=5.8,1.0Hz,1H),5.03(d,J=5.8Hz,1H),3.14(p,J=7.9Hz,1 H), 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), 1.42ppm (s, 3H). 13 C NMR (75 MHz, methanol-d4) δ 156.01, 152.50, 148.98, 140.38, 118.94, 112.98, 89.51, 85.02, 84.05, 81.51, 43.70, 38.56, 38.44, 25.40, 24.05 ppm. LCMS (ESI + )m / z:C 15 H 20 N6O3[M+H] +Calculated value = 333.16, found 333.05, RT: 0.966min, method 3.

[1036] Preparation of compound 36

[1037]

[1038] To compound 35 (155 mg, 0.470 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL) and the mixture was heated to 40° C. for 3 h. Subsequently, the solution was cooled to room temperature and carefully quenched with NaHCO 3 to pH = 7. The mixture was extracted with CH 2 Cl 2 (3×2 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19*250 mm 10 u; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: ACN; 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 36.

[1039] 37% yield (50 mg, 0.17 mmol), white solid. 1 H NMR (400MHz, DMSO-d6) δ8.26(d,J=4.8Hz,1H),8.13(s,1H),7.24(s,2H),5.81(d,J=7.2Hz,1H),5.33(s,2H),4.98(dd,J= 7.1, 4.1Hz, 1H), 3.86 (d, J = 4.0Hz, 1H), 3.17 (m, 3H), 2.91-2.69 (m, 2H), 1.85 (q, J = 10.4Hz, 1H), 1.67ppm (t, J = 9.9Hz, 1H). 13 C NMR (101MHz, DMSO) δ156.50,153.01,150.25,140.36,119.77,86.96,79.77,75.28,73.34,49.06,46.93,41.66ppm. LCMS(ESI + )m / z:C 12 H 16 N6O3[M+H] + Calculated value = 293.13, found 293.20, RT: 0.948min, method 2.

[1040] Preparation of compound 37

[1041]

[1042] Compound 33 (190 mg, 0.46 mmol, 1.00 eq) was dissolved in n-PrNH2 (2 mL) and the mixture was heated to 90°C for 48 h. Subsequently, the solution was cooled to room temperature and purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19*250 mm 10 u; mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 8% B to 12% B in 7 min; 210 / 254 nm). The fractions containing the product were collected and the solvent was evaporated to give compound 37.

[1043] 68% yield (130 mg, 0.35 mmol), white solid. 1 H NMR (300MHz, methanol-d4) δ8.21 (d, J=2.1Hz, 2H), 6.14 (s, 1H), 5.80 (dd, J=5.9, 1.0Hz,1H),5.13(d,J=5.8Hz,1H),2.99(dt,J=13.0,6.3Hz,1H),2.92-2.83 (m,2H),2.66(dd,J=7.7,3.1Hz,2H),2.30(dd,J=12.4,8.7Hz,1H),1.69(d t,J=15.1,7.6Hz,3H),1.52(s,3H),1.43(s,3H),1.01ppm(t,J=7.5Hz,3H). 13 C NMR (75 MHz, methanol-d4) δ 165.19, 152.54, 148.85, 140.60, 113.16, 84.96, 84.09, 81.85, 43.93, 40.27, 38.06, 35.06, 23.99, 20.58, 20.25, 20.25, 10.02, 9.70 ppm. LCMS (ESI+) m / z: C 12 H 16 N6O3[M+H] + Calculated value = 375.21, found 375.20, RT: 1.263min, method: 3.

[1044] Preparation of compound 38

[1045]

[1046] To compound 37 (130 mg, 0.35 mmol, 1.00 eq) in MeOH (2 mL) was added 2 M HCl (2 mL) and the mixture was heated to 40 ° C for 3 h. Subsequently, the solution was cooled to room temperature and carefully quenched with NaHCO 3 to pH = 7. The mixture was extracted with CH 2 Cl 2 (3×2 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Atlantis Prep T3 OBD column, 19*250 mm 10 u; mobile phase A: water (10 mM NH 4 HCO 3 ), mobile phase B: ACN; 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 38.

[1047] 34% yield (40 mg, 0.12 mmol), white solid. 1 H NMR (400MHz, methanol-d4) δ8.22(d,J=5.5Hz,2H),5.98(d,J=6.7Hz,1H),5.07(dd ,J=6.6,4.3Hz,1H),4.12(d,J=4.3Hz,1H),2.94(tq,J=15.0,7.5,7.0Hz,2H) ,2.66(dt,J=12.2,6.2Hz,1H),2.51(t,J=7.5Hz,2H),2.14(dd,J=11.8,7.5 Hz, 1H), 2.05-1.90 (m, 1H), 1.52 (h, J = 7.4Hz, 2H), 0.95ppm (t, J = 7.4Hz, 3H). 13 C NMR (101 MHz, methanol-d4) δ 155.91, 152.42, 149.56, 140.10, 119.29, 88.01, 80.72, 75.31, 73.77, 48.59, 44.12, 42.60, 37.53, 22.26, 10.69 ppm. LCMS (ESI + )m / z:C 12 H 16 N6O3[M+H] + Calculated value = 335.18, found 335.15, RT: 1.937 min, method 3.

[1048] Preparation of compound 67.1

[1049]

[1050] Zinc powder (25.0g, 0.380mol) is added into a two-necked round-bottom flask (500ml) equipped with softened water (100ml), and the solution is degassed with nitrogen for 15 minutes. Subsequently, copper sulfate (II) (1.85g, 11.5mmol) is added, and the solution being stirred is degassed for 45 minutes. The mixture is filtered, and the solid is washed with degassed water (250ml) and degassed acetone (250ml) respectively. The zinc-copper couple is vacuum dried for 12 hours. CAS6991-65-7 (5.00g, 26.9mmol, 1.00eq) is dissolved in anhydrous Et2O (150ml, through inert argon atmosphere) and precipitated at 400 ℃ for 10 minutes. A solution of 67.1 (dried over 400 molecular sieves) in 4% paraffin (1% paraffin) was added to a zinc-copper couple (12.2 g, 186 mmol, 7.00 eq) in a flame-dried flask. Subsequently, a solution of trichloroacetyl chloride (4.29 ml, 37.7 mmol, 1.40 eq) in anhydrous Et2O (30 ml) was added dropwise to the stirring mixture at 25°C over a period of 3 hours. After complete addition, stirring was stopped, and the organic layer was decanted from the precipitated zinc salt and washed with pentane / Et2O (100 ml). The organic phase was washed with NaHCO3 (saturated aqueous solution 3 x 150 ml) and brine (3 x 100 ml), dried (MgSO4), filtered, and the filtrate concentrated in vacuo to afford compound 67.1 (7.20 g, crude).

[1051] 1 H NMR (250MHz, CDCl3) δ5.10(d,J=5.7Hz,1H),5.07(s,1H),4.68(d,J=5.7Hz),3.61(dd,J=28.2,18.7,2H),3.52(s,1H),1.43(s,3H),1.34ppm(s,3H). 13 C NMR (63MHz, CDCl3) δ191.6,113.5,110.0,91.1,87.6,85.3,81.2,57.3,50.0,26.5,25.5ppm.

[1052] Preparation of compound 93

[1053]

[1054] Compound 67.1 (63 g, 212.83 mmol, 1.00 eq) was dissolved in THF (630 mL) and then NaBH4 (16.2 g, 426 mmol, 2.00 eq) was added at 0°C. The mixture was stirred at 0°C for 30 min and then added to a saturated NH4Cl aqueous solution (1000 mL) at 0°C. The product was extracted with EtOAc (3 × 1000 mL) and the combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified via a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 70:30). The fractions containing the product were collected and the solvent was evaporated to give compound 93.

[1055] 72% yield (45 g, 151.00 mmol), light yellow oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.99 (d, J = 5.7 Hz, 1H), 4.95 (s, 1H), 4.68 (d, J = 5.8 Hz, 1H), 4.21 (dd, J = 9.7, 8.0 Hz, 1H), 3.53 (s, 3H), 2.89 (dd, J = 11.8, 8.0 Hz, 1H), 2.16 (dd, J = 11.8, 9.7 Hz, 1H), 1.44 (s, 3H), 1.36 ppm (s, 3H). 13 C NMR (75MHz, DMSO) δ112.5,108.9,95.9,86.9,84.7,82.0,71.0,56.3,35.4,26.7,25.5ppm.

[1056] Preparation of Compound 94

[1057]

[1058] Compound 93 (45 g, 151 mmol, 1.00 eq) was dissolved in CH2Cl2 (450 mL), and pyridine (35.8 g, 453.16 mmol, 3.00 eq) and Tf2O (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 a saturated aqueous NaHCO3 solution (500 mL) at 0°C, and then extracted with EtOAc (3×500 mL). The organic phase was dried over Na2SO4. Filtered and the filtrate was concentrated in vacuo. The residue (45 g, crude product) was dissolved in AcOH:MeOH (1:1, 20 V) and zinc (136 g, 2092.30 mmol, 20.0 eq) was added. The mixture was stirred at 60°C for 16 hours. The residue was added to a saturated aqueous NaHCO solution (500 mL) at 0°C, the solid was filtered off, and the aqueous solution was extracted with ethyl acetate (500 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99:1 to 20:1). The fractions containing the product were collected and the solvent was evaporated to give compound 94.

[1059] 69% yield (25.5 g, 217 mmol, 2 steps). 1 H NMR (300MHz, chloroform-d) δ6.17(t,J=1.1Hz,1H),4.97(s,1H),4.79(d,J=5.9Hz,1H),4.60(d,J=5.9Hz,1H), 3.36(s,3H),2.99(dd,J=12.1,1.2Hz,1H),2.58(dd,J=12.2,1.1Hz,1H),1.45(s,3H),1.33ppm(s,3H). 13 C NMR (75MHz, CDCl3) δ133.0,132.3,112.5,107.5,93.6,85.1,81.2,54.5,36.4,26.4,25.3ppm.

[1060] Preparation of compound 95a

[1061]

[1062] Compound 94 (25 g, 102 mmol, 1.00 eq) was dissolved in DCM (250 mL) and m-CPBA (52.0 g, 302 mmol, 3.00 eq) was added at 0 ° C. The mixture was stirred at 40 ° C for 16 hours. After the mixture was cooled, the solid was filtered and iPrOH (250 mL) was added at 0 ° C, followed by NaBH3CN (12.8 g, 203 mmol, 2.00 eq). The mixture was stirred at 60 ° C for 2 hours. After the mixture was cooled to room temperature, the residue was added to a saturated NaHCO3 aqueous solution, and the aqueous layer was extracted with EtOAc (3×300 mL). The combined organic fractions were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99: 1 to 95: 5). The fractions containing the product were collected and the solvent was evaporated to obtain compound 95a.

[1063] 52% yield (12.1 g, 52.6 mmol, 2 steps), colorless oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.00 (d, J = 5.8 Hz, 1H), 4.83 (s, 1H), 4.52 (d, J = 5.8 Hz, 1H), 4.03-3.97 (m, 1H), 3.41 (s, 3H), 2.21-2.09 (m, 2H), 1.74 (td, J = 11.3, 8.9 Hz, 1H), 1.67-1.56 (m, 1H), 1.43 (s, 3H), 1.35 ppm (s, 3H). 13 C NMR (75MHz, DMSO) δ111.5,107.3,91.0,85.1,78.1,73.9,54.5,26.7,25.5,23.4,20.0ppm.

[1064] Preparation of Compound 96

[1065]

[1066] Compound 95a (300 mg, 1.30 mmol, 1.00 eq) was dissolved in DCM (3 mL) and 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 quenched by adding saturated Na2S2O3 aqueous solution (20 mL) and saturated NaHCO3 aqueous solution (20 mL), and then extracted with EtOAc (3 × 20 mL). The organic phase was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified via a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc from 99: 1 to 90: 10). The fractions containing the product were collected and the solvent was removed in vacuo to obtain compound 96.

[1067] 63% yield (187 mg, 0.82 mmol), white solid. 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.97 (s, 1H), 4.76 (d, J = 5.9 Hz, 1H), 4.63 (d, J = 5.9 Hz, 1H), 3.39 (s, 3H), 2.95-2.81 (m, 2H), 2.64 (ddd, J = 12.2, 10.6, 6.0 Hz, 1H), 2.15 (dt, J = 12.1, 10.4 Hz, 1H), 1.37 (s, 3H), 1.34 ppm (s, 3H). 13 CNMR (75MHz, CDCl3) δ206.2,113.1,107.1,101.6,85.0,79.0,54.9,39.5,26.3,25.4,20.0ppm.

[1068] Preparation of compound 97a

[1069]

[1070] Compound 95a (12.0 g, 52.2 mmol, 1.00 eq) and DMAP (5.79 g, 26.1 mmol, 0.50 eq) were dissolved in pyridine (120 mL), and benzoyl chloride (14.6 g, 104 mmol, 2.00 eq) was added dropwise at 0 ° C. The resulting solution was stirred at 0 ° C for 1 hour. HCl (1 M, aqueous solution, 20 ml) was then added to the reactant until pH < 7 was reached. The product was extracted with EtOAc (3 × 200 mL) and the combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified via a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 80:20). The fractions containing the product were collected and the solvent was removed in vacuo to obtain compound 97a.

[1071] 79% yield (13.7 g, 41.0 mmol), colorless oil. 1 H NMR (300MHz, chloroform-d) δ8.04-7.97(m,2H),7.63-7.56(m,1H),7.50-7.44(m,2H),5.37-5.31(m,1H),5.21(d,J=5.8Hz,1H),4.86(s, 1H), 4.62 (d, J = 5.9Hz, 1H), 3.28 (s, 3H), 2.48-2.34 (m, 2H), 2.01-1.89 (m, 1H), 1.86-1.73 (m, 1H), 1.49 (s, 3H), 1.44ppm (s, 3H). 13 C NMR (75MHz, CDCl3) δ165.1,130.2,132.9,129.5,128.4,112.4,107.7,89.0,85.2,78.7,74.3,55.0,26.4,25.6,22.0,20.8ppm.

[1072] Preparation of compound 98a

[1073]

[1074] Compound 97a (7.00 g, 21.0 mmol, 1.00 eq) was dissolved in MeOH (70 mL) and HCl (2 M, 70 mL aqueous solution) was added. The mixture was heated to 35° C. for 16 hours. The solution was then cooled to room temperature and concentrated in vacuo. This afforded 12 g of crude compound 98a.

[1075] Half the residue (6 g, crude product) was dissolved in anhydrous pyridine (60 mL) and stirred for 30 minutes. 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. Subsequently, the mixture was poured into ice-cold water (200 ml) and stirred at room temperature for 30 minutes. The crude mixture was extracted with CH2Cl2 (3 × 200 ml) and the combined organic layer was washed with brine (3 × 200 ml), dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (gradient elution: PE / EA from 100: 1 to 10: 1). The fractions containing the product were combined and the solvent was removed in vacuo to obtain compound 98a.

[1076] 40% yield (3.10 g, 8.20 mmol, 2 steps), yellow oil. 1H NMR (300MHz, methanol-d4) δ8.06-8.00(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 C NMR (101MHz, CDCl3) δ174.2,174.0,168.9,137.1,136.6,132.3,132.0,109.3,90.4,80.0,78.3,74.4,58.7,57.3,26.2,25.0,23.0ppm.

[1077] Preparation of compound 99a

[1078]

[1079] 6-Chloropurine (1.40 g, 8.99 mmol, 1.10 eq) was dissolved in MeCN (25 mL) and N,O-bis(trimethylsilyl)acetamide (1.65 mg, 8.13 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80°C for 16 hours. After the mixture was cooled to room temperature, compound 98a (3.10 g, 8.20 mmol, 1.00 eq) in MeCN (22 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (2.15 g, 9.68 mmol, 1.20 eq) and the mixture was heated to 80°C for 2 hours. The mixture was cooled to room temperature and diluted with EtOAc (50 mL), washed with saturated NaHCO (3 × 50 mL) and saturated aqueous NaCl solution (3 × 50 mL). The organic layer was dried (NaSO), filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel using PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 4:1).The fractions containing the product were collected and the solvent was removed in vacuo to give Compound 99a.

[1080] 57% yield (2.30 g, 4.60 mmol), white solid. 1H NMR(400MHz, methanol-d4)δ8.66(s,1H),8.33-8.28(m,2H),8.12(s,1H),7.70-7.6 4(m,1H),7.55(t,J=7.7Hz,2H),6.55(dd,J=7.4,4.2Hz,1H),6.39(d,J=7.5Hz ,1H),6.26(d,J=4.2Hz,1H),5.55(dd,J=9.1,7.6Hz,1H),2.39-2.32(m,2H),2 .29(s,3H),2.04(s,3H),1.98(dd,J=12.4,9.9Hz,1H),1.80-1.73ppm(m,1H). 13 C NMR (75 MHz, MeOD) δ 170.2, 169.8, 165.6, 151.3, 151.1, 150.4, 146.6, 133.3, 132.1, 129.7, 129.5, 128.4, 88.4, 86.4, 73.9, 72.6, 70.8, 22.0, 20.3, 19.0, 18.8 ppm. LCMS (ESI+) m / z: Calcd. for C23H21ClN4O7 [M+H]+ = 501.11, found 501.20, RT: 1.806 min, (Method 3).

[1081] Preparation of compound 100a

[1082]

[1083] Compound 99a (110 mg, 0.22 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.2 mL) and NH3 (0.3 mL aqueous solution) was added. The mixture was heated to 80 ° C for 16 hours. After the mixture was cooled to room temperature, the solvent was removed in vacuo and the product was dissolved in MeOH (1.2 ml). Sodium methoxide (11.8 g, 0.22 mmol, 1.00 eq) was added and the mixture was stirred at room temperature for 30 minutes, and then stirred with hydrogen exchange resin (CAS: 78922-04-0) for 30 min to pH = 7. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography with dichloromethane / methanol (gradient elution: DCM / MeOH from 99: 1 to 5: 1). The fractions containing the product were collected and the solvent was removed in vacuo to obtain compound 100a.

[1084] 43% yield (30 mg, 0.10 mmol), white solid. 1H NMR (400 MHz, methanol-d4) δ 8.27 (s, 1H), 8.22 (s, 1H), 5.98 (d, J = 7.1 Hz, 1H), 5.02 (dd, J = 7.1, 4.4 Hz, 1H), 4.42 (d, J = 4.4 Hz, 1H), 4.17 (t, J = 8.7 Hz, 1H), 2.37-2.29 (m, 1H), 2.10-2.01 (m, 1H), 1.62-1.44 (m, 2H). 13 C NMR (75MHz, MeOD) δ156.2, 152.3, 148.9, 140.6, 119.7, 91.4, 88.5, 74.8, 73.5, 70.0, 20.7, 20.1ppm. LCMS(ESI + )m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.00, RT: 0.799 min (Method 3).

[1085] Preparation of Compound 95

[1086]

[1087] Compound 94 (5.00 g, 20.3 mmol, 1.00 eq) was dissolved in DCM (50 mL) and m-CPBA (10.4 g, 60.5 mmol, 3.00 eq) was added at 0 ° C. The mixture was stirred at 40 ° C for 16 hours. After the mixture was cooled to room temperature, the solid was removed by filtration, and iPrOH (50 mL) and NaBH3CN (2.6 g, 40.63 mmol, 2.00 eq) were added at 0 ° C. The mixture was stirred at 60 ° C for 2 hours. After the mixture was cooled to room temperature, the residue was added to a saturated NaHCO3 aqueous solution, and the aqueous layer was extracted with EtOAc (3 × 300 mL). The combined organic fractions were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99:1 to 95:5). The product containing fractions were collected and the solvent removed in vacuo to give Compound 95a and Compound 95b as a 44:56 mixture, respectively.

[1088] 45% yield (2.1 g, 9.13 mmol, 2 steps), colorless oil.

[1089] Preparation of Compound 97

[1090]

[1091] Compound 95 (2.1 g, 9.13 mmol, 1.00 eq) and DMAP (1.01 g, 4.54 mmol, 0.5 eq) were dissolved in pyridine (20 mL), and benzoyl chloride (2.5 mg, 17.9 mmol, 2.00 eq) was added dropwise at 0°C, and the resulting solution was stirred at 0°C for 1 hour. HCl (aqueous solution, 1 M) was then added to the reaction mixture until pH < 7. DCM (200 mL) and H2O (200 ml) were added to the resulting solution. The product was extracted with DCM (3 x 200 ml), and the combined organic layers were dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: C18 column, 20-30 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 100 mL / min; gradient: 30B to 70B in 30 min; 210 / 254 nm). The fractions containing the product were collected and the solvent was evaporated to give Compound 97a and Compound 97b.

[1092] Compound 97b: 50% yield (1.5 g, 3.96 mmol), colorless oil. 1 H NMR (300MHz, chloroform-d) δ8.08 (dt, J = 7.1, 1.4Hz, 2H), 7.59-7.53 (m, 1H), 7.48-7.42 (m, 2H), 5.14-5.06 (m, 1H), 4.92(d,J=6.0Hz,1H),4.87(s,1H),4.58(d,J=6.0Hz,1H),2.42-2.14(m,4H),1.44(s,3H),1.35(s,3H)ppm. 13 C NMR (75MHz, CDCl3) δ166.2,132.8,130.3,129.6,128.2,112.2,109.4,92.5,85.4,84.2,72.9,55.8,26.4,25.3,24.6,23.8ppm.

[1093] Compound 97a: 25% yield (1.0 g, 2.64 mmol), colorless oil.

[1094] Preparation of compound 98b

[1095]

[1096] Compound 97b (800 mg, 2.11 mmol, 1.00 eq) was dissolved in MeOH (8 mL) and HCl (2 M, 8 mL) was added. The mixture was heated to 35 ° C for 16 hours. Subsequently, the solution was cooled to room temperature and the filtrate was concentrated in vacuo. The residue (700 mg) was dissolved in anhydrous pyridine (7 mL) and stirred for 30 minutes. Acetic anhydride (364 mg, 3.56 mmol, 1.5 eq) was added to the stirring solution at room temperature. The mixture was stirred at room temperature for 3 hours. Subsequently, the mixture was poured into ice-cold water (30 ml) and stirred at room temperature for 30 min. The crude mixture was extracted with CH2Cl2 (3 × 30 ml) and the combined organic layer was washed with brine (3 × 200 ml), dried over Na2SO4 and concentrated and purified by silica gel chromatography (gradient elution: PE / EA from 100: 1 to 10: 1). The fractions containing the product were combined and the solvent was removed in vacuo to obtain compound 98b.

[1097] 43% yield (2 steps, 390 mg, 1.03 mmol), yellow oil. 1 H NMR (300MHz, chloroform-d) δ8.13-8.09(m,2H),7.58-7.53(m,1H),7.47-7.41(m,2H),5.64(d,J=4.9Hz,1H),5.31(d,J=2.0Hz,1H),5.24 (dd,J=4.9,2.2Hz,1H),4.96(d,J=2.2Hz,1H),3.14(s,3H),2.43-2.28(m,2H),2.22-2.15(m,2H),2.13(s,3H),2.06ppm(s,3H). 13 C NMR (75MHz, CDCl3) δ169.7,169.4,165.8,132.9,130.0,129.7,128.3,105.9,88.9,75.5,74.1,71.5,55.7,25.4,24.1,22.8,20.5ppm.

[1098] Preparation of compound 99b

[1099]

[1100] 6-Chloropurine (177 mg, 1.13 mmol, 1.10 eq) was dissolved in MeCN (3.2 mL), and N,O-bis(trimethylsilyl)acetamide (208 mg, 1.02 mmol, 1.00 eq) was added dropwise. The mixture was heated to 80°C for 16 hours. After the mixture was cooled, compound 98b (390 mg, 1.03 mmol, 1.00 eq) in MeCN (2.8 mL) was added, followed by trimethylsilyl trifluoromethanesulfonate (272 mg, 1.22 mmol, 1.20 eq), and the mixture was heated to 80°C for 2 hours. After cooling to room temperature, the mixture was diluted with EtOAc and washed with saturated NaHCO3 and saturated NaCl aqueous solution. 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 from 99:1 to 4:1). The fractions containing the product were collected and the solvent was evaporated to yield compound 99b.

[1101] 57% yield (294 mg, 0.58 mmol), white solid. 1 H NMR (300MHz, chloroform-d) δ8.55(s,1H),8.38(s,1H),7.96-7.88(m,2H),7.58-7.51(m,1H),7.40(t,J=7.7Hz,2H),6.37(d,J=7.5Hz,1H) ,6.17(dt,J=7.6,4.2Hz,1H),5.91(d,J=5.0Hz,1H),5.38(td,J=5.6,2.7Hz,1H),2.49-2.31(m,4H),2.25(s,3H),2.02ppm(s,3H). 13 C NMR (101MHz, CDCl3) δ169.7,169.1,166.8,152.2,152.0,151.2,143.6,133.7,131 .8,129.6,128.7,128.6,87.2,84.2,74.2,73.3,72.1,27.2,21.8,20.6,20.3ppm. LCMS(ESI+)m / z:C 23 H 21 Calcd. for ClN4O7[M+H]+ = 501.11, found 501.10, RT: 1.767 min (Method 3).

[1102] Preparation of compound 100b

[1103]

[1104] Compound 99b (130 mg, 0.26 mmol, 1.00 eq) was dissolved in 1,4-dioxane (1.2 mL) and ammonia (0.3 mL aqueous solution) was added. The mixture was heated to 80 ° C for 16 hours. After cooling to room temperature, the solvent was removed in vacuo. The product was dissolved in MeOH (1.2 ml) and sodium methoxide (12 mg, 0.22 mmol, 1.00 eq) was added. The reactants were stirred at room temperature for 30 minutes and then stirred with hydrogen exchange resin (CAS: 78922-04-0) to pH = 7 for 30 minutes. The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified via silica gel column chromatography (gradient elution: DCM / MeOH from 99: 1 to 5: 1). The fractions containing the product were collected and the solvent was evaporated to give compound 100b.

[1105] 30% yield (23 mg, 0.07 mmol), white solid. 1 H NMR (400MHz, methanol-d4) δ8.34(s,1H),8.21(s,1H),6.07(d,J=7.3Hz,1H),4.67(dd,J=7.4,4.1Hz,1H),4.25(ddt ,J=7.1,4.7,1.9Hz,1H),4.07(d,J=4.1Hz,1H),2.39-2.31(m,1H),2.14-2.03(m,2H),1.94-1.83ppm(m,1H). 13 C NMR (101MHz, MeOD) δ 156.2, 152.2, 148.7, 140.7, 119.6, 89.6, 89.1, 74.6, 74.1, 72.1, 24.4, 24.3ppm. LCMS(ESI + )m / z:C 12 H 15 Calculated for N5O4 [M+H]+ = 294.11, found 294.00, RT: 0.660 min (Method 3).

[1106] Preparation of compound 39

[1107]

[1108] Under a nitrogen atmosphere, bis(ethylene)rhodium(I) acetylacetonate (837 mg, 3.24 mmol, 0.02 eq) and (R)-N,N-dimethylnaphtho[2,1-D:1',2'-F][1,3,2]dioxaphosphacycloheptane-4-amine (2.91 g, 8.11 mmol, 0.05 eq) were dissolved in EtOH (625 ml). The mixture was stirred at room temperature and purged with nitrogen for 15 minutes. Then, (-)-(3AR,6AR)-3A,6A-dihydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-one (25.0 g, 162.16 mmol, 1.00 eq) and potassium ethylene trifluoroborate (45.7 g, 324 mmol, 2.00 eq) were added and the reaction mixture was stirred and refluxed for 4 hours. The reaction mixture (suspension) was cooled to room temperature. The precipitate was filtered through a pad of celite and washed with ethanol. The solvent of the filtrate was evaporated. n-heptane was added to the residue and the resulting suspension was filtered through a pad of celite and washed with heptane to obtain a dark brown solid residue. The filtrate was washed with NH4OH (3×300ml), washed with brine, dried over MgSO4, filtered, and the filtrate was evaporated to give compound 39 (16.2g, 51% crude yield).

[1109] Preparation of compound 40

[1110]

[1111] Under a nitrogen atmosphere, a solution of compound 39 (16.2 g, 82.6 mmol, 1.00 eq) in THF (200 ml) was added dropwise to a stirring solution of lithium aluminum hydride (24.8 ml, 1 M THF solution, 24.8 mmol, 0.30 eq) in THF (400 ml) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 minutes under a nitrogen atmosphere. The reaction was quenched by the addition of acetone (6.1 mL) at -78 ° C, followed by the addition of water (50 ml). After addition, the reaction mixture was warmed to room temperature and EtOAc (400 ml) was added. The mixture was shaken vigorously. The organic layer was separated, washed three times with water, washed with brine, dried (MgSO ), filtered and the filtrate was evaporated. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1: 0 to 1: 1). The fractions containing the product were collected and the solvent was evaporated to afford the desired compound 40 (10.7 g, 71% yield).

[1112] Preparation of compound 41

[1113]

[1114] Compound 40 (3.10 g, 16.6 mmol, 1.00 eq) was dissolved in pyridine (10.3 ml) and tert-butyldimethylsilyl chloride (2.88 g, 19.1 mmol, 1.15 eq) was added in batches at room temperature. The mixture was stirred at room temperature for 17 hours and diluted with EtOAc (250 ml). The organic layer was washed with brine (4 × 80 ml), dried (MgSO ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 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) as a light yellow oil.

[1115] Preparation of compound 42

[1116]

[1117] Compound 41 (20.1 g, 43.8 mmol, 1.00 eq) was dissolved in CH2Cl2 (400 ml), and the mixture was cooled to -78 ° C. Ozone was generated from oxygen by an ozone generator (Fischer OZ500 / 5) and bubbled in the cooled solution by a glass pipette. Blue was observed after 1.5 hours, and ozone was added again at -78 ° C for 20 minutes. Subsequently, the mixture was purged with nitrogen for 5 minutes (blue color disappeared), and dimethyl sulfide (25.7 ml, 350 mmol, 8.00 eq) was added at -78 ° C. The nitrogen stream was stopped, and the mixture was stirred for 1 hour while the temperature was raised to -40 ° C. The mixture was concentrated in vacuo to a minimum volume at 30 ° C, and the gained yellow oil was redissolved in methanol (220 ml) and water (110 ml). The solution was cooled to 0 ° C, and sodium borohydride (19.8 g, 526 mmol, 12.0 eq) was added in batches. The ice bath was removed after 1.5 hours, and stirring was continued at room temperature. After stirring for 4 hours, the mixture was diluted in CH2Cl2 (350ml) and NH4Cl (saturated aqueous solution 150ml) was added. The product was extracted with CH2Cl2 (3×350ml), and the combined organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1:0 to 0:1). The fractions containing the product were collected and the solvent was evaporated to obtain the desired compound 42 (8.30g, 63% yield) as a light yellow oil.

[1118] 1H NMR (400MHz, 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),0.09ppm(d,J=2.9Hz,6H)

[1119] 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, 18.4, -4.5 ppm

[1120] Preparation of compound 43

[1121]

[1122] Compound 42 [CAS: 514206-18-9] (8.30 g, 27.4 mmol, 1.00 eq) is dissolved in THF (140 ml). Add imidazoles (4.67 g, 68.6 mmol, 2.50 eq) and triphenylphosphine (8.03 g, 29.1 mmol, 1.05 eq), then at room temperature add iodine (8.79 g, 34.3 mmol, 1.25 eq) in batches. After one hour, add triphenylphosphine (2.29 g, 8.31 mmol, 0.30 eq) and iodine (2.46 g, 9.60 mmol, 0.35 eq) of other amount. Continue to react for 2 hours, then, the mixture is concentrated in vacuo to minimum volume, and n-heptane (400 ml) is added. Precipitate triphenylphosphine oxide, and the mixture is ultrasonically treated 30 minutes. Separate the organic layer by filtration, and rinse the solid with n-heptane (100 ml). Sodium thiosulfite (saturated aqueous solution 150 ml) was added to the filtrate and the product was extracted with n-heptane (3×400 ml). The combined organic fractions were dried (MgSO 4 ), filtered, and the filtrate was concentrated in vacuo to give compound 43 (9.84 g, 87% calculated by HNMR) as a colorless oil.

[1123] 1H NMR (400MHz, chloroform-d): δ = 4.29-4.39 (m, 1H), 4.21 (dd, J = 6.1, 2.4Hz, 1H), 4.05 (dt, J = 7.8, 5.0Hz, 1H), 2.97-3.15 (m, 2H), 2.22-2.38 ( 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)

[1124] Preparation of compound 44

[1125]

[1126] Compound 43 (9.84 g, 23.9 mmol, 1.00 eq) was dissolved in THF (168 ml) and 1,8-diazabicyclo [5.4.0] undec-7-ene (5.35 ml, 35.8 mmol, 1.50 eq) was added. The mixture was heated to 65 ° C for 2.5 hours and then cooled to room temperature. The precipitated DBU salt was filtered and rinsed with THF, and the filtrate was concentrated in vacuo to a minimum volume. Subsequently, n-heptane (400 ml) and brine (100 ml) were added, and the product was extracted with n-heptane (3 × 400 ml). The combined organic layer was dried (MgSO 4 ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1: 0 to 1: 1). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 44 (6.00 g, 77% yield over 2 steps) as a colorless liquid.

[1127] 1 H NMR (400MHz, 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),1.35(s,3H),0.92(s,9H),0.11ppm(d,J=2.8Hz,6H)

[1128] 13C NMR (101 MHz, chloroform-d): δ = 145.6, 113.6, 111.2, 80.8, 80.4, 72.3, 37.5, 26.4, 26.0, 24.7, 18.4, -4.5 ppm

[1129] Preparation of compound 45

[1130]

[1131] Zinc powder (25.0 g, 0.38 mol, 1.00 eq) was added to a two-necked round-bottom flask (500 ml) containing demineralized water (100 ml), and the solution was degassed with nitrogen over a 15-minute period. Subsequently, copper (II) sulfate (1.85 g, 11.5 mmol, 0.03 eq) was added, and the stirred solution was degassed and stirred for 45 minutes. The mixture was filtered, and the black solid was washed with degassed water (250 ml) and degassed acetone (250 ml), respectively. The zinc-copper couple was vacuum-dried for 12 hours. Compound 44 (2.50 g, 8.79 mmol, 1.00 eq) was dissolved in anhydrous Et2O (70 ml, eluted with 4% ethanol). The mixture was stirred for 1 h (10 min) and dried over 400 molecular sieves (100 mL). 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 dissolved in anhydrous Et2O (20 mL), placed in a glass syringe, and added dropwise at a rate of 6.5 mL / h at room temperature. After 3 h, the zinc-copper couple was removed by decantation, and the organic layer was diluted with Et2O (500 mL) and washed with NaHCO3 (saturated aqueous solution, 3 x 150 mL) and brine (3 x 150 mL), dried (MgSO4), filtered, and the filtrate concentrated in vacuo to afford compound 45 (3.36 g, crude product).

[1132] 1 H NMR (400MHz, chloroform-d): δ = 4.79 (dd, J = 5.8, 1.0Hz, 1H), 4.55 (t, J = 5.3Hz, 1H), 4.11 (dt, J = 9.8, 5.1Hz, 1H), 3.65 (d, J = 18.3Hz, 1H), 3.12 (d, J = 18 .3Hz,1H),2.36(dd,J=12.9,5.4Hz,1H),2.15(dd,J=12.9,9.8Hz,1H),1.48(s,3H),1.37(s,3H),0.91-0.93(m,9H),0.12ppm(d,J=2.2Hz,6H)

[1133] 13C NMR (101 MHz, chloroform-d): δ = 191.8, 112.3, 80.7, 80.1, 71.5, 51.7, 26.1, 25.9, 18.4, -4.6, -4.9 ppm

[1134] Preparation of compound 46

[1135]

[1136] Compound 45 (1.25 g, 3.16 mmol, 1.00 eq) was dissolved in THF (30 ml) and zinc (2.07 g, 31.6 mmol, 10.0 eq) and acetic acid (1.45 ml, 25.3 mmol, 8.00 eq) were added. The mixture was heated to 70 ° C for 6 hours and then cooled to room temperature. The mixture was filtered through diatomaceous earth, the solid was rinsed with THF, and the filtrate was concentrated in vacuo to a minimum volume. Subsequently, the oil was redissolved in CH Cl (100 ml) and brine (50 ml) was added. The product was extracted in CH Cl (3 × 100 ml), and the combined organic fractions were dried (MgSO ), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1: 0 to 2: 3). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 46 (0.648 mg, 63% over 2 steps) as a colorless oil.

[1137] 1 H NMR (400MHz, chloroform-d): δ = 4.49 (t, J = 5.1Hz, 1H), 4.29-4.34 (m, 1H), 3.88 (dt, J = 10.9 ,5.3Hz,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)

[1138] 13 C NMR (101 MHz, chloroform-d): δ = 206.0, 111.1, 85.2, 80.2, 72.3, 56.7, 52.8, 41.3, 34.4, 26.0, 26.0, 24.5, 18.4, -4.4, -4.7 ppm

[1139] Preparation of compound 47

[1140]

[1141] Compound 46 (also referred to as intermediate 44) (600 mg, 1.84 mmol, 1.00 eq) is dissolved in methanol (20.0 ml) and cooled to 0 ° C. Sodium borohydride (282 mg, 7.35 mmol, 4.00 eq) is added in batches, and the mixture is stirred at 0 ° C for 1 hour. The solution is concentrated in vacuo to a minimum volume and dissolved in CH2Cl2 (100 ml), and NH4Cl (saturated aqueous solution 50 ml) is added. The product is extracted in CH2Cl2 (3 × 100 ml), and the combined organic layers are dried (MgSO4), filtered, and the filtrate is concentrated in vacuo to obtain compound 47 (also referred to as intermediate 45) (515 mg, 85% yield) in a 1: 1 mixture.

[1142] Preparation of compound 48

[1143]

[1144] Methyltriphenylphosphonium bromide (1.45 g, 3.98 mmol, 1.30 eq) was weighed into an oven-dried vial and THF (12.0 ml) was added. The heterogeneous solution was cooled to 0°C and potassium tert-butoxide (3.98 ml, 1 M in THF, 3.98 mmol, 1.30 eq) was added dropwise. The mixture was stirred at 0°C for 20 minutes. Freshly prepared Wittig reagent was added dropwise to compound 46 (1.00 g, 3.06 mmol, 1.00 eq) dissolved in THF (12.0 ml) at 0°C via syringe. The yellow 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 and redissolved in n-heptane (300 ml). Triphenylphosphine oxide is precipitated, and the mixture is ultrasonically treated for 5 minutes, filtered, and the filtrate is washed with NH4Cl (saturated aqueous solution 2×50ml) and brine (2×50ml). The organic layer is dried (MgSO4), filtered and the filtrate is concentrated in vacuo. The residue is purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1:0 to 7:3). The fractions containing the product are collected and the solvent is evaporated to obtain the desired compound 48 (931mg, 94% yield).

[1145] 1H NMR (400 MHz, chloroform-d): δ = 4.81 (quintet, J = 2.4 Hz, 1H), 4.78 (quintet, J = 2.4 Hz, 1H), 4.40 (t, J = 5.1 Hz, 1H), 4.26 (dd, J = 5.5, 0.9 Hz, 1H), 3.80 (dt, J = 11.2, 5.5 Hz, 1H), 2.87 (dd, J = 16.1, 2.2 Hz,1H),2.54(dq,J=15.9,2.4Hz,1H),2.31-2.46(m,2H),1.95(t,J=11.4Hz,1H),1.76( dd,J=11.7,5.7Hz,1H),1.45(s,3H),1.32(s,3H),0.91(s,9H),0.10ppm(d,J=2.2Hz,6H)

[1146] 13 C NMR (101 MHz, chloroform-d): δ = 144.7, 110.4, 106.8, 85.3, 79.9, 72.0, 42.5, 41.2, 39.2, 36.8, 26.0, 26.0, 24.5, 18.4, -4.4, -4.6 ppm

[1147] Preparation of compound 49

[1148]

[1149] 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 solution in THF, 10.0 mmol, 3.50 eq) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo to a minimum volume, dissolved in EtOAc (250 ml) and washed with NH4Cl (saturated aqueous solution 3×50 ml) and brine (3×50 ml). The organic layer was dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 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).

[1150] 1H NMR (400 MHz, chloroform-d): δ = 4.83 (quintet, J = 2.3 Hz, 1H), 4.80 (quintet, J = 2.4 Hz, 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, 2.4 Hz, 1H), 2.38-2.46 (m, 2H), 2.27-2.38 (m, 1H), 1.97 (dd, J = 12.0, 5.9 Hz, 1H), 1.74 (t, J = 11.4 Hz, 1H), 1.47 (s, 3H), 1.36 ppm (s, 3H)

[1151] 13 C NMR (101 MHz, chloroform-d): δ = 144.1, 110.6, 107.2, 85.4, 78.7, 70.8, 41.7, 41.2, 39.5, 36.6, 25.9, 24.3 ppm

[1152] Preparation of compound 50

[1153]

[1154] Potassium 6-chloro-7-deazapurine was prepared as follows. A mixture of 4-chloro-7H-pyrrolo[2,3-D]pyrimidine CAS3680-69-1 (100 g, 651 mmol, 1.00 eq) and KOtBu (73.1 g, 651 mmol, 1.00 eq) in THF (1 1) was stirred at room temperature for 45 minutes until a clear solution was obtained. The solvent was evaporated. The residue was triturated in DIPE. The white solid was filtered off and dried under vacuum at 30 ° C to give potassium 6-chloro-7-deazapurine (113 g, 90% yield).

[1155] Compound 49 (647 mg, 3.08 mmol, 1.00 eq) was dissolved in anhydrous CH Cl (20.0 ml) and pyridine (0.62 ml, 7.69 mmol, 2.50 eq) was added. The mixture was cooled to 0° C. and trifluoromethanesulfonic anhydride (0.57 ml, 3.39 mmol, 1.10 eq) was added dropwise. The mixture was stirred at 0° C. for 30 minutes, diluted in CH Cl (100 ml) and NaHCO (40 ml aqueous solution) was added. The product was extracted in CH Cl (3×100 ml) and the combined organic layers were dried (MgSO ), filtered and the filtrate was concentrated in vacuo and used immediately in this procedure.

[1156] 6-Chloro-7-deazapurine potassium (5.90g, 30.8mmol, 10.0eq) was dissolved in anhydrous DMF (35.0ml) and stirred at 0°C for 30 minutes. Subsequently, crude trifluoromethanesulfonate (1.05g, 3.08mmol, 1.00eq) dissolved in anhydrous DMF (8.00ml) was added dropwise at 0°C over 15 minutes. The mixture was stirred at 0°C for 2 hours and then warmed to room temperature and stirred for an additional 2 hours. The mixture was poured into NH4Cl (saturated aqueous solution 50ml) and the product was extracted in EtOAc (3×100ml). The combined organic layers were washed with brine (3×100ml), dried (MgSO4), filtered and the filtrate was concentrated in vacuo to a minimum volume. To the resulting powder, n-heptane (100ml) was added and the mixture was sonicated for 10 minutes. The solid was filtered, rinsed with n-heptane, and the filtrate was concentrated in vacuo to a minimum volume. The residue was purified by column chromatography on silica gel (gradient elution: n-heptane / EtOAc from 1:0 to 0:1). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 50 (856 mg, 80% over 2 steps).

[1157] 1 H NMR (400 MHz, chloroform-d): δ = 8.64-8.65 (m, 1H), 7.18 (d, J = 3.7 Hz, 1H), 6.61 (d, J = 3.7 Hz, 1H), 5.10 (dd, J = 6.3, 3.1 Hz, 1H), 4.96 (td, J = 6.8, 3.1 Hz, 1H), 4.80 (double quintet, J = 18.2, 2.4 Hz, 2H), 4.69 (d, J = 6.5 Hz, 1H), 3.18 (dd, J = 15.5, 2.4 Hz, 1H), 2.75 (dd, J = 15.3, 2.6 Hz, 1H), 2.48-2.58 (m, 2H), 2.33-2.44 (m, 2H), 1.55 (s, 3H), 1.35 ppm (s, 3H)

[1158] 13 C NMR (101 MHz, chloroform-d): δ = 152.3, 150.6, 143.4, 127.5, 117.9, 112.7, 107.0, 99.8, 85.7, 84.9, 61.5, 43.0, 42.3, 42.2, 38.3, 26.6, 24.7 ppm

[1159] Preparation of compound 51

[1160]

[1161] Compound 50 (850 mg, 2.46 mmol, 1.00 eq) was dissolved in 1,4-dioxane (20.0 ml) and NH 3 (60.0 ml, 25% in H 2 O) was added. The solution was heated to 100 ° C in a pressure reactor for 24 hours. The mixture was concentrated in vacuo to a minimum volume and co-evaporated twice with toluene. The residue was purified by silica gel column chromatography (gradient elution: CH 2 Cl 2 / MeOH from 1: 0 to 7: 3). The fractions containing the product were collected and the solvent was evaporated to give the desired compound 51 (790 mg, 98% yield).

[1162] 1 H NMR (400 MHz, chloroform-d): δ = 8.33 (s, 1H), 6.89 (d, J = 3.7 Hz, 1H), 6.35 (d, J = 3.5 Hz, 1H), 5.18 (br s, 2H), 5.09 (dd, J = 6.4, 2.9 Hz, 1H), 4.93 (td, J = 6.7, 2.9 Hz, 1H), 4.81 (quintet, J = 2.4 Hz, 1H), 4.76 (quintet, J = 2.4 Hz, 1H), 4.67 (d, J = 6.4 Hz, 1H), 3.16 (dd, J = 15.6, 2.4 Hz, 1H), 2.74 (dd, J = 15.2, 2.4 Hz, 1H), 2.45-2.55 (m, 2H), 2.30-2.45 (m, 2H), 1.97 (br s, 1H), 1.55 (s, 3H), 1.35 ppm (s, 3H)

[1163] 13 C NMR (101 MHz, chloroform-d): δ = 156.6, 151.7, 150.5, 143.8, 123.0, 112.4, 106.8, 103.5, 97.6, 85.9, 85.1, 60.8, 43.1, 42.5, 42.3, 38.3, 26.6, 24.7 ppm

[1164] Preparation of compounds 52, 52a and 52b

[1165]

[1166] To compound 51 (255 mg, 0.78 mmol, 1.00 eq) was added 9-borabicyclo[3.3.1]nonane (7.81 ml, 0.5 M in THF, 3.91 mmol, 5.00 eq), and the mixture was stirred at room temperature for 30 minutes. The solution was cooled to 0°C, and NaOH (7.81 ml, 1 M in H2O, 7.81 mmol, 10.0 eq) was added, followed by the dropwise addition of hydrogen peroxide (1.99 ml, 30% in H2O, 19.5 mmol, 25.0 eq). The mixture was stirred at room temperature for 1 hour, then diluted in CHCl (250 ml) and washed with NaHCO3 (saturated aqueous solution 3×50 ml) and brine (1×50 ml). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: CHCl / MeOH from 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 diastereomers. A sample of intermediate 72 was purified via preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO 2 , EtOH + 0.4% iPrNH 2 ) to give compound 52a (15 mg) and compound 52b (18 mg).

[1167]

[1168] 1 H NMR (400MHz, chloroform-d): δ = 8.31 (s, 1H), 6.89 (d, J = 3.5Hz, 1H), 6.34 (d, J = 3.5Hz, 1H), 5.24 (br s,2H),5.02(dd,J=6.8,3.5Hz,1H),4.55(d,J=6.8Hz,1H),2.35-2.52(m,3H), 2.27(dd,J=11.8,8.3Hz,1H),1.76-1.95(m,3H),1.53(s,3H),1.33ppm(s,3H)

[1169] 13 C NMR (101 MHz, chloroform-d): δ = 156.7, 151.7, 150.4, 123.1, 112.7, 97.7, 86.2, 84.6, 66.9, 60.3, 43.4, 43.3, 34.1, 31.6, 30.4, 26.5, 24.8 ppm

[1170]

[1171] 1H NMR (400MHz, chloroform-d): δ = 8.31 (s, 1H), 6.88 (d, J = 3.7Hz, 1H), 6.32 (d, J = 3.7Hz, 1H), 5.29 (br s,1H),5.00(dd,J=6.3,2.8Hz,1H),4.86-4.94(m,1H),4.66(d,J=6.4Hz,1H),3.50-3.64(m,2H),2.46-2.58(m,1H), 2.36-2.46(m,2H),2.20(dd,J=13.6,5.9Hz,1H),2.05-2.15(m,2H),1.64-1.74(m,2H),1.54(s,3H),1.35ppm(s,3H)

[1172] 13 C NMR (101 MHz, chloroform-d): δ = 156.7, 151.7, 150.4, 122.7, 112.3, 97.7, 86.6, 85.4, 66.9, 60.5, 43.7, 43.5, 35.4, 31.5, 30.2, 26.6, 24.7 ppm

[1173] Preparation of compound 53

[1174]

[1175] To compound 51 (60 mg, 0.18 mmol, 1.00 eq) was added 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 1.84 ml, 0.92 mmol, 5.00 eq) at room temperature. The mixture was stirred for 30 minutes. Subsequently, potassium phosphate (312 mg, 1.47 mmol, 8.00 eq) dissolved in water (0.58 ml, 32.0 mmol, 174 eq) was degassed with nitrogen for 10 minutes and added to the reaction mixture. The solution was stirred at room temperature while degassed for 10 minutes, and 7-bromoimidazo[1,2-a]pyridine [CAS: 808744-34-5] (54.3 mg, 0.28 mmol, 1.50 eq) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride [CAS: 95408-45-0] (30.2 mg, 0.05 mmol, 0.25 eq) dissolved in THF (2.4 ml) were added to the mixture. Degassing with nitrogen was continued for 15 minutes, and the mixture was then heated to 70°C. After 2 hours, the dark brown solution was cooled to room temperature, diluted with EtOAc (90 ml), and washed with NH4OH (25% in H2O, 2 x 30 ml) and brine (2 x 30 ml). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to provide compound 53 (219 mg, crude) as a 1:1 mixture of diastereomers, which was used in the next step without purification.

[1176] Preparation of compounds 54a and 54b

[1177]

[1178] Compound 53 (crude product from the previous step) was dissolved in EtOH (4.00 ml), and HCl (16.0 ml, 1 M in H O) was added, and the mixture was stirred at room temperature for 2 hours. The solution was diluted with water (20 ml), frozen and lyophilized to give a solid residue. Purification was performed by preparative SFC (stationary phase: Chiralcel Diacel OJ 20×250 mm, mobile phase: CO , EtOH+0.4% iPrNH ) to give Compound 54a (14.5 mg, 0.03 mmol, 19% yield over 2 steps) and Compound 54b (15.0 mg, 0.04 mmol, 20% yield over 2 steps).

[1179] Compound 54a:

[1180] 11H NMR (400 MHz, DMSO-d6): δ = 8.42 (d, J = 6.9 Hz, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 7.30 (s, 1H), 7.16 (d, J = 3.3 Hz, 1H), 6.88 (s, 2H), 6.73 (d, J = 6.9 Hz, 1H), 6.53 (d, J = 3.3 Hz, 1H), 4.71 - 4.88 (m, 3H), 4.17 - 4.25 (m, 1H), 3.71 (br t, J = 4.3 Hz, 1H), 2.71 (br d, J = 7.7 Hz, 2H), 2.52 - 2.59 (m, 1H), 2.35 (dd, J = 13.0, 9.8 Hz, 1H), 2.01 - 2.17 (m, 2H), 1.92 (dd, J = 13.0, 8.5 Hz, 1H), 1.77 - 1.86 (m, 1H), 1.68 - 1.77 ppm (m, 1H).

[1181] 13 13C NMR (101 MHz, DMSO-d6): δ = 157.4, 151.2, 149.8, 144.8, 137.8, 132.8, 126.2, 122.3, 114.6, 113.7, 112.3, 102.7, 98.6, 77.9, 75.5, 59.4, 42.2, 41.6, 41.2, 38.0, 34.1, 29.7 ppm.

[1182] LCMS (ESI+): [M + 1]+ = 405.3, RT 1.15 min (Method 9)

[1183] Compound 54b:

[1184] 1H NMR (400MHz, DMSO-d6): δ = 8.42 (d, J = 6.9Hz, 1H), 8.01 (s, 1H), 7.84 (s, 1H), 7.49 (s, 1H), 7.29 (s, 1H), 7.12 (d, J = 3.3Hz, 1H), 6.88 (s, 2H), 6.73(d,J=6.9Hz,1H),6.54(d,J=3.7Hz,1H),4.77-4.89(m,3H),4.24-4.33(m,1H),3.79(t,J=3.9Hz,1H),3.18(d,J=4.5Hz,1H),2.70(br d,J=6.5Hz,2H),2.47(br d,J=4.1Hz,1H),2.29(dd,J=13.6,10.4Hz,1H),2.08-2.19(m,1H),1.74-1.88(m,2H),1.45-1.56ppm(m,1H).

[1185] 13 C NMR (101MHz, DMSO-d6): δ=157.4,151.2,150.0,144.9,137.8,132.8,126.2,121.9,1 14.6,113.8,112.3,102.7,98.7,77.4,75.7,58.7,42.6,41.9,40.3,33.9,29.6ppm.

[1186] LCMS (ESI+): [M+1]+=405.2, RT 1.13 min (Method 9)

[1187] Preparation of compounds 55a and 55b

[1188]

[1189] Compounds 55a and 55b were prepared by methods analogous to those used to prepare compounds 54a and 54b.

[1190] Compound 55a

[1191] 11H NMR (DMSO-d6, 400 MHz): δ = 8.45 (d, J = 4.0 Hz, 1H), 8.01 (s, 1H), 7.66 (td, J = 7.6, 1.8 Hz, 1H), 7.11 - 7.23 (m, 3H), 6.87 (br s, 2H), 6.53 (d, J = 3.5 Hz, 1H), 4.66 - 4.88 (m, 3H), 4.14 - 4.24 (m, 1H), 3.67 - 3.73 (m, 1H), 3.17 (d, J = 3.5 Hz, 1H), 2.81 (d, J = 7.7 Hz, 2H), 2.54 - 2.69 (m, 1H), 2.33 (dd, J = 13.0, 9.7 Hz, 1H), 2.10 (dd, J = 11.2, 8.8 Hz, 1H), 1.98 - 2.05 (m, 1H), 1.90 (dd, J = 13.0, 8.6 Hz, 1H), 1.81 (br dd, J = 10.7, 8.7 Hz, 1H), 1.71 ppm (ddd, J = 11.3, 7.9, 3.5 Hz, 1H)

[1192] 13 13C NMR (DMSO-d6, 101 MHz): δ = 160.9, 157.9, 151.7, 150.4, 149.4, 136.7, 123.1, 122.7, 121.6, 103.2, 99.1, 78.4, 76.0, 59.9, 45.1, 42.8, 41.7, 38.6, 34.7, 29.8 ppm

[1193] LCMS (ESI+): [M + 1]+ = 366.3, RT 1.20 min (Method 9)

[1194] Compound 55b

[1195] 1H NMR (DMSO-d6, 400MHz): δ = 8.45 (d, J = 4.0Hz, 1H), 8.01 (s, 1H), 7.66 (td, J = 7.6, 1.8Hz, 1H), 7.14-7.24 (m ,2H),7.10(d,J=3.5Hz,1H),6.86(s,2H),6.53(d,J=3.5Hz,1H),4.73-4.90(m,3H),4.24-4.33(m,1H),3. 77(t,J=4.0Hz,1H),2.80(d,J=7.5Hz,2H),2.51-2.60(m,1H),2.43(tt,J=7.4,4.0Hz,1H),2.26(dd,J=1 3.6,10.3Hz,1H),2.11(ddd,J=11.2,7.6,4.1Hz,1H),1.73-1.85(m,2H),1.50ppm(dd,J=11.0,8.6Hz,1H)

[1196] 13 C NMR (DMSO-d6, 101MHz): δ=160.9,157.9,151.7,150.5,149.4,136.7,123.2,122.4 ,121.6,103.2,99.2,77.9,76.2,59.3,55.4,45.4,43.1,42.4,40.9,34.4,29.7ppm

[1197] LCMS (ESI+): [M+1]+=366.3, RT 1.20 min (Method 9)

[1198] Preparation of compound 56

[1199]

[1200] Compound 17 (2.00 g, 5.50 mmol, 1.00 eq) was weighed into a 100 ml three-necked flask equipped with a reflux condenser, a thermometer, and a CaCl2 tube. A solution of bis(cyclopentadienyl)dimethyltitanium (39.4 mL, 7.97 mmol, 1.45 eq, CAS: 1271-66-5) (5 wt% in toluene) was added to the substrate. The flask was covered with aluminum foil to protect from light and heated to 70°C. [Note: Upon heating, an active petasis reagent is generated and 1 equivalent of methane gas is released relative to the cyclopentadienyltitanium. Therefore, the reaction setup in the glassware should avoid a closed system. In addition, the reaction in the metal pressurized reactor showed only low conversion because the cyclopentadienyltitanium reagent adhered to the reactor wall.] 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 solid was sonicated for 5 minutes and removed by diatomaceous earth filtration (rinsed with n-heptane). The organic layer was concentrated in vacuo to a minimum volume. The residue was purified by silica gel column chromatography (gradient elution: n-heptane / EtOAc from 1:0 to 3:7, 15 column volumes). The fractions containing the product were collected and the solvent was evaporated to give compound 56 (58% yield, 1.14 g; 3.19 mmol, colorless oil).

[1201] 1 H NMR (500 MHz, chloroform-d): δ 5.42 (d, J = 4.5 Hz, 1H), 5.17, (dd, J = 4.5, 1.7 Hz, 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), 1.20 ppm (s, 9H).

[1202] 13 C NMR (125 MHz, chloroform-d): δ 177.4, 177.2, 139.7, 107.6, 105.7, 80.6, 75.6, 74.5, 55.6, 44.8, 41.5, 39.2, 39.0, 27.4, 27.3 ppm.

[1203] Preparation of compound 57

[1204]

[1205] CAS 176098-48-9 (1.8 g, 6.87 mmol, 1 eq) was dissolved in Et2O (18 mL), and zinc (0.89 g, 13.7 mmol, 2.00 eq) was added. A solution of trichloroacetyl chloride (1.6 g, 8.9 mmol, 1.3 eq) in Et2O (6 mL) was then added dropwise with stirring at 0°C. The resulting solution was stirred at room temperature for 2 hours. Zinc (4.47 g, 68.7 mmol, 10.0 eq) and AcOH (1.8 mL) were then added at 0°C, and the mixture was stirred at room temperature for 3 hours. The residue was added to saturated aqueous NaHCO3 (50 mL) at 0°C, the solid was filtered off, and the aqueous phase was extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99:1 to 5:1). The fractions containing the product were collected and the solvent was evaporated to give the title compound 57.

[1206] 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 = 11.8 Hz, 1H), 4.00 (s, 1H), 3.50-3.35 (m, 3H), 3.28-3.19 (m, 1H), 1.45 (s, 3H), 1.33 ppm (s, 3H). 13 C NMR (101 MHz, chloroform-d) δ 204.58, 136.96, 128.69, 128.26, 127.83, 111.90, 105.70, 85.25, 82.92, 78.60, 71.91, 59.13, 54.53, 26.26, 25.75 ppm. LCMS (ESI+) m / z: C 15 H 18 O4[M+H] + Calculated value = 305.13, found 305.15, RT: 0.887 min, method 1.

[1207] Preparation of compound 58

[1208]

[1209] Compound 57 (900 mg, 2.96 mmol, 1 eq) was dissolved in MeOH (9 mL) and 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 added to a saturated NH4Cl aqueous solution (50 mL) at 0 ° C., then extracted with EA (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99: 1 to 70: 30). The fractions containing the product were collected and the solvent was evaporated to give the title compound 58.

[1210] 55% yield (550 mg, 1.63 mmol), colorless oil. 1 H NMR (300MHz, chloroform-d) δ7.41-7.31(m,5H),5.86(d,J=4.0Hz,1H),4.76(d,J=12.2Hz,1H),4.64(d,J=4.0Hz,1H),4.52(d,J=12.2Hz,1H),3.87-3.74( m,2H),2.92(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,2H),1.80(s,1H),1.47(s,3H),1.31ppm(s,3H). 13 C NMR (101 MHz, chloroform-d) δ 137.37, 128.58, 128.06, 127.80, 111.78, 104.90, 84.72, 83.18, 79.04, 71.68, 59.85, 46.63, 40.53, 26.52, 25.94 ppm, LCMS (ESI+) m / z: C 17 H 22 O5[M+H] + Calculated value = 307.15, found 307.20, RT: 0.734min, method 1.

[1211] Preparation of compound 59

[1212]

[1213] Compound 58 (1.96 mmol, 600 mg, 1 eq) was dissolved in DMF (6 mL), imidazole (267 mg, 3.92 mmol, 2 eq) and TBDPSiCl (537 mg, 1.96 mmol, 1 eq) were added, and the mixture was stirred at 50 ° C for 10 h. The mixture was cooled to room temperature and poured into EtOAc (10 mL), followed by washing with brine (3 × 10 mL). The organic phase was dried over MgSO4, filtered and evaporated to a minimum. An additional washing step with brine (5 × 10 mL) was required to remove the remaining DMF after the obtained residue was dissolved in EtOAc (10 mL). The residue was purified by silica gel column chromatography (PE / EtOAc from 99: 1 to 90: 10). The fractions containing the product were collected and the solvent was evaporated to obtain compound 59.

[1214] 56% yield (600 mg, 1.10 mmol), colorless oil. 1 H NMR (400MHz, chloroform-d) δ7.74-7.59(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 CNMR (101 MHz, chloroform-d) δ 135.52, 135.50, 134.83, 129.67, 129.65, 129.61, 128.45, 127.89, 127.74, 127.64, 127.62, 127.59, 111.69, 104.81, 84.56, 83.26, 79.36, 71.55, 60.47, 46.68, 40.66, 26.71, 26.59, 26.56 ppm, LCMS (ESI+) m / z: C 33 H 40 O5Si[M+NH4] + Calculated value = 562.26, found 562.25, RT: 2.657 min, method 1.

[1215] Preparation of Compound 60

[1216]

[1217] Compound 59 (530 mg, 0.97 mmol, 1.0 equiv) was dissolved in methanol and Pd / C (106 mg) was added. The reaction was stirred at 50 ° C for 48 h. After completion, the solution was filtered. The filter cake was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with dichloromethane / methanol (gradient elution: PE / EtOAc from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to give compound 60.

[1218] 33% yield (150 mg, 0.33 mmol), colorless oil. 1 H NMR (300MHz, chloroform-d) δ7.64(dt,J=7.9,1.8Hz,4H),7.43-7.34(m,6H),5.80(d,J=3.9Hz,1H),4.48(d,J=3.9Hz,1H),3.96(p ,J=7.1Hz,1H),3.81(s,1H),2.64-2.53(m,2H),2.40(dt,J=12.6,6.7Hz,2H),1.43(s,3H),1.25(s,3H),1.02ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 135.49, 133.87, 129.69, 127.68, 127.66, 111.73, 104.45, 85.99, 79.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69, 26.31, 25.78, 18.95 ppm. LCMS (ESI+) m / z: C 26 H 34 O5Si[M+NH4] + Calculated value = 472.22, found 472.25, RT: 1.835min, method 1.

[1219] Synthesis of compound 60.1

[1220]

[1221] Compound 60 (200 mg, 0.44 mmol, 1 eq) was dissolved in DCM (2 mL), and DMP (224 mg, 0.52 mmol, 1.2 eq) was added at 0 ° C. The mixture was stirred at room temperature for 2 h. The reaction was quenched by adding 2 mL of saturated Na2S2O3 aqueous solution and 2 mL of saturated NaHCO3 aqueous solution, and then extracted with EtOAc (3×20 mL). The organic phase was dried over Na2SO4. The residue was purified by silica gel column chromatography using PE / EA (gradient elution: PE / EtOAc from 99:1 to 90:10). The fractions containing the product were collected and the solvent was evaporated to obtain compound 60.1.

[1222] 75% yield (150 mg, 0.33 mmol), light yellow oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 7.64-7.62 (m, 4H), 7.44-7.36 (m, 6H), 5.96 (d, J = 4.4 Hz, 1H), 4.39-4.21 (m, 2H), 2.76-2.66 (m, 1H), 2.59-2.49 (m, 2H), 2.44-2.37 (m, 1H), 1.43 (s, 3H), 1.38 (s, 3H), 1.05 (s, 9H). 13 C NMR (75MHz, CDCl3) δ211.71,135.42,133.70,133.64,129.72,127.68,114.02,102.1 8,76.21,75.97,59.28,47.73,44.56,27.31,26.72,22.69,18.94,LCMS(ESI+)m / z:C 26 H 32 O5Si[M+NH4] + Calculated value = 470.20, found 470.30, RT: 2.228min, method 1.

[1223] Synthesis of compound 60.2

[1224]

[1225] Compound 60.1 (130 mg, 0.28 mmol, 1 eq) was dissolved in EtOH (1.3 mL), and NaBH4 (20 mg, 0.56 mmol, 2 eq) was added at 0°C. The mixture was stirred at 0°C for 30 min. The mixture was added to a saturated aqueous NH4Cl solution (30 mL) at 0°C, and then extracted with EtOAc (3×30 mL). The organic phase was dried over Na2SO4. The residue was purified by silica gel column chromatography using PE / EA (gradient elution: PE / EtOAc from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to give compound 60.2.

[1226] 69% yield (90 mg, 0.19 mmol), light yellow oil. 1 H NMR (300MHz, chloroform-d) δ7.66-7.60(m,4H),7.42-7.32(m,6H),5.68(d,1H),4.44(dd,J=5.3,4.1Hz,1H),4.03(q,J=7.1Hz,1H),3 .72(dd,J=10.9,5.3Hz,1H),2.71-2.62(m,1H),2.57-2.49(m,1H),2.40-2.32(m,2H),1.46(s,3H),1.27(s,3H),1.03(s,9H). 13 C NMR (75 MHz, chloroform-d) δ 135.49, 134.14, 134.06, 129.55, 127.57, 112.41, 103.70, 78.80, 77.08, 75.66, 60.30, 44.63, 42.54, 26.75, 26.37, 26.11, 18.95, LCMS (ESI+) m / z: C 26 H 34 O5Si[M+NH4] + Calculated value = 472.22, found 472.20, RT: 2.062min, method 1.

[1227] Preparation of compound 61

[1228]

[1229] CAS 6983-40-0 (2.00 g, 11.6 mmol, 1.0 eq) was dissolved in pyridine (20 mL), cooled to 0 ° C and PivCl (1.81 g, 15.08 mmol, 1.3 eq) was added. The mixture was stirred at 0 ° C to room temperature for 17 h. Subsequently, the mixture was slowly poured into ice-cold NH4Cl (aqueous solution 30 mL) and the product was extracted with n-heptane (3 × 50 mL). The combined organic layer was washed with brine, dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified via silica gel column chromatography (gradient: PE / EtOAc from 99: 1 to 90: 10). The fractions containing the product were collected and the solvent was evaporated to obtain compound 61.

[1230] 67% yield (2.0 g, 7.81 mmol), colorless oil. 1 H NMR (400 MHz, chloroform-d): δ 6.05-6.11 (m, 1H), 5.48 (s, 1H), 4.56-4.60 (m, 1H), 4.55 (d, J = 3.7 Hz, 1H), 4.34 (d, J = 2.0 Hz, 1H), 1.48 (s, 3H), 1.39-1.41 (m, 3H), 1.19-1.21 ppm (m, 9H). 13 C NMR (101 MHz, chloroform-d): δ 176.9, 158.5, 114.1, 106.4, 88.8, 83.0, 75.3, 38.6, 28.0, 27.2, 26.9 ppm. LCMS (ESI+) m / z: C 13 H 20 O5[M+H] + Calculated value = 257.13, found 257.10, RT: 1.113 min, Method 6.

[1231] Preparation of compound 62

[1232]

[1233] Compound 61 (2.2 g, 8.5 mmol, 1.0 eq) was dissolved in Et2O (22 mL), and Zn(Cu) (10.1 g, 59.5 mmol, 7.0 eq) was added. A solution of trichloroacetyl chloride (4.4 g, 24.5 mmol, 2.8 eq) in Et2O (6 mL) was then added dropwise with stirring at 0°C. The resulting solution was stirred at room temperature for 2 hours. Zinc (5.58 g, 85 mmol, 10.00 eq) and AcOH (2.2 mL) were then added at 0°C, and the mixture was stirred at room temperature for 3 hours. The residue was added to a saturated aqueous NaHCO3 solution (50 mL) at 0°C, the solid was filtered off, and the aqueous phase was extracted with EA (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to yield compound 62.

[1234] 60% yield (1.5 g, 5.03 mmol). 1 H NMR (400MHz, chloroform-d) δ5.99(d,J=3.9Hz,1H),5.35(s,1H),4.60(d,J=3.9Hz,1H),3.44(t,J= 4.0Hz,2H),3.37(dd,J=13.2,4.6Hz,1H),3.27-3.20(m,1H),1.33(s,3H),1.24ppm(s,9H), 13 C NMR (75 MHz, chloroform-d) δ 202.93, 177.27, 112.18, 105.40, 84.26, 79.34, 78.02, 59.05, 54.40, 38.97, 27.02, 26.07, 25.61 ppm, LCMS (ESI+) m / z: C 15 H 22 O6[M+H] + Calculated value = 299.14, found 299.10, RT: 0.991 min, method 6.

[1235] Preparation of compound 63

[1236]

[1237] Compound 62 (1.54 g, 5.16 mmol, 1 eq) was dissolved in MeOH (15 mL) and then NaBH (0.37 g, 10.3 mmol, 2 eq) was added at -78 ° C. The resulting solution was stirred for 1 h at -78 ° C. The mixture was added to a saturated NH4Cl aqueous solution (50 mL) at 0 ° C., then extracted with EA (50 mL), and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 99: 1 to 70: 30). The fractions containing the product were collected and the solvent was evaporated to obtain compound 63.

[1238] 52% yield (780 mg, 2.6 mmol). 1 H NMR (400MHz, chloroform-d) δ5.84(d,J=3.9Hz,1H),5.13(s,1H),4.48(d,J=3.9Hz,1H),2.89(dt,J=12.5,6.4 Hz, 1H), 2.49 (dt, J = 12.6, 6.3Hz, 1H), 2.30-2.23 (m, 2H), 1.49 (s, 3H), 1.28 (s, 3H), 1.22ppm (s, 9H). 13 C NMR (101 MHz, chloroform-d) δ 177.50, 112.10, 104.66, 84.38, 79.04, 78.60, 59.54, 46.10, 40.32, 38.95, 27.12, 26.40, 25.85 ppm. LCMS (ESI+) m / z: C 15 H 24 O6[M+NH4] + Calculated value = 318.20, found 318.16, RT: 1.228min, method 1.

[1239] Preparation of compound 64

[1240]

[1241] Compound 63 (750 mg, 2.50 mmol, 1.0 eq) was dissolved in DMF (8 mL), and imidazole (340 mg, 5.00 mmol, 2.0 eq) and TBDPS (688 mg, 2.50 mmol, 1.0 eq) were added. The mixture was stirred at 50 ° C for 10 h. The mixture was cooled to room temperature and poured into EtOAc (15 mL), followed by washing with brine (3 × 15 mL). The organic phase was dried over MgSO4, filtered and evaporated to a minimum. An additional washing step with brine (5 × 15 mL) was required after the obtained residue was dissolved in EtOAc (15 mL) to remove the remaining DMF. The residue was purified by silica gel column chromatography (PE / EtOAc from 99: 1 to 95: 5). The fractions containing the product were collected and the solvent was evaporated to obtain compound 64.

[1242] 52% yield (700 mg, 1.30 mmol), white solid. 1 H NMR (300MHz, chloroform-d) δ7.62 (ddd, J=7.8, 2.8, 1.7Hz, 4H), 7.36 (qt, J=8.7, 2.7Hz, 6 H),5.78(d,J=3.9Hz,1H),4.91(s,1H),4.38(d,J=3.9Hz,1H),3.98(p,J=7.1Hz, 1H), 2.67 (dt, J=12.3, 6.3Hz, 1H), 2.35 (td, J=12.2, 7.5Hz, 2H), 2.21 (dt, J=12. 4, 6.3Hz, 1H), 1.45 (s, 3H), 1.25 (d, J = 1.9Hz, 3H), 1.12 (s, 9H), 1.03ppm (s, 9H). 13 C NMR (75 MHz, chloroform-d) δ 135.49, 135.45, 133.93, 133.84, 129.63, 129.61, 127.61, 127.59, 112.03, 104.54, 84.38, 79.02, 78.77, 65.54, 60.25, 46.30, 40.56, 38.82, 30.58, 27.02, 26.72, 26.43, 25.88 ppm, LCMS (ESI+) m / z: C 31 H 42 O6Si[M+NH4] + Calculated value = 556.28, found 556.20, RT: 2.697 min, method 3.

[1243] Alternative preparation of compound 60

[1244]

[1245] Compound 64 (1.37 mmol, 740 mg, 1 eq) was dissolved in MeOH (8 mL) and sodium methoxide (74.0 mg, 1.37 mmol, 1.00 equiv) was added. The reaction was stirred at room temperature for 30 min and then stirred with H exchange resin until pH = 7. It was then filtered and the filtrate was concentrated under reduced pressure. The residue was applied to a silica gel column with PE / EtOAc (gradient elution: PE / EtOAc from 99:1 to 80:20). The fractions containing the product were collected and the solvent was evaporated to give compound 60.

[1246] 36% yield (230 mg, 0.50 mmol), colorless oil. 1 H NMR (300MHz, chloroform-d) δ7.64(dt,J=7.9,1.8Hz,4H),7.43-7.34(m,6H),5.80(d,J=3.9Hz,1H),4.48(d,J=3.9Hz,1H),3.96(p ,J=7.1Hz,1H),3.81(s,1H),2.64-2.53(m,2H),2.40(dt,J=12.6,6.7Hz,2H),1.43(s,3H),1.25(s,3H),1.02ppm(s,9H). 13 C NMR (101 MHz, chloroform-d) δ 135.49, 133.87, 129.69, 127.68, 127.66, 111.73, 104.45, 85.99, 79.87, 78.10, 60.33, 53.43, 46.09, 39.80, 26.69, 26.31, 25.78, 18.95 ppm. LCMS (ESI+) m / z: C 26 H 34 O5Si[M+NH4] + Calculated value = 472.22, found 472.25, RT: 1.835 min, method 4.

[1247] Preparation of compounds 66a and 66b

[1248]

[1249] Preparation of compound 66.1

[1250]

[1251] ((3aR,5R,6R,6aR)-2,2-dimethyl-6-(naphthalen-2-ylmethoxy)tetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methanol (4.71 g, 14.3 mmol, 1.00 eq, CAS: 1217482-83-1) was dissolved in THF (87 ml). Triphenylphosphine (8.98 g, 34.2 mmol, 2.4 eq) and imidazole (2.91 g, 42.79 mmol, 3.3 eq) were added, followed by the addition of iodine (8.80 g, 34.6 mmol, 2.4 eq) in portions. The reaction mixture was stirred at reflux under a nitrogen atmosphere for 2 hours. Saturated aqueous NaSO was added, followed by stirring for 5 minutes. Next, the reaction mixture was extracted with EtOAc (4 × 100 ml) and the combined organic layers were washed with saturated Na2SO3 aqueous solution (1 × 200 ml), saturated NaHCO3 aqueous solution (1 × 200 ml) and brine (1 × 200 ml), then dried over MgSO4, filtered and the filtrate was concentrated in vacuo. n-Heptane was added to the residue and the mixture was stirred for 5 minutes. The solid was removed by filtration and rinsed with n-heptane, and the filtrate was then concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane / EtOAc gradient from 95: 5 to 80: 20). The tubes containing the product were combined and concentrated in vacuo to obtain compound 66.1.

[1252] 87% yield (26.3 g, 12.4 mmol), white solid. 1 H NMR (400MHz, chloroform-d): δ7.94-7.83 (m, 4H), 7.54 (dd, J = 8.54, 1.63Hz, 1H), 7.53-7.4 8(m,2H),5.75(d,J=3.74Hz,1H),4.95(d,J=12.10Hz,1H),4.76(d,J=12.10Hz,1H) ,4.59(t,J=3.96Hz,1H),3.78(m,1H),3.66(dd,J=8.47,4.29Hz,1H),3.55(dd,J= 11.00, 3.08Hz, 1H), 3.34 (dd, J = 11.22, 4.40Hz, 1H), 1.62 (s, 3H), 1.38ppm (s, 3H). 13 C NMR (100 MHz, chloroform-d): δ 134.72, 133.23, 133.20, 128.49, 127.90, 127.75, 127.05, 126.28, 126.16, 125.80, 113.24, 103.95, 81.71, 77.47, 76.32, 72.46, 26.84, 26.57, 7.30 ppm. ESI-MS: m / z 458.0 [M+NH4]+ R f (n-heptane / EtOAc; 1:1) = 0.77

[1253] LCMS: [M+1] + =458.0[M+1] + , 2.29 min (Method 13)

[1254] Preparation of compound 66.2

[1255]

[1256] 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) was added. The reaction mixture was stirred at 80-85 ° C for 2 hours and DBU (3.46 mL, 23.2 mmol, 1.2 eq) was added. The reaction mixture was stirred at 85 ° C for 1.5 hours. A second portion of DBU (0.87 mL, 5.80 mmol, 0.3 eq) was added and stirring was continued at 85 ° C for 1.5 hours. Next, the reaction mixture was 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 / sodium hydroxide (pH=4) buffer solution (3x) and brine (1x). The organic layer was dried (MgSO 4 ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane / EtOAc gradient from 90:10 to 80:20).The fractions containing the product were combined and the solvent was removed in vacuo to give compound 66.2.

[1257] 65% yield (3.94 g, 12.5 mmol), white solid. 1 H NMR (400MHz, chloroform-d): δ7.89-7.83(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=12.42H z,1H),4.88(d,J=12.42Hz,1H),4.59(m,1H),4.52(m,1H),4.36(m,1H),4.34(dd,J=4.50,2.15Hz,1H),1.57(s,3H),1.43ppm(s,3H). 13C NMR (100 MHz, chloroform-d): δ 158.79, 134.77, 133.20, 133.17, 128.45, 127.67, 127.75, 126.92, 126.28, 126.15, 125.74, 114.78, 104.27, 83.94, 77.42, 72.57, 27.91, 27.28 ppm. R f (n-heptane / EtOAc; 1:1) = 0.77. MP: 102.01°C.

[1258] LCMS: [M+1] + =313.1[M+1] + , 2.17 min (Method 13)

[1259] Preparation of compound 66.3

[1260]

[1261] Compound 66.2 (3.88 g, 12.4 mmol, 1.00 eq) was dissolved in anhydrous THF (48 mL) and activated zinc * (5.69 g, 87.0 mmol, 7.00 eq) prepared as described below was introduced. At room temperature, a solution of trichloroacetyl chloride (2.28 mL, 20.2 mmol, 1.80 eq) dissolved in anhydrous THF (16 ml) was added dropwise over 1 hour. Subsequently, the mixture was stirred for 2 hours. The zinc salts were removed by filtration and rinsed with EtOAc. The filtrate was washed with saturated aqueous NaHCO3 (3x) and brine (2x). The organic layer was dried (MgSO4), filtered, and the filtrate was concentrated in vacuo to give compound 66.3 as an orange viscous oil. The product was used directly in the next step.

[1262] (5.85g, crude product), 1 H NMR (400MHz, chloroform-d): δ7.92-7.80(m,4H),7.54-7.48(m,3H),5.84(d,J=3.30Hz,1H),4.94(d,J=11.67Hz,1H),4.86(d,J=11.66Hz,1 H), 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). 13C NMR (100 MHz, chloroform-d δ 191.48, 134.14, 133.25, 133.11, 128.24, 127.94, 127.77, 127.02, 126.34, 126.27, 125.91, 120.23, 113.94, 104.28, 83.22, 79.22, 78.08, 72.75, 51.45, 26.78, 26.03 ppm.

[1263] Zinc powder (100 g, 1.54 mol) was added to deionized water (500 ml). The mixture was stirred and nitrogen was bubbled through the solution for 10 minutes, after which anhydrous CuSO (7.36 g, 46.1 mmol) was added. The suspension was stirred and bubbled for 45 minutes, then filtered. The zinc powder was rinsed with degassed deionized water (1.25 L) and degassed acetone (550 mL), and then vacuum-dried overnight. The resulting black powder (100 g) was stored under an inert atmosphere.

[1264] Preparation of compound 66.4

[1265]

[1266] Compound 66.3 (5.26 g, 12.4 mmol, 1.00 eq) was dissolved in THF (49 ml) and zinc (8.12 g, 124 mmol, 10.0 eq) was added. The reaction mixture was cooled to 0°C and glacial acetic acid (3.56 ml, 62.1 mmol, 5.00 eq) was carefully added. The reaction mixture was stirred at room temperature for 20 hours and then heated to 40°C. Zinc was removed by filtration and rinsed with EtOAc. The filtrate was washed with saturated NaHCO (3x) and brine (3x). The aqueous phase was extracted with EtOAc (1x). The combined organic layer was dried (MgSO ), filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (n-heptane / EtOAc gradient from 95:5 to 75:25). The fractions containing the product were combined and the solvent was removed in vacuo to obtain compound 66.4.

[1267] 44% yield (2 steps, 1.94 g, 5.46 mmol), white solid. 1H NMR (400 MHz, chloroform-d): δ 7.89-7.77 (m, 4H), 7.54-7.48 (m, 3H), 5.77 (d, J = 4.07 Hz, 1H), 5.04 (d, J = 12.21 Hz, 1H), 4.78 (d, J = 12.21 Hz, 1H), 4.68 (t, J = 4.07 Hz, 1H), 3.92 (d, J = 4.48 Hz, 1H), 3. 80(ddd,J=17.70,6.92,2.24Hz,1H),3.31(ddd,J=17.50,6.11,2.04Hz,1H),3.24(ddd,J=17 .91, 6.10, 2.44Hz, 1H), 2.99 (ddd, J = 17.80, 6.82, 2.24Hz, 1H), 1.55 (s, 3H), 1.35ppm (s, 3H). 13 C NMR (100 MHz, chloroform-d): δ 204.66, 134.54, 133.22, 133.11, 128.61, 127.86, 127.79, 126.92, 126.99, 126.41, 125.61, 112.93, 104.16, 79.91, 76.83, 75.25, 72.46, 56.10, 55.01, 26.32, 25.80 ppm. f (n-heptane / EtOAc; 1:1) = 0.67. MP: 101.79°C.

[1268] LCMS: [M+1] + =355.3[M+1] + , 2.08 min (Method 9)

[1269] Preparation of compounds 66a and 66b

[1270]

[1271] Compound 66.4 (598 mg, 1.69 mmol, 1.00 eq) was dissolved in a mixture of THF, deionized water and methanol (6:2:5, 13 ml) and then cooled to 0 ° C. Sodium borohydride (140 mg, 3.71 mmol, 2.20 eq) was added and stirred for 30 minutes. Subsequently, 10 equivalents of acetic acid (0.97 ml) were added to quench the reaction. The mixture was diluted with EtOAc (20 ml) and neutralized with a saturated aqueous Na2CO3 solution. The aqueous layer was separated and extracted with EtOAc (2 × 20 mL), and the combined organic phases were washed with a saturated aqueous Na2CO3 solution (2 × 20 mL) and brine (3 × 20 mL), dried over MgSO4, filtered and the filtrate was concentrated in vacuo to give compound 66 (619.9 mg, crude product, white solid) as a mixture of cis / trans isomers (ratio of 0.9: 1, respectively).

[1272] LCMS: [M+1] + =357.2[M+1] + , 1.89min (Method 13)

[1273] To obtain analytically pure samples of both isomers, compound 66b and compound 66a, the mixture of alcohols was protected (tert-butyldiphenylsilyl) and the silylated intermediates were separated via silica gel chromatography followed by deprotection with TBAF to afford the isolated products below.

[1274] Compound 66b

[1275]

[1276] 1 H NMR (400MHz, chloroform-d): δ7.96-7.82 (m, 4H), 7.59 (dd, J = 8.47, 1.65Hz, 1H), 7.55-7 .48(m,2H),5.69(d,J=3.96Hz,1H),5.13(d,J=11.88Hz,1H),4.85(d,J=11.88Hz ,1H),4.61(t,J=4.18Hz,1H),4.28(tt,J=7.10,3.47Hz,1H),3.63(d,J=4.40Hz ,1H),2.76-2.57(m,4H),2.20-1.93(m,1H),1.57(s,3H),1.33-1.31ppm(m,3H). 13C NMR (100 MHz, chloroform-d): δ 134.20, 133.22, 133.14, 128.63, 127.88, 127.74, 127.22, 126.34, 126.26, 125.74, 112.69, 104.08, 81.55, 80.89, 76.51, 72.45, 62.79, 42.92, 41.91, 26.39, 25.85 ppm. ESI-MS: m / z 379.2 [M+Na] +

[1277] R f (n-heptane / EtOAc; 1:1) = 0.45

[1278] LCMS: [M+1] + =379.2[M+Na] + , 1.89min (Method 9)

[1279] Compound 66a

[1280]

[1281] 1 H NMR (400 MHz, chloroform-d): δ7.89-7.82 (m, 4H), 7.59-7.47 (m, 3H), 5.65 (d, J = 3.87 Hz, 1H), 5.02 (d, J = 12.23 Hz, 1H), 4.76 (d, J = 12.33 Hz, 1H), 4.57 (t, J = 4.13 Hz, 1H), 4.20-4.09 ( m,1H),3.63(d,J=4.29Hz,1H),3.27(ddd,J=12.23,6.85,5.28Hz,1H),2.54-2.40(m, 1H), 2.40-2.26 (m, 3H), 2.18 (dd, J = 12.12, 7.00Hz, 1H), 1.57 (s, 3H), 1.32ppm (s, 3H). 13 C NMR (100 MHz, chloroform-d): δ 134.98, 133.10, 128.39, 127.81, 127.72, 126.68, 126.28, 126.11, 125.53, 112.84, 103.86, 81.21, 77.19, 76.17, 72.30, 59.91, 44.13, 43.50, 26.55, 25.97 ppm. R f (n-heptane / EtOAc; 1:1) = 0.45

[1282] LCMS: [M+1] + =357.3[M+1]+ , 1.88 min (Method 9)

[1283] Preparation of Compound 141

[1284]

[1285] Methylaluminoxane (MAO, 10 wt% in toluene, 3.06 mL) was slowly added to a solution of methyl propiolate (45.15 mg, 0.537 mmol, 1 equiv) in 6 mL of anhydrous CHCl at room temperature under an argon atmosphere. The reaction mixture was stirred at room temperature for 15 min, followed by the addition of a solution of CAS 6991-65-7 (100 mg, 0.537 mmol, 1 equiv) in anhydrous CHCl (1 mL). After stirring for 2 h, H2O (10 mL) was carefully added and the aqueous phase was washed with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue that was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100:1 to 80:20) to give the desired compound 141 (20% yield; 0.272 mmol; 73.6 mg) as a yellow oil.

[1286] R f :0.25 (petroleum ether / EtOAc 90:10 v / v, UV)

[1287] 1 H NMR (CDCl3, 400MHz): δ = 6.91 (t, 1H, J = 1.2Hz), 4.96 (s, 1H), 4.96 (d, 1H, J = 5.8Hz), 4.74 (d, 1H, J = 5.8Hz), 3.72 (s ,3H),3.28(s,3H),3.08(dd,1H,J=15.6Hz,1.2Hz),2.68(dd,1H,J=15.6Hz,1.2Hz),1.47(s,3H),1.34(s,3H)ppm. 13 C NMR (CDCl3, 125MHz): δ=161.8,145.8,142.9,112.3,108.9,89.2,85.7,82.0,54.8,51.2,37.1,26.3,25.2ppm. LCMS(ESI+)m / z:C 12 H 15 Calculated value of O5[M-OMe]+ = 239.1, found 239.1, RT: 1.341 min, Method 2.

[1288] Preparation of Compound 142

[1289]

[1290] Compound 141 (1.20 g, 4.44 mmol, 1.00 eq), EA (12 ml) and Pt / C (300 mg, 20%) were added and bubbled with H (5 atm) overnight. The catalyst was then filtered through a pad of celite and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100:1 to 90:10). The leading peak was compound 142a and the trailing peak was compound 142b.

[1291] 33% of compound 142a (400 mg, 1.47 mmol) as a yellow oil. 1 H NMR (400 MHz, CHLOROFORM-d) δ 5.38 (d, J = 5.8 Hz, 1H), 4.81 (s, 1H), 4.50 (d, J = 5.8 Hz, 1H), 3.64 (s, 3H), 3.32 (s, 3H), 3.16-3.09 (m, 1H), 2.46-2.39 (m, 1H), 2.23-2.13 (m, 1H), 2.07-1.86 (m, 2H), 1.42 (s, 3H), 1.36 ppm (s, 3H). 13 C NMR (101MHz, CDCl3) δ172.21,111.97,108.13,87.37,84.75,78.91,54.84,51.30,50.09,27.11,26.33,25.28,17.79ppm. GCMS(ESI+)m / z:C 13 H 20 O6[M-Me] - Calculated value = 257.1, found 257.1, RT: 6.909 min, method 1.

[1292] 50% of compound 142b (600 mg, 1.47 mmol) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ4.84(s,1H),4.68-4.62(m,2H),3.73(s,3H),3.26(s,3H),3.06-3.00(m,1H),2.7 7-2.66(m,1H),2.53-2.44(m,1H),2.15-2.02(m,1H),1.90-1.79(m,1H),1.42(s,4H),1.36ppm(s,3H). 13CNMR (101MHz, CDCl3) δ172.68,112.76,109.27,86.67,85.17,85.01,56.06,51.69,50.79,28.87,26.43,25.58,17.29ppm. GCMS(ESI+)m / z:C 13 H 20 O6[M-Me] - Calculated value = 257.1, found 257.1, RT: 7.303 min, method 1.

[1293] Preparation of compound 143a

[1294]

[1295] Compound 142a (150 mg, 0.55 mmol, 1.00 eq) was dissolved in anhydrous THF (2 mL). The solution was cooled to -78 ° C and LiAlH4 (42.82 mg, 1.10 mmol, 2.00 eq) was added. The resulting mixture was stirred at -78 ° C for 3 h. The reaction was then quenched by adding 5 ml of H2O, 15 ml of a 3 M aqueous solution of NaOH, and 5 ml of H2O. The solution was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100: 1 to 90: 10) to obtain compound 143a.

[1296] 73% (98 mg, 0.40 mmol) off-white solid. 1 H NMR (300MHz, chloroform-d) δ4.94(d,J=5.8Hz,1H),4.85(s,1H),4.68(d,J=5.8Hz,1H),3.72-3.53(m,2H),3.42(s,3H),2.74-2 .58(m,1H),2.45-2.33(m,1H),2.23-2.08(m,1H),1.96-1.81(m,1H),1.43(s,3H),1.36(s,3H),1.31-1.23ppm(m,1H). 13 C NMR (75MHz, CDCl3) δ112.23,108.30,87.74,85.57,79.09,62.97,55.26,48.58,26.30,25.73,25.20,15.92ppm. GCMS(ESI+)m / z:C 12 H 20 O5[M-Me] - Calculated value = 229.1, found 229.1, RT: 6.944min, Method 1.

[1297] Preparation of compound 144a

[1298]

[1299] Compound 142a (100 mg, 0.36 mmol, 1.00 eq) was dissolved in MeOH / H2O (5 / 1, 2 mL). The solution was cooled to 0°C and LiOH (17.28 mg, 0.72 mmol, 2.00 eq) was added. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by adding 10 ml of CA aqueous solution (1 M), extracted with dichloromethane (3 × 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The solution was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100:1 to 90:10) to obtain compound 144a.

[1300] 53% (51 mg, 0.19 mmol) light yellow solid. 1 H NMR (400MHz, chloroform-d) δ4.93 (s, 1H), 4.86 (d, J = 5.6Hz, 1H), 4.68 (d, J = 5.7Hz, 1H), 3.52 (s, 3H), 3.19 (t, J=9.6Hz,1H),2.46-2.37(m,1H),2.29-2.17(m,1H),2.13-2.02(m,2H),1.42(s,3H),1.33ppm(s,3H). 13 C NMR (101MHz, CDCl3) δ171.59,111.74,107.61,87.26,83.64,79.17,54.50,49.95,25.12,24.28,23.99,14.92ppm. GCMS(ESI+)m / z:C 12 H 18 O6[M-Me] - Calculated value = 243.0, found 243.0, RT: 7.490 min, method 1.

[1301] Preparation of compound 143b

[1302]

[1303] Compound 142b (150 mg, 0.55 mmol, 1.00 eq) was dissolved in anhydrous THF (2 mL). The solution was cooled to -78 ° C and LiAlH4 (42.82 mg, 1.10 mmol, 2.00 eq) was added. The resulting mixture was stirred at -78 ° C for 3 h. The reaction was then quenched by adding 5 ml of H2O, 15 ml of a 3 M aqueous solution of NaOH, and 5 ml of H2O. The solution was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100: 1 to 90: 10) to obtain compound 143b.

[1304] 29% (40 mg, 0.16 mmol) yellow oil. 1 H NMR (300 MHz, CHLOROFORM-d) δ 4.91 (s, 1H), 4.69-4.58 (m, 2H), 3.89-3.79 (m, 1H), 3.59-3.50 (m, 1H), 3.47 (s, 3H), 2.55-2.39 (m, 2H), 2.28-2.09 (m, 1H), 1.85-1.70 (m, 1H), 1.61-1.48 (m, 1H), 1.44 (s, 3H), 1.35 (m, 3H), 1.26 ppm (s, 1H). 13 C NMR (101MHz, CDCl3) δ112.62,110.33,88.92,85.71,85.15,62.21,56.49,47.67,27.82,26.54,25.41,16.19ppm. GCMS(ESI+)m / z:C 12 H 20 Calculated value for O5[M-Me]- = 229.1, found 229.1, RT: 7.008 min, Method 1.

[1305] Preparation of compound 144b

[1306]

[1307] Compound 142b (220 mg, 0.81 mmol, 1.00 eq) was dissolved in MeOH / H2O (5 / 1, 2.5 mL). The solution was cooled to 0°C and LiOH (38.88 mg, 1.62 mmol, 2.00 eq) was added. The resulting mixture was stirred at room temperature overnight. The reaction was then quenched by adding 10 ml of CA aqueous solution (1 M), extracted with dichloromethane (3 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product (175 mg, containing compound 144a and compound 144b, ratio 1:2) was purified by silica gel column chromatography (gradient elution: PE / EtOAc from 100:1 to 90:10), with the leading peak being compound 144a and the trailing peak being compound 144b.

[1308] 17% (35 mg, 1.47 mmol, containing compound 144a and compound 144b in a ratio of 1:15) off-white solid. 1 HNMR (300 MHz, chloroform-d) δ 4.87 (s, 1H), 4.72-4.65 (m, 2H), 3.33 (s, 3H), 3.06-2.98 (m, 1H), 2.76-2.62 (m, 1H), 2.56-2.44 (m, 1H), 2.19-2.05 (m, 1H), 1.93-1.79 (m, 1H), 1.42 (s, 3H), 1.36 ppm (s, 3H). 13 C NMR (101MHz, CDCl3) δ176.29,111.92,108.28,85.39,84.00,83.72,55.09,49.96,27.83,25.38,24.53,15.89ppm. GCMS(ESI+)m / z:C 12 H 18 O6[M-Me] - Calculated value = 243.0, found 243.0, RT: 7.634 min, Method 1.

[1309] Preparation of Compound 149

[1310]

[1311] Compound 143a (138 mg, 0.56 mmol, 1.00 eq) was dissolved in H2O (1.5 mL) and formic acid (FA) (1.5 mL) was added. T...

Claims

1. A compound of formula (A) or a salt thereof, wherein: Y is -O- or -CH2-; n is 0 or 1; When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2; When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; The direction R 1 or R 2 Key When R 1 or R 2 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, C substituted by silyl group 1-6 When R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond; Each R a are independently hydrogen or C 1-6 alkyl; Each R b is hydrogen or two R b Taken together to form a boronic acid protecting group, the boronic acid protecting group is catechol borane, pinacol borane, N-methyliminodiacetic acid borate, neopentyl glycol borane, pinanediol borane, bicyclohexyl glycol borane or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol borane; R c C 1-6 Alkyl or aryl; PG is a hydroxyl protecting group, wherein the hydroxyl protecting group is a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; 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, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 Alkyl)2-; or R 4 and R 5 Together they form the diol protecting group -C(C 1-4 Alkyl)2-; The conditions are: (a) the compound is not a compound of the formula: Wherein Y is -O- or -CH2-; R 4 is hydrogen or a hydroxyl protecting group, wherein the hydroxyl protecting group is C 1-4 Alkyl, tert-butyldimethylsilyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, tert-butyldiphenylsilyl, benzyl, -C(=O)-C 1-4 Alkyl or -C(=O)-phenyl; R 2 is -OH, =O, -CH2-OH or =CH2; and R 5 and R 6 are independently -C(=O)-C 1-4 alkyl, benzoyl, benzyl or -CH2-naphthyl, wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted with one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they are -C(C 1-4 or wherein Y is -O- or -CH2, R 4 is methyl, R 2 =O or =CH2, and R 5 and R 6 are independently hydrogen or -C(=O)-C 1-4 Alkyl; and (b) the compound is not a compound of the formula: Where R v =O, -OH or =CH2; and (c) the compound is not a compound of the formula: Where R w is methyl or H; and (d) the compound is not a compound of the formula: wherein R is CO2Et or CH2OH or any stereoisomer thereof.

2. The compound according to claim 1, wherein the compound is a compound of formula (A-1a), (A-3a), (A-1b) or (A-3b): or a salt thereof.

3. The compound according to any one of claims 1 to 2, wherein Y is O.

4. The compound of any one of claims 1 to 2, wherein Y is CH2.

5. The compound according to any one of claims 1 to 2, wherein n is 1.

6. The compound of claim 5, wherein: R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or R 2 is hydrogen and R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2.

7. The compound according to any one of claims 1 to 2, wherein n is 0.

8. The compound of claim 7, wherein R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -C(O)OR a 、-C(O)NR a 2OR-B(OR b )2.

9. The compound of claim 1, wherein the compound is selected from: or a salt thereof.

10. A compound of formula (B): or a salt thereof, wherein: Y is -O- or -CH2-; R 4 , R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 Alkyl)2-; or R 4 and R 5 Together they form the diol protecting group -C(C 1-4 Alkyl)2-.

11. The compound of claim 10, wherein the compound is selected from: or a salt thereof.

12. A compound of formula (C): in: Y is -O- or -CH2-; R 4 , R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 4 and R 5 Together they form the diol protecting group -C(C 1-4 alkyl)2-; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 Alkyl)2-; Provided that the compound is not:

13. The compound of claim 12, wherein the compound is selected from: or a salt thereof.

14. A compound of formula (D): or a salt thereof, wherein: Y is -O- or -CH2-; in is a single bond or a double bond; and when When it is a single bond, R 1 ' and R 2 ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by 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 ; when When it is a double bond, R 1 ' and R 2 ' is hydrogen or C 1-6 alkyl and the other is a silyl group, C optionally substituted by a silyl group 1-6 Alkyl, -OC 1-6 Alkyl or C(O)R a ; and R a is hydrogen or C 1-6 alkyl; Each R b is hydrogen or two R b Taken together to form a boronic acid protecting group, the boronic acid protecting group is catechol borane, pinacol borane, N-methyliminodiacetic acid borate, neopentyl glycol borane, pinanediol borane, bicyclohexyl glycol borane or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol borane; R 3 is OR 4 or R 10 ; R 10 is a nucleobase or a nucleobase derivative, wherein the nucleobase or nucleobase derivative comprises any purine or pyrimidine nitrogenous base, wherein one or more substituents R are present on the heteroaryl core of the nitrogenous base, replacing hydrogen or another substituent moiety, wherein R is selected from, but not limited to, halogen, -NR * R ** , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, C substituted by one, two or three halogen atoms 1-4 Alkyl, where R * For hydrogen, C 1-4 Alkyl or -C(O)OC 1-4 Alkyl and R ** For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl; R 4 , R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 4 and R 5 Together they form the diol protecting group -C(C 1-4 alkyl)2-; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 Alkyl)2-.

15. The compound of claim 14, wherein R 3 OR 4 .

16. The compound of claim 14, wherein the compound is selected from: or a salt thereof.

17. A compound of formula (E): or a salt thereof, wherein: Y is -O- or -CH2-; n is 0 or 1; When n is 1, R 1 is hydrogen and R 2 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2, -(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or When n is 1, R 2 is hydrogen and R 1 -(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, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2; When n is 0, R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2, -(CH2) m S(O) x R c or =CH2; The direction R 1 or R 2 Key When R 1 or R 2 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 , a silyl group, a C1-6 alkyl group substituted with a silyl group, or an -O-aryl group, or when R 1 or R 2 =O, =CH2 or =CR a 2 is a double bond; Each R a are independently hydrogen or C 1-6 alkyl; Two R's b All are hydrogen or two R b Taken together to form a boronic acid protecting group, the boronic acid protecting group is catechol borane, pinacol borane, N-methyliminodiacetic acid borate, neopentyl glycol borane, pinanediol borane, bicyclohexyl glycol borane or 1-(4-methoxyphenyl)-2-methylpropane-1,2-diol borane; R c C 1-6 Alkyl or aryl; x is 0, 1, or 2; m is 0 or 1; R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 Alkyl)2-; R 10 is a nucleobase or a nucleobase derivative, wherein the nucleobase or nucleobase derivative comprises any purine or pyrimidine nitrogenous base, wherein one or more substituents R are present on the heteroaryl core of the nitrogenous base, replacing hydrogen or another substituent moiety, wherein R is selected from, but not limited to, halogen, -NR * R ** , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, C substituted by one, two or three halogen atoms 1-4 Alkyl, where R * For hydrogen, C 1-4 Alkyl or -C(O)OC 1-4 Alkyl and R ** For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl; PG is a hydroxyl protecting group, wherein the hydroxyl protecting group is a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; Provided that the compound is not any of the following: in R 5 is hydrogen or -C(=O)-C 1-4 alkyl; R 6 is hydrogen or -C(=O)-C 1-4 Alkyl; or R 5 and R 6 Together they form -C(CH3)2- Y is -O- or -CH2-; R 10 for Q 1 CR 6a ; Q 2 N or CR 6b ; R 6a and R 6b Each independently represents hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b or C substituted by one, two or three halogen atoms 1-4 alkyl; R 9a and R 9b Each independently represents hydrogen or C 1-4 alkyl; R 3a is hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl; R 7a is hydrogen; R 7b For hydrogen, C 3-6 Cycloalkyl or C 1-4 alkyl; R 4a is hydrogen, halogen, -NR 8a R 8b or C 1-4 Alkyl; and R x for or a salt thereof.

18. The compound according to claim 17, wherein the compound is a compound of formula (G-1a) or (G-1b): or a salt thereof.

19. The compound of any one of claims 17 or 18, wherein n is 1.

20. The compound of claim 19, wherein: R 1 is hydrogen and R 2 -(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, C substituted by silyl group 1-6 Alkyl, =O or =CR a 2; or R 2 is hydrogen and R 1 -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m S(O) x R c , silyl group, C substituted by silyl group 1-6 Alkyl, -O-aryl, =O or =CR a 2.

21. The compound of any one of claims 17 or 18, wherein n is 0.

22. The compound of claim 19, wherein R 1 and R 2 One of them is hydrogen and the other is -(CH2) m NR a 2. -(CH2) m OR a 、-(CH2) m OPG, -(CH2) m C(O)OR a 、-(CH2) m C(O)NR a 2. -(CH2) m C(O)R a 、-(CH2) m B(OR b )2 or =CH2.

23. The compound of claim 17, wherein the compound is selected from: or a salt thereof.

24. The compound of claim 23, wherein the compound is selected from: or a salt thereof.

25. The compound of claim 17, wherein the compound is selected from: or a salt thereof.

26. A compound of formula (H): or a salt thereof, wherein: Y is -O- or -CH2; R 5 and R 6 are each independently hydrogen or a hydroxyl protecting group, the hydroxyl protecting group being a silyl group, a C 1-4 Alkyl, C 1-4 Alkyl-OC 1-4 alkyl, tetrahydropyranyl, allyl, benzyl, -CH2-naphthyl, benzoyl, -C(=O)-C 1-4 alkyl or -C(=O)-phenyl; wherein benzyl, -CH2-naphthyl and benzoyl are optionally substituted by one or two substituents each independently selected from -CH3 and -OCH3; or R 5 and R 6 Together they form the diol protecting group -C(C 1-4 alkyl)2-; and R 10 is a nucleobase or a nucleobase derivative, wherein the nucleobase or nucleobase derivative comprises any purine or pyrimidine nitrogenous base, wherein one or more substituents R are present on the heteroaryl core of the nitrogenous base, replacing hydrogen or another substituent moiety, wherein R is selected from, but not limited to, halogen, -NR * R ** , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH, -OC 1-4 Alkyl, C substituted by one, two or three halogen atoms 1-4 Alkyl, where R * For hydrogen, C 1-4 Alkyl or -C(O)OC 1-4 Alkyl and R ** For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl.

27. A compound as described in any one of claims 14 to 18, wherein R 10 When present, it is cytosine, thymine or uracil, or a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), (a-2), (a-3), (a-4) and (a-5): R 3a , R 3b , R 3c , R 3d and R 3e are independently hydrogen, halogen, -NR 7a R 7b , C 1-4 Alkyl, C 2-4 Alkenyl, C 3-6 Cycloalkyl, -OH or -OC 1-4 alkyl; R 7a Hydrogen, -C(O)OC 1-4 Alkyl or R 7b For hydrogen, C 3-6 Cycloalkyl, C 1-4 Alkyl or -C(O)OC 1-4 alkyl; R 4a , R 4b , R 4c , R 4d , R 4e , R 4f and R 4g are independently hydrogen, halogen, -NR 8a R 8b or C 1-4 alkyl; R 8a and R 8b are independently hydrogen or C 1-4 alkyl; Q 1 N or CR 6a ; Q 2 N or CR 6b ; Q 3 N or CR 6c ; Q 4 N or CR 6d ; The condition is Q 3 and Q 4 At most one of them is N; Q 8 N or CR 6g ; Q 9 N or CR 6h ; Q 10 N or CR 6i ; Q 11 N or CR 6j ; Q 5 CR 3d ;Q 6 is N; and Q 7 CR 4f ;or Q 5 CR 3d ;Q 6 CR 4e ; and Q 7 is N; or Q 5 N; Q 6 CR 4e ; and Q 7 CR 4f ;or Q 5 N; Q 6 CR 4e ; and Q 7 is N; or Q 5 N; Q 6 is N; and Q 7 CR 4f ;or Q 5 N; Q 6 is N; and Q 7 is N; R 6a , R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i and R 6j are independently hydrogen, halogen, C 1-4 Alkyl, -NR 9a R 9b , or C substituted by one, two or three halogen atoms 1-4 alkyl; R 9a and R 9b are independently hydrogen or C 1-4 alkyl.

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