WO2021053158A1

WO2021053158A1 - Novel histone methyltransferase inhibitors

Info

Publication number: WO2021053158A1
Application number: PCT/EP2020/076131
Authority: WO
Inventors: Roland SCHÜLE; Eric Metzger; Sheng Wang; Manfred Jung; Nicolas P. F. BARTHES; Bernhard Breit; Daad SARRAF; Tabea PAPPERT
Original assignee: Albert-Ludwigs-Universität Freiburg
Priority date: 2019-09-18
Filing date: 2020-09-18
Publication date: 2021-03-25

Abstract

The present invention relates to novel compounds of formula (I) as defined herein. The compounds are inhibitors of histone methyltransferases of the seven-beta-strand family, in particular of KMT9.

Description

Novel histone methyltransferase inhibitors Field of Invention The present invention relates to novel histone methyltransferase (HMT) inhibitors. In particular, the present invention is concerned with a compound of formula (I)

wherein R¹, R², R³, X¹ and X² are as defined herein. Further, the present invention is concerned with a pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula (I). The present invention also relates to a compound of formula (I) and a pharmaceutical composition comprising a compound of formula (I) for use in medicine. Yet further, the present invention is concerned with a compound of formula (I) and a pharmaceutical composition comprising a compound of formula (I) for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably for use as inhibitor of KMT9. Finally, the present invention is concerned with a compound of formula (I), wherein R¹, R², R³, X¹ and X² are as defined herein, for use in the treatment of a cancer selected from the group as defined herein. Background of the Invention Posttranslational modifications of histones such as methylation regulate chromatin structure and gene expression, and dysregulation of these mostly reversible modifications has been shown to have a central role in cancer onset and cancer progression (Strahl, B. D. & Allis, C. D. Nature 403, 41-45, doi:10.1038/47412 (2000)). Histone methyl transferases (HMT) possess high selectivity as regards the targeted histone lysine residue. Further, the pattern of methylation is specific for each HMT. There are two families of HMTs, namely the SET domain-containing HMTs (with the four subfamilies SET1 [a specific member here is EZH2], SET2, SUV39 and RIZ) and other HMTs, wherein e.g. DOT1L does not contain a SET domain but is a member of the seven-beta-strand family of histone methyltransferases. Further details in this respect as well as information on the effect of HMT- inhibition and specific inhibitors be found in the review by Morera et al. Clinical Epigenetics, 8:57 (2016), doi: 10.1186/s13148-016-0223-4., 2016. EZH2 and DOT1L have in particular been studied over the last years when it comes to their role in cancer. EZH2 is the catalytic component of the polycomb repressive complex 2 (PRC2), which performs three successive methyl transfer reactions arriving at H3K27me3. DOT1L is capable of catalyzing mono-, di-, and trimethylation of H3K79. While H3K79 is an activating mark when it comes to gene transcription, H3K27me3 is associated with gene silencing. The inhibition of DOT1L is in particular implicated in the treatment of leukemias presenting a chromosomal translocation of the mixed-lineage leukemia (MLL) gene (chromosome 11q23), such as e.g. acute myeloid leukemias (AML), acute lymphoblastic leukemias (ALL) and the biphenotypic (mixed lineage) leukemias (MLL). Recently, a further member of the of the seven-beta-strand family of histone methyltransferases was identified by Metzger et al., namely KMT9, a heterodimer comprised of KMT9alpha and KMT9beta (see Metzger et al., Nat. Struct. Mol. Biol., 2019 May, 26(5): 361). KMT9 writes the methylation mark on lysine 12 of histone H4 and H4K12 methylation has been shown to be implicated in prostate tumor cell proliferation. There is of course an ongoing need for novel compounds that inhibit HMTs, in particular members of the seven-beta-strand family, preferably KMT9 as recent member of this family. Objects and Summary of the Invention The inventors of the present invention have found compounds that inhibit KMT9, a HMT of the seven-beta-strand family. Since KMT9 inhibition is linked to a pronounced negative effect on the proliferation of specific cancer cells, the afore-mentioned compounds can be used in medicine, in particular for the treatment of the respective cancers. In a first aspect, the present invention therefore relates to a compound of formula (I)

or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl), (C₃-C₅-alkyl)-NHR^A, (C₂-C₅-alkyl)-NR^AR^H, (C₁-C₃-alkyl)- CR^BR^CNH₂, (C₂-C₄-alkyl)-NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)- CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is (C₁-C₄-alkyl)-phenyl, (C₁-C₄-alkyl)-naphthyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^H is (C=O)-(C₁-C₃-alkyl)-C(C₁-C₃-alkyl)₂R^V; R^M is H or halogen; R^V is H, C₁-C₂₀ hydrocarbyl, C₁-C₂₀ oxaalkyl, C₁-C₂₀ thiaalkyl, C₁-C₂₀ azaalkyl, a benzoquinone, a hydrobenzoquinone, or a phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl, with the proviso that when R² is (i) (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl) or (ii) (C₃-C₅-alkyl)-NHR^A and R^A is unsubstituted (C₁-C₄-alkyl)-phenyl, X¹ is CH₂ and/or X² is CH. In the following, preferred embodiments of the substituents in the above formula (I) are described in further detail. It is to be understood that each preferred embodiment is relevant on its own as well as in combination with other preferred embodiments. Furthermore, it is to be understood that the preferences in each case also apply to the salts, stereoisomers, and tautomers of the compounds of the invention. In a preferred embodiment A1a of the first aspect, X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl), (C₃-C₅-alkyl)-NHR^A, (C₁-C₃-alkyl)-CR^BR^CNH₂, (C₂-C₄-alkyl)- NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)-CHR^FR^G; and R³ is H, C1-C4-alkyl, C1-C4-haloalkyl, or phenyl; and wherein R^A is (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C1-C4-alkyl, phenyl, C2-C4-phenyl, benzyl, fluorinated C1-C4-alkyl, (C1-C3-alkyl)-NH-(C1-C3- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^M is H or halogen; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl. In a preferred embodiment A1b of the first aspect, the proviso is that when R² is (i) (C₃-C₅-alkyl)- NH-( C₁-C₃-alkyl) or (ii) (C₃-C₅-alkyl)-NHR^A and R^A is unsubstituted (C₁-C₄-alkyl)-phenyl, X¹ is CH₂ and X² is CH. In a preferred embodiment A1c of the first aspect, the proviso is that when R² is (i) (C₃-C₅-alkyl)- NH-( C₁-C₃-alkyl) or (ii) (C₃-C₅-alkyl)-NHR^A and R^A is (C₁-C₄-alkyl)-phenyl, X¹ is CH₂ and/or X² is CH. In a preferred embodiment A1d of the first aspect, the proviso is that when R² is (i) (C₃-C₅-alkyl)- NH-( C₁-C₃-alkyl) or (ii) (C₃-C₅-alkyl)-NHR^A and R^A is (C₁-C₄-alkyl)-phenyl, X¹ is CH₂ and X² is CH. In a preferred embodiment A1 of the first aspect, R³ is selected from the group consisting of H, methyl, and phenyl. It can be especially preferred that R³ is H or methyl, in particular H. It is presently assumed that embodiment A1 with R³ being H or methyl is a particular preferred embodiment when it comes to the specific inhibition of seven-beta-strand HMTs. In a preferred embodiment A2 of the first aspect, R² is (C₃-C₄-alkyl)-NHR^A; wherein R^A is (C₁-C₃- alkyl)-phenyl or (C₁-C₃-alkyl)-naphthyl, preferably (C₂-C₃-alkyl)-phenyl or (C₁-C₃-alkyl)-naphthyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; wherein R^W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br. It can be preferred that R² is (C₃-alkyl)-NHR^A; wherein R^A is (C₁-C₂-alkyl)-phenyl or (C_1- C₂-alkyl)-naphthyl, preferably (C₂-alkyl)-phenyl or (C_1-C₂-alkyl)-naphthyl, wherein each substitutable carbon in the phenyl or naphthyl group is independently unsubstituted or substituted with one or more, same or different substituents R^W; wherein R^W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br. In a preferred embodiment A3 of the first aspect, R² is (C₃-alkyl)-NH-(C₁-C₃-alkyl) [preferably (C₃-alkyl)-NH-(C₁-alkyl)] or (C₃-alkyl)-NHR^A; wherein R^A is (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, halogen, C(=O)-(C1-C4-alkyl), phenyloxy, or benzyloxy, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; and R^Y is H, halogen, CN, or NO₂. It can be particularly preferred that R² is (C₃-alkyl)-NHR^A; wherein R^A is (C₁-C₄-alkyl)-phenyl, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, or halogen. It is presently assumed that embodiment A3 is a particular preferred embodiment when it comes to the specific inhibition of KMT9. In a preferred embodiment A4 of the first aspect, R² is (C₂-alkyl)-CR^BR^CNH₂; wherein R^B is H; and R^C is C₁-C₃-alkyl. In a preferred embodiment A5 of the first aspect, R² is (C₁-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N-atom is non- oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; wherein R^Z is H or (C₁-C₂-alkyl)-phenyl. It can be can be preferred in this embodiment that R² is (C₁-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N- atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; wherein R^Z is H or (C₁-C₂-alkyl)-phenyl. It can further be preferred in this embodiment that R² is (C₁-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N- atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted. Alternatively, it can be preferred that R² is (C₁-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N- atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is substituted with one or more, same or different substituents R^Z; wherein R^Z is (C2-alkyl)-phenyl. In a preferred embodiment A6 of the first aspect, R² is (C₁-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N- atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; wherein R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cyclohexyl. It can be particularly preferred that R² is (C1-alkyl)-CHR^FR^G; wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; wherein R^Z (C₁-C₃-alkyl)-phenyl, or (C₁-C₂- alkyl)-cyclohexyl. It is presently assumed that embodiment A6 is a particular preferred embodiment when it comes to the specific inhibition of KMT9. In a preferred embodiment A7 of the first aspect, R¹ is or C1-C4-alkyl (preferably methyl or ethyl, most preferably methyl); and/or R² is (C₂-C₅-alkyl)-NR^AR^H; R^H is (C=O)-(C₁-C₂-alkyl)-C(C₁-C₂- alkyl)₂R^V; and R^V is H, a benzoquinone, a hydrobenzoquinone, or a phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z. It is particularly preferred that R^V is a benzoquinone, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z, preferably wherein R^Z is C₁-C₃-alkyl, more preferably wherein R^Z is methyl. It is also particularly preferred that R^V is a benzoquinone, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different C₁-C₃-alkyl, more preferably wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more methyl. Embodiment A7 is of particular importance when it comes to prodrugs that are considered to be cell-permeable since the definition of R¹ and R² results in esters and amides, respectively, that are assumed to be cleaved by cellular enzymes after the respective compounds have entered the cell. In a preferred embodiment A8 of the first aspect, X² is N or CR^M; wherein R^M is F, Cl, or Br. It can be preferred that X² is N or CR^M; R³ is H; wherein R^M is F, Cl, or Br. It is in particular preferred that X² is N or CH. In a preferred embodiment A9 of the first aspect, X¹ is CH₂. In a preferred embodiment A10 of the first aspect, X¹ is CH₂ and X² is CH. In a preferred embodiment A11 of the first aspect, R³ is methyl, X¹ is CH₂, and X² is CH. It is presently assumed that embodiment A11 is a particular preferred embodiment when it comes to specific inhibition of seven-beta-strand HMTs. In a preferred embodiment A12 of the first aspect, R¹ is H, R² is C3-alkyl-NHR^A, wherein R^A is C2- alkyl-phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, halogen, phenyloxy, or benzyloxy, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; and R^Y is H, halogen, CN, or NO₂; R³ is methyl; X¹ is CH₂ and X² is CH. It can be particularly preferred that R¹ is H, R² is C₃-alkyl-NHR^A, wherein R^A is C2-alkyl-phenyl, wherein the phenyl is substituted in the meta-position by F and in the para-position by phenyloxy, wherein said phenyloxy is substituted in the para position by Cl; R³ is methyl; X¹ is CH₂ and X² is CH. In a particularly preferred embodiment A13 of the first aspect, R¹ is H; R² is either as defined in embodiment A3 or embodiment A6 above; R³ is methyl, X¹ is CH₂, and X² is CH. It is presently assumed that embodiment A13 is a particular preferred embodiment when it comes to the specific inhibition of KMT9. In a preferred embodiment A14 of the first aspect, the compound according to formula (I) is selected from the group consisting of (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(piperidin-3-yl)amino)butanoic acid; (2S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-ylmethyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((5-ethylpiperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-(cyclohexylmethyl)piperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-benzylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)- 2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-phenethylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(6- ethylpiperidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(2-(piperidin-3-yl)ethyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(pyrrolidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-3- phenylpropyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-4-((3-((1-acetylazetidin-3-yl)amino)propyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-aminobutanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-(pyrrolidin-2-yl)ethyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- morpholinopropyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6- (phenylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl)(3- (methylamino)propyl)amino)butanoic acid; (2S,2'S)-4,4'-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)azanediyl)bis(2-aminobutanoic acid); (S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((R)-3- aminobutyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-4,4,4-trifluorobutyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-((3-amino-3-methylbutyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-(((S)-3-amino-4- methylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-5-methylhexyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-aminohexyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5- phenylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5-(phenylamino)pentyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-(((S)-3-amino-4-(methylamino)butyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1s,3S)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1r,3R)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-(methylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(4-(methylamino)butyl)amino)butanoic acid; methyl (S)-2-amino-4-((((2R,3S,4R,5R)-5- (6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (phenethylamino)propyl)amino)butanoate; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3- (phenethylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoic acid; methyl (S)-2-amino-4-((((1R,2R,3S,4R)-2,3- dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoate; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((S)-3,4-diamino-4- oxobutyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid; (S)-ethyl 2-amino-4-((3- ((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate; (S)-2- amino-4-((3-((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4- (4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid; (S)- methyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3- dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)methyl)amino)butanoate; (S)-ethyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorophenethyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate; ethyl (S)-2-amino-4-((3-((2-(6,7- dichloronaphthalen-2-yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)methyl)amino)butanoate; (S)-2-amino-4-((3-((2-(6,7-dichloronaphthalen-2- yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)butanoic acid; (S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-(benzylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxybenzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((naphthalen-2- ylmethyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-(3-methyl-N-(3- phenoxybenzyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1- yl)butanamido)propyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid; and methyl (S)-2-amino-4- ((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)methyl)(3-((4-phenoxyphenethyl)amino)propyl)amino)butanoate. In a preferred embodiment of A14, the invention relates to a salt of any of the compounds listed in A14. In a particular preferred embodiment of A14, the invention relates to a trifluoroacetate salt of any of the compounds listed in A14. It is to be understood that a trifluoroacetate salt may be the mono-trifluoroacetate, the di-trifluoroacetate, the tri- trifluoroacetate, the tetra-trifluoroacetate, and mixtures thereof. In another particularly preferred embodiment of A14, the invention relates to the chloride salt of any of the compounds listed in A14. In a preferred embodiment A15 of the first aspect, the compound according to formula (I) is selected from the group consisting of

. In a preferred embodiment A16, of the first aspect, R² is (C₃-C₅-alkyl)-NHR^A, wherein R^A is (C₁- C₄-alkyl)-phenyl, wherein the phenyl is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^B is H or C₁-C₄-alkyl; and R^Y is H, halogen, CN, or NO₂. In a preferred embodiment A17 of the first aspect, R^B is H or C1-C4-alkyl; R^W is selected from the group consisting of H, halogen, C(=O)-(C₁-C₄-alkyl), phenyloxy, benzyloxy, and NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; and R^Y is H, halogen, CN, or NO₂. In a second aspect, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compound as defined in the first aspect (including all embodiments thereof as described herein) and optionally a pharmaceutically acceptable carrier, diluent, or excipient. In a third aspect, the present invention relates to the pharmaceutical composition of the second aspect and/or the compounds as defined in the first aspect (including all embodiments thereof as described herein) for use in medicine. In a fourth aspect, the present invention relates to the pharmaceutical composition of the second aspect for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9. This may also be referred to as a pharmaceutical composition of the second aspect for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9. In a fifth aspect, the present invention relates to the compounds as defined in the first aspect (including all embodiments thereof as described herein) for use in the treatment of cancer, preferably for use in the treatment of cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma, leukemia, colorectal cancer, rectal adenocarcinoma, mesothelioma, endometrium adenocarcinoma, erythroleukemia, medulloblastoma, astrocytoma, Ewing sarcoma, myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, leukemia, myelogenic leukemia, medulloblastoma, myeloid leukemia, acute monocytic leukemia, gallbladder carcinoma, cecum adenocarcinoma, gastric adenocarcinoma, stomach adenocarcinoma, renal cell carcinoma, bladder carcinoma, melanoma, cervical squamous cell carcinoma, pancreatic carcinoma, chondrosarcoma, duodenal adenocarcinoma, rhabdomyosarcoma, hepatocellular carcinoma and uterine adenocarcinoma. It is noted that the prostate cancer may be hormone-dependent prostate cancer or castration-resistant prostate cancer, and that the castration-resistant prostate cancer may further be resistant to enzalutamide. It is further noted that the lung cancer may be non-small cell lung cancer or small cell lung cancer. In a preferred embodiment E1 of the fifth aspect, the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, colorectal cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma and leukemia. It can also be preferred that the cancer is selected from the group consisting of prostate cancer, breast cancer, colorectal cancer and lung cancer. In a preferred embodiment E2 of the fifth aspect, the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, colorectal cancer, and bladder carcinoma, in particular wherein the cancer is selected from the group consisting of prostate cancer, breast cancer, colon cancer, lung cancer, and bladder carcinoma. In a preferred embodiment E3 of the fifth aspect, the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of prostate cancer, in particular castration-resistant prostate cancer that may be resistant to enzalutamide. In a preferred embodiment E4 of the fifth aspect, the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) in the treatment of colorectal cancer. In a sixth aspect, the present invention relates to the compound as defined in the first aspect (including all embodiments thereof as described herein) for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9. This may also be referred to as a compound of the first aspect for use as inhibitor of a histone methyltransferase of the seven-beta-strand family, preferably as inhibitor of KMT9. In a seventh aspect, the present invention relates to a compound of formula (I)

or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is H, (C₂-C₅-alkyl)-NHR^A, (C₁-C₃-alkyl)-CR^BR^CNH₂, (C₂-C₅-alkyl)-NR^AR^H, (C₂-C₄-alkyl)-NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)-CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is H, C₁-C₃-alkyl, (C₁-C₄-alkyl)-phenyl, (C₁-C₄-alkyl)-naphthyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^H is (C=O)-(C₁-C₃-alkyl)-C(C₁-C₃-alkyl)₂RV; R^M is H or halogen; R^V is H, C₁-C₂₀ hydrocarbyl, C₁-C₂₀ oxaalkyl, C₁-C₂₀ thiaalkyl, C₁-C₂₀ azaalkyl, a benzoquinone, a hydrobenzoquinone, or a phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^W is H, halogen, C(=O)-(C1-C4-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl; for use in the treatment of castration-resistant prostate cancer. In a preferred embodiment G1 of the seventh aspect, the castration-resistant prostate cancer is resistant to enzalutamide. It is to be understood that the preferred embodiments as listed above for the first aspect also apply for the seventh aspect. In an eighth aspect, the present invention relates to a PROTAC molecule consisting of (i) a compound as defined in the first aspect (including all embodiments thereof as described herein) and (ii) a ligand to an E3 ubiquitin ligase, preferably connected by a linker. It can be preferred that the ligand (ii) as mentioned above binds to an E3 ubiquitin ligase selected from the group consisting of MDM2, IPA, VHL and cereblon. The ligand (ii) may be selected from the group consisting of an LCL 161 derivative, VHL-1, a hydroxyproline derivative, pomalidomide, thalidomide, a HIF-1b-derived (R)-hydroxyproline and VHL ligand 2. Figure legends Fig.1 shows that a compound of the present invention blocks proliferation of LNCaP prostate tumour cells, SW-480 colorectal cancer cells, MDA-MB-468 breast cancer cells, and A549 lung tumour cells, while it does not affect proliferation of the KMT9 non-responsive HepG2 cells (compound “KMI95423411” is also referred to as compound 75b in the present application). Fig. 2. N6AMT1 (KMT9alpha) controls proliferation of breast cancer cells, ovarian carcinoma cells, colon carcinoma cells and glioblastoma cells. (A-D) Cell proliferation assays. Breast cancer cells as indicated (SK-BR3, MCF-7, MDA-MB-231, or T47-D) (A); Ovarian carcinoma cells (OVCAR- 3) (B); colon carcinoma cells (SW480) (C); and glioblastoma cells (U-251MG or T98G) (D); were transfected with siRNA Ctrl or siRNA against N6AMT1 as indicated. Data represent means ± s.e.m. Fig. 3. N6AMT1 (KMT9alpha) controls proliferation of lung cancer cells and neuroblastoma cells. (A, B) Cell proliferation assays. Lung tumour cells (A549, NCI-H2087, NCIH-1299, A427, ChaGO-K- 1, GLC-2, GLC-1, or NCIH-1792) (A) and neuroblastoma cells (SY5Y, LAN-1, SK-N-SH, or SK-N-MC) (B) were transfected with siRNA Ctrl or siRNA against N6AMT1 as indicated. Data represent means ± s.e.m. Fig. 4 shows that KMT9a controls proliferation and migration of bladder cancer cells. (a-f) depict cell proliferation and migration assays. Bladder cancer cells (TCCSUP, HT-1376, JON, 5637, CAL-29, and T24) were transfected with siRNA Ctrl or two different siRNAs against KMT9a as indicated. Data represent means ± s.d. To verify depletion of KMT9a, Western blots were carried out and the results are also shown. Fig. 5 shows that the KMT9a inhibitor KMI95423512 blocks proliferation of colon, bladder, prostate, breast, and lung cancer cells. (a) depicts the structure of KMI95423512; (b-e, g, and h) depict cell proliferation assays; controls (HepG2, HEK293 KMT9a KO), bladder cancer cells (HT- 1376, 5637, CAL-29, TCCSUP, T24), colon cancer cells (SW480, Caco-2, RKO), prostate cancer cells (LAPC4, PC-3M, C42B, DU145, 22Rv1), breast cancer cells (BT-20, MDA-MB-231), and lung cancer cells (GLC2, PC-9) were incubated with the indicated concentrations of KMI95423712. HepG2 and HEK293 KMT9a KO cells were used as controls. Data represent means ± s.d. (f) Cellular thermal shift assays (CETSA) of KMI95423712 (15 µM) for KMT9 and KMT5a (control) were carried out in Caco2, PC-3M and RKO cells. In brief, the protein-levels at indicated temperate points were analyzed by Western blots as indicated. The intensities of the protein (KMT9a and KMT5a, respectively) signals were quantified and are shown in the graphs. Fig. 6 shows that the KMT9a inhibitor KMI95423712 blocks proliferation of bladder cancer cells. (a) depicts the structure of KMI95423712; (b, c) depict cell proliferation assays. HepG2 (control cells) and the bladder cancer cells HT-1376 and CAL-29 were incubated with the indicated concentrations of KMI95423712. Data represent means ± s.d. Detailed Description Before describing in detail exemplary embodiments of the present invention, definitions important for understanding the present invention are given. As used in this specification and in the appended claims, the singular forms of "a" and "an" also include the respective plurals unless the context clearly dictates otherwise. In the context of the present invention, the terms "about" and "approximately" denote an interval of accuracy that a person skilled in the art will understand to still ensure the technical effect of the feature in question. The term typically indicates a deviation from the indicated numerical value of ±20 %, preferably ±15 %, more preferably ±10 %, and even more preferably ±5 %. It is to be understood that the term "comprising" is not limiting. For the purposes of the present invention the term "consisting of" is considered to be a preferred embodiment of the term "comprising of". If hereinafter a group is defined to comprise at least a certain number of embodiments, this is meant to also encompass a group which preferably consists of these embodiments only. Furthermore, the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)" etc. and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. In case the terms "first", "second", "third" or "(a)", "(b)", "(c)", "(d)", "i", "ii" etc. relate to steps of a method or use or assay there is no time or time interval coherence between the steps, i.e. the steps may be carried out simultaneously or there may be time intervals of seconds, minutes, hours, days, weeks, months or even years between such steps, unless otherwise indicated in the application as set forth herein above or below. It is to be understood that this invention is not limited to the particular methodology, protocols, reagents etc. described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention that will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. On a general level, an inhibitor may be a reversible or an irreversible inhibitor. Reversible inhibitors attach to enzymes with non-covalent interactions such as hydrogen bonds, hydrophobic interactions, and ionic bonds. Hence, reversible inhibitors generally do not undergo chemical reactions when bound to the enzyme and can be removed by dilution or dialysis. Irreversible inhibitors bind in general covalently to the enzyme and therefore modify said enzyme. Hence, inhibition cannot be reversed. When it comes to the compounds of the present invention, they may be classified as reversible inhibitors. The term "compound(s) according to the invention", or "compounds of formula (I)" comprises the compound(s) as defined herein as well as a stereoisomer, salt, or tautomer thereof. Depending on the substitution pattern, the compounds according to the invention may have one or more centers of chirality. The invention provides both the single pure enantiomers or pure diastereomers of the compounds according to the invention, and their mixtures and the use according to the invention of the pure enantiomers or pure diastereomers of the compounds according to the invention or their mixtures. Suitable compounds according to the invention also include all possible geometrical stereoisomers (cis/trans isomers or E/Z isomers) and mixtures thereof. Cis/trans isomers may e.g. be present with respect to an amide group. The term "stereoisomer(s)" encompasses both optical isomers, such as enantiomers or diastereomers, the latter existing due to more than one center of chirality in the molecule, as well as geometrical isomers (cis/trans isomers). The present invention relates to every possible stereoisomer of the compounds of formula (I), i.e. to single enantiomers or diastereomers, as well as to mixtures thereof. The compounds of formula (I) may be amorphous or may exist in one or more different crystalline states (polymorphs) which may have different macroscopic properties such as stability or show different biological properties such as activities. The present invention relates to amorphous and crystalline compounds of formula (I), mixtures of different crystalline states of the respective compound of formula (I), as well as amorphous or crystalline salts thereof. Salts of the compounds of the formula (I) may be pharmaceutically acceptable salts, such as those containing counterions present in drug products listed in the US FDA Orange Book database. They can be formed in a customary manner, e.g. by reacting the compound with an acid of the anion in question if the compound of formula (I) has a basic functionality, or by reacting acidic compounds according to the invention with a suitable base. Suitable cationic counterions are in particular the ions of the alkali metals, preferably lithium, sodium and potassium, of the alkaline earth metals, preferably calcium, magnesium and barium, and of the transition metals, preferably manganese, copper, silver, zinc and iron, and also ammonium (NH₄ ⁺) and substituted ammonium in which one to four of the hydrogen atoms are replaced by C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, C₁-C₄-alkoxy, (C₁-C₄-alkoxy)-(C₁-C₄-alkyl), hydroxy- (C₁-C₄-alkoxy)-(C₁-C₄-alkyl), phenyl or benzyl. Examples of substituted ammonium ions comprise methylammonium, isopropylammonium, dimethylammonium, diisopropylammonium, trimethylammonium, tetramethylammonium, tetraethylammonium, tetrabutylammonium, 2- hydroxyethylammonium, 2-(2-hydroxyethoxy)ethyl-ammonium, bis(2-hydroxyethyl)ammonium, benzyltrimethylammonium and benzyltriethylammonium, furthermore the cations of 1,4- piperazine, meglumine, benzathine and lysine. Suitable anionic counterions are in particular chloride, bromide, hydrogensulfate, sulfate, dihydrogenphosphate, hydrogenphosphate, phosphate, nitrate, bicarbonate, carbonate, hexafluorosilicate, hexafluorophosphate, benzoate, and the anions of C₁-C₄-alkanoic acids, preferably formate, acetate, trifluoroacetate, propionate and butyrate, furthermore lactate, gluconate, and the anions of poly acids such as succinate, oxalate, maleate, fumarate, malate, tartrate and citrate, furthermore sulfonate anions such as besylate (benzenesulfonate), tosylate (p-toluenesulfonate), napsylate (naphthalene-2-sulfonate), mesylate (methanesulfonate), esylate (ethanesulfonate), and ethanedisulfonate. They can be formed by reacting compounds according to the invention that have a basic functionality with an acid of the corresponding anion. Preferred salts of the compounds of formula (I) are trifluoroacetate salts. In this connection, it is to be understood, that trifluoroacetate may be the mono-trifluoroacetate, the di-trifluoroacetate, the tri-trifluoroacetate, the tetra-trifluoroacetate, and mixtures thereof. Tautomers may be formed, if a substituent is present at the compound of formula (I), which allows for the formation of tautomers such as keto-enol tautomers, imine-enamine tautomers, or the like. The term "substituted", as used herein, means that a hydrogen atom bonded to a designated atom is replaced with a specified substituent, provided that the substitution results in a stable or chemically feasible compound. Unless otherwise indicated, a substituted atom may have one or more substituents and each substituent is independently selected. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen, which can be replaced with a suitable substituent. When it is referred to certain atoms or moieties being substituted with “one or more” substituents, the term “one or more” is intended to cover at least one substituent, e.g. 1 to 10 substituents, preferably 1, 2, 3, 4, or 5 substituents, more preferably 1, 2, or 3 substituents, most preferably 1, or 2 substituents. When neither the term “unsubstituted” nor “substituted” is explicitly mentioned concerning a moiety, said moiety is to be considered as unsubstituted. The organic moieties mentioned in the above definitions of the variables are - like the term halogen - collective terms for individual listings of the individual group members. The prefix Cn- C_m indicates in each case the possible number of carbon atoms in the group. The term "halogen" denotes in each case fluorine, bromine, chlorine, or iodine, in particular fluorine, chlorine, or bromine. The term “hydrocarbyl” as used herein denotes univalent groups formed by removing a hydrogen atom from a hydrocarbon, e.g. alkyl such as ethyl or phenyl. The term "alkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 5 carbon atoms, preferably from 1 to 4 carbon atoms. Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, 1,1- dimethylpropyl, and 1,2-dimethylpropyl. Methyl, ethyl, n-propyl, iso-propyl, and iso-butyl, are particularly preferred. The term "alkoxy" as used herein denotes in each case a straight-chain or branched alkyl group which is bonded via an oxygen atom and has usually from 1 to 6 carbon atoms, preferably 1 to 2 carbon atoms, more preferably 1 carbon atom. Examples of an alkoxy group are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy, tert.-butyloxy, and the like. The term “oxaalkyl” as used herein refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy, 3,6,9-trioxadecyl and the like. It is to be understood that the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, “thiaalkyl” and “azaalkyl” refer to alkyl residues in which one or more carbons had been replaced by sulfur or nitrogen, respectively. Examples of azaalkyl include ethylaminoethyl and aminohexyl. The term "(C_n-C_m-alkyl)" as used herein denotes in each case a linker moiety, wherein the thereto attached moieties are attached to the terminal carbons. The skilled person is aware that e.g. the term (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl), is to be understood as follows:

The term “C(=O)” as used therein denotes in each case a carbonyl moiety. The term “C(=O)-(C_n-C_m-alkyl)” as used herein denotes in each case an alkylcarbonyl, referring to a straight-chain or branched alkyl group as defined above, which is bonded via the carbon atom of a carbonyl group (C=O) to the remainder of the molecule. The term "haloalkyl" as used herein denotes in each case a straight-chain or branched alkyl group having usually from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, especially 1 or 2 carbon atoms, wherein the hydrogen atoms of this group are partially or totally replaced with halogen atoms. Preferred haloalkyl moieties are selected from C₁-C₄-haloalkyl, more preferably from C₁-C₃-haloalkyl or C₁-C₂-haloalkyl, in particular from C₁-C₂-fluoroalkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, pentafluoroethyl, and the like. Trifluoromethyl is particularly preferred according to the invention. The term “cycloalkyl” as used herein denotes in each case a monocyclic cycloaliphatic radical having usually from 3 to 10 or from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl or cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term “heterocyclic” or “heterocyclyl” includes, unless otherwise indicated, in general a 3- to 9-membered, preferably a 4- to 8-membered or 5- to 7-membered, more preferably 5- or 6- membered, in particular 6-membered monocyclic ring. The heterocycle may be saturated, partially or fully unsaturated, or aromatic, wherein saturated means that only single bonds are present, and partially or fully unsaturated means that one or more double bonds may be present in suitable positions, while the Hückel rule for aromaticity is not fulfilled, whereas aromatic means that the Hückel (4n + 2) rule is fulfilled. The heterocycle typically comprises one or more, e.g. 1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S- atoms as ring members may be present as S, SO or SO₂. The remaining ring members are carbon atoms. In one embodiment, the heterocycle is an aromatic heterocycle, preferably a 5- or 6- membered aromatic heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, where S-atoms as ring members may be present as S, SO or SO₂. Examples of aromatic heterocycles are provided below in connection with the definition of “hetaryl”. “Hetaryls” or “heteroaryls” are covered by the term “heterocycles”. The saturated or partially or fully unsaturated heterocycles usually comprise 1, 2, 3, 4 or 5, preferably 1, 2 or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO₂. In a preferred embodiment, the heterocycle is a 4- to 6-membered saturated heterocycle comprising one or more, e.g.1, 2, 3, or 4, preferably 1, 2, or 3 heteroatoms selected from N, O and S as ring members, where S-atoms as ring members may be present as S, SO or SO₂. The skilled person is aware that S, SO or SO₂ is to be understood as follows:

Further, a skilled person is aware that resonance structures of the oxidized forms may be possible. Preferred saturated heterocycles include pyrrolidine, piperidine, or morpholine. The term "hetaryl" or “heteroaryl” or “aromatic heterocycle” or “aromatic heterocyclic ring” includes monocyclic 5- or 6-membered aromatic heterocycles comprising as ring members 1, 2, 3 or 4 heteroatoms selected from N, O and S, where S-atoms as ring members may be present as S, SO or SO₂. Examples of 5- or 6-membered aromatic heterocycles include pyridyl (also referred to as pyridinyl), i.e.2-, 3-, or 4-pyridyl, pyrimidinyl, i.e.2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e.2- or 3-thienyl, furyl, i.e.2-or 3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e.2-, 3- or 5-oxazolyl, isoxazolyl, i.e.3-, 4- or 5-isoxazolyl, thiazolyl, i.e.2-, 3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl, pyrazolyl, i.e. 1-, 3-, 4- or 5- pyrazolyl, i.e.1-, 2-, 4- or 5-imidazolyl, oxadiazolyl, e.g.2- or 5-[1,3,4]oxadiazolyl, 4- or 5-(1,2,3- oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or 5-(1,3,4-thiadiazol)yl, thiadiazolyl, e.g.2- or 5-(1,3,4- thiadiazol)yl, 4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl, e.g.1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or 4H-1,2,4-triazolyl and tetrazolyl, i.e.1H- or 2H-tetrazolyl. As used herein, the terms “phenyloxy” and “benzyloxy” (i.e. “phenylmethyloxy”) refer to the corresponding groups, which are bonded to the remainder of the molecule via an oxygen atom. It is to be understood that S-phenyl, S(=O)-phenyl, and S(=O)2-phenyl, refer to the phenyl moiety being bond to the remainder of the molecule as follows:

It is to be understood that according to the present application “(6-Amino-2,2- dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methanol“ refers to the molecule having the following structure:

It may further be referred to as „(6-amino-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol- 4-yl)methanol“. This applies to structures comprising an equal bicycle accordingly. Therefore, e.g. 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)- N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine is a synonym for 7-((3aS,4R,6R,6aR)-6- (aminomethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-methyl-7H- pyrrolo[2,3-d]pyrimidin-4-amine, which both describe the compound of the following formula:

The term “pharmaceutically acceptable excipient” as used herein refers to compounds commonly comprised in pharmaceutical compositions, which are known to the skilled person. Examples of suitable excipients are exemplary listed below. Typically, a pharmaceutically acceptable excipient can be defined as being pharmaceutically inactive. The term “seven-beta-strand family of histone methyltransferases” refers to the respective family of enzymes. Presently, this family comprises DOT1L and KMT9. The term “KMT9” means the heterodimer composed of KMT9 alpha and KMT9beta. The term “KMT9alpha” as used herein refers to the protein “N-6 adenine-specific DNA methyltransferase 1” [Homo sapiens (human)], with the underlying Gene ID: 29104 (updated on 11-Sep-2019, database: https://www.ncbi.nlm.nih.gov/gene). “N6AMT1” or “KMT9alpha” is the corresponding gene. Other names for KMT9alpha are C21orf127, Hemk2, Mtq2, N6amt1, PrmC or PRED28. The sequence of the KMT9alpha protein (isoform 1 [Homo sapiens]) is depicted in SEQ ID NO: 1. The term “KMT9beta” as used herein refers to the protein “tRNA methyltransferase subunit11-2” [Homo sapiens (human)] with the underlying Gene ID: 51504 (updated on 11-Sep-2019, database: https://www.ncbi.nlm.nih.gov/gene). “TRMT112” or “KMT9beta” is the corresponding gene. The sequence of the KMT9beta protein (isoform 2 [Homo sapiens]) is depicted in SEQ ID NO: 2. The term “PROTAC” means “proteolysis-targeting chimeras”. It relates to a chimera consisting of a ligand of a target (here e.g. KMT9) and a ligand of an E3 ubiquitin ligase. By this chimera, the intracellular ubiquitin-proteasome system is used to selectively degrade target proteins. Further information on PROTAC can be derived e.g. from An and Fu, EBioMedicine, 36 (2018), 553-562. Description of pharmaceutical compositions according to the present invention A pharmaceutical composition according to the present invention may be formulated for oral, buccal, nasal, rectal, topical, transdermal, or parenteral application. Preferred non-parenteral routes include mucosal (e.g., oral, vaginal, nasal, cervical, etc.) routes, of which the oral application may be preferred. Preferred parenteral routes include but, are not limited to, one or more of subcutaneous, intravenous, intra-muscular, intraarterial, intradermal, intrathecal, and epidural administrations. Preferably administration is by subcutaneous, intratumoral or peritumoral routes. Particularly preferred is intratumoral administration. The compound according to formula (I) should be applied in pharmaceutically effective amounts, for example in the amounts as set out herein below. A pharmaceutical composition of the present invention may also be designated as formulation or dosage form. A compound of formula (I) may also be designated in the following as (pharmaceutically) active agent, active ingredient, or active compound. Pharmaceutical compositions may be solid or liquid dosage forms or may have an intermediate, e.g. gel-like character depending inter alia on the route of administration. In general, the inventive dosage forms can comprise various pharmaceutically acceptable excipients which will be selected depending on which functionality is to be achieved for the dosage form. A “pharmaceutically acceptable excipient” in the meaning of the present invention can be any substance used for the preparation of pharmaceutical dosage forms, including coating materials, film-forming materials, fillers, disintegrating agents, release-modifying materials, carrier materials, diluents, binding agents, and other adjuvants. Typical pharmaceutically acceptable excipients include substances like sucrose, mannitol, sorbitol, starch and starch derivatives, lactose, and lubricating agents such as magnesium stearate, disintegrants, and buffering agents. The term “carrier” denotes pharmaceutically acceptable organic or inorganic carrier substances with which the active ingredient is combined to facilitate the application. Suitable pharmaceutically acceptable carriers include, for instance, water, aqueous salt solutions, alcohols, oils, preferably vegetable oils, propylene glycol, polyoxyethelene sorbitans, polyethylene- polypropylene block co-polymers such as poloxamer 188 or poloxamer 407, polyethylene glycols such as polyethylene glycol 200, 300, 400, 600, etc., gelatin, lactose, amylose, magnesium stearate, surfactants, perfume oil, fatty acid monoglycerides, diglycerides and triglycerides, polyoxyethylated medium or long chain fatty acids such as ricinoleic acid, and polyoxyethylated fatty acid mono-, di, and triglycerides such as capric or caprilic acids, petroethral fatty acid esters, hydroxymethyl celluloses such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxypropyl acetate succinate, polyvinylpyrrolidone, crosspovidone, and the like. The pharmaceutical compositions can be sterile and, if desired, mixed with auxiliary agents, like lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compound. If liquid dosage forms are considered for the present invention, these can include pharmaceutically acceptable emulsions, solutions, suspensions, and syrups containing inert diluents commonly used in the art such as water. These dosage forms may contain e.g. microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer and sweeteners/flavoring agents. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Pharmaceutical formulations for parenteral administration are particularly preferred and include aqueous solutions of the compounds of formula (I) in water-soluble form. Additionally, suspensions of the compounds of formula (I) may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. In one preferred embodiment, dosage forms are injectable preparations of a compound of formula (I). Thus, sterile injectable aqueous or oleaginous suspensions can for example be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be used are water and isotonic sodium chloride solution. Sterile oils are also conventionally used as solvent or suspending medium. Preferred applications for injectable preparations comprising the compounds of the present invention are intravenous, intratumoral and peritumoral administration. Suppositories for rectal administration of a compound of formula (I) can be prepared by e.g. mixing the compound with a suitable non-irritating excipient such as cocoa butter, synthetic triglycerides and polyethylene glycols which are solid at room temperature but liquid at rectal temperature such that they will melt in the rectum and release the compound according to formula (I) from said suppositories. For administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. In one preferred embodiment the pharmaceutical composition is an oral dosage form. Oral dosage forms may be liquid or solid and include e.g. tablets, troches, pills, capsules, powders, effervescent formulations, dragees, and granules. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. The oral dosage forms may be formulated to ensure an immediate release of the compound of formula (I) or a sustained release of the compound of formula (I). A solid dosage form may comprise a film coating. For example, the inventive dosage form may be in the form of a so-called film tablet. A capsule of the invention may be a two-piece hard gelatin capsule, a two-piece hydroxypropylmethylcellulose capsule, a two-piece capsule made of vegetable or plant-based cellulose or a two-piece capsule made of polysaccharide. The dosage form according to the invention may be formulated for topical application. Suitable pharmaceutical application forms for such an application may be a topical nasal spray, sublingual administration forms and controlled and/or sustained release skin patches. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compositions may conveniently be presented in unit dosage forms and may be prepared by any of the methods well known in the art of pharmacy. The methods can include the step of bringing the compounds into association with a carrier, which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the compounds into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product. Liquid dose units are vials or ampoules. Solid dose units are tablets, capsules and suppositories. As regards human patients, the compound of formula (I) may be administered to a patient in an amount of about 0.001 mg to about 5000 mg per day, preferably of about 0.01 mg to about 1000 mg per day, more preferably of about 0.05 mg to about 250 mg per day, which is the effective amount. The phrase “effective amount” means an amount of compound that, when administered to a mammal in need (i.e. a patient in need) of such treatment, is sufficient to treat or prevent a particular disease or condition. In one embodiment, the pharmaceutical composition may contain the compound of formula (I) in the form of a prodrug. A prodrug is generally any compound, which is converted under physiological conditions or by solvolysis to a more potent compound. A prodrug may be inactive or only slightly active prior to administration but may be converted to an active compound of the invention in vivo. In the present invention, it is assumed by the inventors that compounds where R¹ is C₁-C₄-alkyl, in particular methyl, are most likely prodrugs. Compounds with a corresponding definition of R¹ are in particular of interest if the compound is applied without any penetration- enhancers or the like to cells since the data gained by the inventors show that such compounds are capable of crossing an intact cell membrane while then intracellularly still showing the desired strong inhibitory activity. This effect could easily be explained by the presence of carboxyl esterases (CE) that are basically present in each cell. CE comprise a multigene family capable of hydrolyzing a variety of carboxylic acid esters, wherein the majority of CE isozymes belong to the CE1 and CE2 families. Preferentially, CE1 isozymes hydrolyse compounds esterified with a small alcohol group whereas CE2 isozymes hydrolyze compounds with a relatively small acyl group and a large alcohol group. It is understood that the use of either a prodrug (with the preferred definition of R¹ being C₁-C₄- alkyl and/or R^H as defined) or a compound that has shown to have strong in vitro inhibitory capacity (with the preferred definition of R¹ being H and R^H not being present) depends on the pharmaceutical composition and the route of administration that is used. If a pharmaceutical composition is used that includes a delivery system of an active agent into an intact cell, one would be inclined to use a compound with a strong in vitro inhibitory capacity (with the preferred definition of R¹ being H and R^H not being present), while rather a compound assumed to be a prodrug (with the preferred definition of R¹ being C₁-C₄-alkyl and/or R^H as defined) would be used if the pharmaceutical formulation rather delivers the compound to the cell membrane of an intact cell. Further embodiments of the present application relate to: 1. A compound of formula (I)

or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl), (C₃-C₅-alkyl)-NHR^A, (C₁-C₃-alkyl)-CR^BR^CNH₂, (C₂-C₄-alkyl)- NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)-CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C1-C3-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^M is H or halogen; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C1-C3-alkyl, (C1-C3-alkyl)-phenyl, or (C1-C2-alkyl)-cycloalkyl. 2. The compound according to embodiment 1, wherein R³ is selected from the group consisting of H, methyl, and phenyl. 3. The compound according to embodiment 1 or 2, wherein R² is (C₃-C₄-alkyl)-NHR^A; and wherein R^A is (C₂-C₃-alkyl)-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br. 4. The compound according to embodiment 1 or 2, wherein R² is (C₃-alkyl)-NH-(C₁-C₃-alkyl) or (C₃-alkyl)-NHR^A; and wherein R^A is (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyloxy, or benzyloxy, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; and R^Y is H, halogen, CN, or NO₂. 5. The compound according to embodiment 1 or 2, wherein R² is (C₁-alkyl)-CHR^FR^G; and wherein R^F and R^G together with the carbon atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^Z is H or (C₁-C₂-alkyl)-phenyl. 6. The compound according to embodiment 1 or 2, wherein R² is (C₁-alkyl)-CHR^FR^G; and wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cyclohexyl. 7. The compound according to any one of embodiments 1 to 6, wherein X² is N or CH. 8. The compound according to any one of embodiments 1 to 7, wherein X¹ is CH2 and X² is CH. 9. The compound according to any one of embodiments 1 to 6, wherein R³ is methyl, X¹ is CH₂, and X² is CH. 10. The compound according to embodiment 1, wherein the compound according to formula (I) is selected from the group consisting of (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin- 9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(piperidin-3-yl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-ylmethyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((5-ethylpiperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-(cyclohexylmethyl)piperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-benzylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)- 2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-phenethylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(6- ethylpiperidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(2-(piperidin-3-yl)ethyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(pyrrolidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-3- phenylpropyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-4-((3-((1-acetylazetidin-3-yl)amino)propyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-aminobutanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-(pyrrolidin-2-yl)ethyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- morpholinopropyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6- (phenylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl)(3- (methylamino)propyl)amino)butanoic acid; (2S,2'S)-4,4'-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)azanediyl)bis(2-aminobutanoic acid); (S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((R)-3- aminobutyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-4,4,4-trifluorobutyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-((3-amino-3-methylbutyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-(((S)-3-amino-4- methylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-5-methylhexyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-aminohexyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5- phenylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5-(phenylamino)pentyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-(((S)-3-amino-4-(methylamino)butyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1s,3S)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1r,3R)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-(methylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(4-(methylamino)butyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (phenethylamino)propyl)amino)butanoic acid; methyl (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (phenethylamino)propyl)amino)butanoate; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3- (phenethylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenylpropyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoic acid; methyl (S)-2-amino-4-((((1R,2R,3S,4R)-2,3- dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoate; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((S)-3,4-diamino-4- oxobutyl)amino)butanoic acid; and (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid. 11. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of embodiments 1 to 10 and optionally a pharmaceutically acceptable carrier, diluent, or excipient. 12. A compound according to any one of embodiments 1 to 10 for use in medicine. 13. A compound of formula (I)

formula (I) or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is H, (C₂-C₅-alkyl)-NHR^A, (C₁-C₃-alkyl)-CR^BR^CNH₂, (C₂-C₄-alkyl)-NR^DR^E, (C₁-C₃-alkyl)- cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)-CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is H, C₁-C₃-alkyl, (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^M is H or halogen; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl; for use in the treatment of a cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma, leukemia, colorectal cancer, rectal adenocarcinoma, mesothelioma, endometrium adenocarcinoma, erythroleukemia, medulloblastoma, astrocytoma, Ewing sarcoma, myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, leukemia, myelogenic leukemia, medulloblastoma, myeloid leukemia, acute monocytic leukemia, gallbladder carcinoma, cecum adenocarcinoma, gastric adenocarcinoma, stomach adenocarcinoma, renal cell carcinoma, bladder carcinoma, melanoma, cervical squamous cell carcinoma, pancreatic carcinoma, chondrosarcoma, duodenal adenocarcinoma, rhabdomyosarcoma, hepatocellular carcinoma and uterine adenocarcinoma. 14. A compound for use according to embodiment 13, wherein the compound for use is the compound of formula (I) according to any one of embodiments 1 to 10. 15. A compound for use according to embodiment 13 or 14, wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma and colorectal cancer. The present invention is further illustrated by the following examples. Examples 1. Synthesis of compounds List of abbreviations

Due to the respective synthetically procedure, the compounds according to the following examples may be provided as the corresponding salt thereof, such as e.g. a trifluoroacetate. Reagents and solvents were obtained from commercial sources and used without any further purification. Column chromatography was accomplished using MACHEREY-NAGEL silica gel 60® (230-400 mesh). Thin layer chromatography was performed on aluminum plates pre-coated with silica gel (MERCK, 60F254), which were visualized by UV fluorescence (lmax = 254 nm) and/or by staining with ninhydrin in EtOH. Chemical shifts are reported herein in parts per million (ppm) relative to residual solvent. Data for ¹H-NMR are described as following: chemical shift (d in ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad signal), coupling constant (Hz), integration. Data for ¹³C-NMR are described in terms of chemical shift (d in ppm). For synthesis resulting in compounds 9a to 9k as described in the following, the following analytic methods were used: NMR spectra were acquired on a BRUKER Avance 400 spectrometer (400 MHz and 100.6 MHz for 1H and 13C respectively) or a Bruker 500 DRX NMR spectrometer with TBI probe head (499.6 MHz and 125.6 MHz for 1H and 13C respectively) at a temperature of 303 K unless specified. HR- MS were obtained on a THERMO SCIENTIFIC Advantage and a THERMO SCIENTIFIC Exactive instrument (APCI/MeOH: spray voltage 4-5 kV, ion transfer tube: 250-300 °C, vaporizer: 300-400 °C). Synthesis of compound 9a ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methanol (1).¹⁹ To a solution of adenosine (10.0 g, 37.4 mmol, 1 equiv.) in acetone (1 L), was added CH(OEt)₃ (31.1 mL, 187 mmol, 5 equiv.) and pTsOH (35.6 g, 187 mmol, 5 equiv.) . The mixture was stirred at rt for 16 h, then quenched with aqueous saturated NaHCO₃, concentrated until a precipitate was obtained. The precipitate was dissolved in MeOH/CH₂Cl₂, filtered and evaporated to give the final product (10.5 g, 34.4 mmol, 92%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) d 8.33 (s, 1H), 8.15 (s, 1H), 7.33 (s, 2H), 6.11 (d, J = 3.1 Hz, 1H), 5.33 (dd, J = 6.2, 3.1 Hz, 1H), 5.29 (d, J = 21.9 Hz, 1H), 4.96 (dd, J = 6.2, 2.5 Hz, 1H), 4.20 (td, J = 4.8, 2.5 Hz, 1H), 3.59 – 3.48 (m, 2H), 1.53 (d, J = 0.7 Hz, 3H), 1.31 (d, J = 0.8 Hz, 3H). 1³C NMR (101 MHz, DMSO) d 156.1, 152.5, 148.8, 139.6, 119.0, 113.0, 89.5, 86.3, 83.2, 81.3, 61.5, 27.0, 25.1. R_f : 0.31 (4 % MeOH in CH₂Cl_2; + 2 % NH₃7 M in MeOH). HRMS (ESI): calcd. for C₁₃H₁₇N₅O₄ [M+H ]⁺: 308.13 found: 308.13. 9-((3aR,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)-9H- purin-6-amine (2). To a solution of ((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol (6.50 g, 21.2 mmol, 1 equiv.) in dioxane (70 mL) at 0 °C were added DPPA (9.12 mL, 42.3 mmol, 2 equiv.) and DBU (9.50 mL, 63.5 mmol, 3 equiv.). The mixture was stirred at rt for 16 h. NaN₃ (6.88 g, 106 mmol, 5 equiv.) and 15-crown-5 (4.66 g, 21.2 mmol, 1 equiv.) were added and the mixture was stirred at 110 °C for 6 h. The organic phase was evaporated, water was added and the aqueous phase was extracted three times with EtOAc. The combined organics were washed with brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel column eluting with 30-100% AcOEt in PE to afford the desired product (6.43 g, 19.3 mmol, 91%) as a light yellow solid. ¹H NMR (400 MHz, CDCl₃) d 8.35 (s, 1H), 7.91 (s, 1H), 6.11 (d, J = 2.4 Hz, 1H), 6.06 – 5.91 (m, 2H), 5.46 (ddd, J = 6.4, 2.3, 0.4 Hz, 1H), 5.06 (ddd, J = 6.4, 3.5, 0.5 Hz, 1H), 4.45 – 4.31 (m, 1H), 3.66 – 3.45 (m, 2H), 1.61 (d, J = 0.7 Hz, 3H), 1.39 (d, J = 0.7 Hz, 3H). 1³C NMR (101 MHz, CDCl₃) d 155.8, 153.2, 149.3, 140.0, 120.4, 114.8, 90.8, 85.7, 84.1, 82.2, 52.4, 27.2, 25.4. R_f : 0.41 (95:5 CH₂Cl₂/MeOH). HRMS (ESI): m/z [M +H]⁺ calcd. for C₁₃H₁₇N₈O₃ : 333.13 found: 333.13. tert-butyl (9-((3aR,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)-9H-purin-6-yl)carbamate (3). To a solution of 2 ( 2.47 g, 7.4 mmol, 1 eq) in dry THF (C = 0.3 M, V = 25 mL) at 0°C under argon was added portionwise 60 % suspended NaH in oil (744 mg, 18 mmol, 2.5 eq). After 45 min at room temperature, Boc₂O was added (1.776 g, 8.14 mmol, 1.1 eq) in 3 mL dry THF at 0°C. After 1 h 30 min at room temperature, Boc2O (807 mg, 3.7 mmol, 0.5 eq) was added at 0°C and the reaction was stirred at room temperature for 1 h 30 min. After that, reaction was quenched with NaCl at 0°C, extracted with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified on silica gel column eluting with 10–100% AcOEt in cyclohexane to afford the desired product (661 mg, 1.53 mmol, 80%) as a light yellow solid. 1H NMR (400 MHz, CDCl₃) d 8.77 (s, 2H), 8.09 (s, 2H), 6.15 (d, J = 2.4 Hz, 1H), 5.46 (dd, J = 6.4, 2.4 Hz, 1H), 5.05 (dd, J = 6.5, 3.6 Hz, 2H), 3.58 (d, J = 5.5 Hz, 2H), 1.63 (d, J = 0.7 Hz, 3H), 1.54 (s, 9H), 1.39 (d, J = 0.7 Hz, 3H). R_f : 0.76 (Ethyl Acetate) HRMS (ESI) : m/z [M +H]⁺ calcd. for C₁₈H₂₅N₈O₅: 433.19 found: 433.19. tert-butyl (9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)-9H-purin-6-yl)carbamate (4). To a solution of 3 (2.56 g, 5.9 mmol, 1eq) in AcOEt/MeOH (1:1, 19 mL) was added Pd/C (256 mg, 10 % w/w). The suspension was put under H₂ and stirred for 16 h at room temperature. The solution was then filtrated on celite and evaporated to afford the desired product as a grey foam (2.39 g, quant). 1H NMR (300 MHz, CDCl₃) d 8.75 (s, 1H), 8.06 (s, 1H), 7.96 (d, J = 12.3 Hz, 1H), 6.07 (d, J = 3.0 Hz, 1H), 5.47 (dd, J = 6.5, 3.1 Hz, 1H), 5.02 (dd, J = 6.5, 3.5 Hz, 1H), 4.27 (ddd, J = 6.0, 4.5, 3.5 Hz, 1H), 3.10 – 2.88 (m, 2H), 1.63 (d, J = 0.7 Hz, 3H), 1.57 (s, 9H), 1.39 (d, J = 0.7 Hz, 3H). R_f : 0.42 (95:5 CH₂Cl₂/MeOH + 1 % Et₃N). HRMS (ESI) : m/z [M +H]⁺ calcd. for C₁₈H₂₇N₆O₅: 407.20 found: 407.20. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)butanoate (6). To a stirred solution of 4 (3.79 g, 9.23 mmol, 1.1 eq.) and aldehyde 5 (2.32 g, 8.39 mmol, 1 eq.) in dry DCE (0.12 ^M based on the aldehyde) was added AcOH (533 µL, 9.23 mmol, 1.1 eq.). The solution was stirred for 4 h at rt, then NaBH(OAc)₃ (4.67 g, 21.82 mmol, 2.6 eq.) was added and the mixture was stirred for 4 h at rt. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na2SO4, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.5:0.5–90.5:9.5) to afford the secondary amine 6 (2.4 g, 3.6 mmol, 43 %). C₃₁H₄₉N₇O₉ (663.77 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 10.14 (bs, 1H, NH carbamate nucleobase), 8.62 (s, 1H, H2), 8.61 (s, 1H, H8), 7.15 (d, ³J = 8.0 Hz, 1H, NH carbamate), 6.17 (d, ³J = 2.7 Hz, 1H, H1'), 5.47 (dd, ³J = 6.0 Hz, 2.7 Hz, 1H, H2'), 4.99 (dd, ³J = 6.0 Hz and ³J = 2.7 Hz, 1H, H3'), 4.22 (td, ³J = 5.6 Hz and ³J = 2.8 Hz, 1H, H4'), 3.94–3.87 (m, 1H, Ha), 2.73 (dd, ²J = 12.4 Hz and ³J = 5.8Hz, 1H, H5_A'), 2.61 (dd, ²J = 12.4 Hz and ³J = 5.8 Hz, 1H, H5B'), 2.56–2.45 (m, 2H, Hg), 1.75–1.71 (m, 1H, HbA), 1.66-1.60 (m, 1H, HbB), 1.55 (s, 3H, CH₃), 1.47 (s, 9H, CH₃ tBu), 1.41–1.29 (m, 22H, CH₃, 2 x CH₃ tBu); HRMS (ESI): calcd. for C₃₁H₅₀N₇O₉ ^M+H ^⁺: 664.3665, found: 664.3661. General procedure for the second reductive amination (8). To a solution of 6 (1eq) and MgSO₄ (1.5 eq) in dry MeOH (0.1 M) was added the respective aldehyde (1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 – 95:5 CH₂Cl₂/MeOH to afford the tertiary amine 8 as yellow oil. General prodecure for the final deprotection (9). The tertiary amine 8 were dissolved (0.02 M) in freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9 as TFA salts as a light yellow foam. tert-butyl (tert-butoxycarbonyl)-L-homoserinate (10). To a solution of (S)-4-(tert-butoxy)-3- ((tert-butoxycarbonyl)amino)-4-oxobutanoic acid (500 mg, 1.73 mmol, 1 eq) and Et₃N (265 ^L, 1.90 mmol, 1.1 eq) in dry THF (6.9 mL) was added isobutyl chloroformate (247 ^L, 1.90 mmol, 1.1 equiv.) at -5 °C. The mixture was stirred for 30 min, then filtered. The solution containing (S)-(S)- 4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic (ethyl carbonic) anhydride was recovered, cooled at 0 °C, MeOH (6.9 mL) and NaBH₄ (131 mg, 3.46 mmol, 2 equiv.) were added portionwise. The solution was then stirred at rt for 2 h. The reaction was quenched with diluted ammonium chloride, extract three times with EtOAc. The combined organics were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified on silica gel column eluting with 20-100% AcOEt in cyclohexane to afford the desired product (345 mg, 0.77 mmol, 45%) as a colorless oil. 1H NMR (400 MHz, CDCl₃) d 5.33 (d, J = 7.8 Hz, 1H), 4.42 – 4.28 (m, 1H), 3.80 – 3.57 (m, 2H), 3.44 (br s, 1H), 2.12 (ddt, J = 17.7, 12.8, 7.0 Hz, 1H), 1.69-1.49 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H). 1³C NMR (101 MHz, CDCl₃) d 172.1, 156.7, 82.4, 80.4, 58.4, 51.1, 36.7, 28.4, 28.1. Rf : 0.26 (67:33 cyclohexane/AcOEt ) HRMS (ESI) : m/z [M +H]⁺ calcd. for C₁₃H₂₆NO₅: 276.17 found: 276.18. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (5). To a solution of oxalyl chloride (1.17 mL, 13.6 mmol, 1.5 equiv.) in dry CH₂Cl₂ (30 mL) at -78 °C was added DMSO (2.15 mL, 18.2 mmol, 2 equiv.) in CH₂Cl₂ (5 mL). After 15 min, tert-butyl (tert-butoxycarbonyl)-L- homoserinate (2.50 g, 9.08 mmol, 1 equiv.) in CH₂Cl₂ (10 mL) was added. After 30 min, NEt₃ was added (6.30 mL, 45.4 mmol, 5 equiv.) and the mixture was allowed to return at rt. The organic phase was washed with a solution of citric acid (5% w/w), then aqueous saturated NaHCO₃, brine, dried over Na₂SO₄, evaporated. The residue was purified on silica gel column (10-100% AcOEt in cyclohexane) to afford the desired product (1.96 g, 79%) as a colorless oil. 1H NMR (400MHz, CDCl₃) 9.75 (s, 1H), 5.35 (m, 1H), 4.42 (m, 1H), 2.84-3.06 (m, 2H), 1.4 (s, 18H). 1³C NMR (101 MHz, CDCl₃) d 199.3, 170.0, 155.4, 82.7, 80.1, 49.5, 46.4, 28.4, 27.9. Rf : 0.44 (76:33 cyclohexane/AcOEt). HRMS (ESI) : m/z [M +H]⁺ calcd. for C₁₃H₂₄NO₅: 274.16 found: 274.16. tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate (11). In 2.7 mL of THF was added piperidin- 3-yl-methanol (0.500 g, 4.34 mmol, 1eq) and a solution of Boc anhydride (1.04 g, 4.8 mmol, 1.1 eq) in 10.8 mL of THF dropwise. The reaction mixture was stirred under argon at room temperature for 4 h. The reaction mixture was washed with 10 mL saturated NH4Cl, extracted 3 x 10 mL of AcOEt, the organic layer was dried with MgSO4, and concentrated in vacuo and the product was used without further purification.¹ ¹H NMR (300 MHz, DMSO-d₆) d 4.48 (t, J = 5.3 Hz, 1H), 3.92 (s, 1H), 3.86 – 3.72 (m, 1H), 3.30 – 3.11 (m, 2H), 2.79 – 2.59 (m, 1H), 1.71 – 1.42 (m, 4H), 1.39 (s, 9H), 1.34 – 0.92 (m, 2H). HRMS (ESI) : m/z [M+H]+ calcd. for C11H22NO3 : 216.15 found: 216.16. tert-butyl 3-formylpiperidine-1-carboxylate (12). Dimethyl sulfoxide (0.8 mL,11.5 mmol, 5 eq) was added at –78 °C to a solution of oxalyl chloride (0.5 mL, 5.75 mmol, 2.5 eq) in dichloromethane (6 mL). After having been stirred for 30 min at –78 °C, the reaction mixture was treated with the solution of the above Boc-carbamate (0.5 g, 2.3 mmol) in dichloromethane (23 mL), stirred for 1 h at –78 °C, treated with triethylamine (5 mL, 36.8 mmol, 16 eq) and allowed to warm up to room temp for 1 h. The solution was washed with citric acid 5%, NaHCO₃, brine, dried with Na₂SO₄ and concentrated to afford the desired product which was used without purification.² ¹H NMR (300 MHz, Chloroform-d) d 9.74 – 9.62 (m, 1H), 3.90 (t, J = 13.6 Hz, 1H), 3.71 – 3.52 (m, 1H), 3.32 (dd, J = 13.5, 8.2 Hz, 1H), 3.20 – 3.01 (m, 2H), 2.42 (d, J = 1.7 Hz, 1H), 1.95 (m, 1H), 1.75 – 1.55 (m, 2H), 1.45 (s, 9H). HRMS (ESI) : m/z [M - H]⁺ calcd. for C₁₁H₁₈NO₃ : 212.14 found: 212.13. tert-butyl 3-(((((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)methyl)piperidine-1-carboxylate (13). To a mixture of 4 (200 mg, 0.49 mmol, 1 eq) and Na₂SO₄ (104 mg, 0.735 mmol, 1.5 eq) in dry DCM ( 3 mL) under argon, was added dropwise 12 (115 mg, 0.54 mmol, 1.1 eq). The reaction mixture was stirred for 3 h, decanted and the solvent evaporated to give the crude imine, which was used without further purification. To a solution of the imine (0.49 mmol) in 3 mL dry MeOH at 0°C was added sodium borohydride NaBH₄ (37 mg, 0.98 mmol, 2 eq) in small portion as a solid. The reaction mixture was allowed to warm to room temperature. After 1 h and 2 h respectively, NaBH4 (1.8 mg, 0.049 mmol, 0.1 eq) was added and the reaction was stirred for further 16 h at room temperature. The mixture was extracted with AcOEt, washed with citric acid 5%, NaHCO₃. The organic layers were washed with brine, dried over Na₂SO₄ and evaporated. The residue was purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the desired product (120 mg, 41%) as a white oil. 1H NMR (500 MHz, Acetone-d6) d 8.59 (d, J = 2.1 Hz, 1H), 8.47 (s, 1H), 6.21 (t, J = 3.2 Hz, 1H), 5.58 (td, J = 6.3, 3.1 Hz, 1H), 5.12 (ddd, J = 9.3, 6.3, 2.9 Hz, 1H), 4.34 (tt, J = 5.4, 2.6 Hz, 1H), 4.05 (dd, J = 13.3, 3.9 Hz, 1H), 3.88 – 3.76 (m, 1H), 2.92 – 2.73 (m, 9H), 2.54 – 2.37 (m, 2H), 1.57 (s, 3H), 1.53 (s, 9H), 1.44 – 1.31 (m, 12H). 1³C NMR (126 MHz, Acetone-d₆) d 155.1, 152.9, 151.9, 151.2, 150.9, 143.5 and 143.4, 124.2, 114.5, 91.5 and 91.4, 86.73, 84.30, 83.37, 81.37, 79.08, 53.84, 52.27, 52.20, 37.15, 28.58, 28.27, 27.56, 27.55, 25.99, 24.9. R_f : 0.38 (95:5 CH₂Cl₂/MeOH). HRMS (ESI): m/z [M + H]⁺ calcd. for C₂₉H₄₆N₇O₇: 604.34 found: 604.34. tert-butyl 3-(((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)methyl)piperidine-1-carboxylate (8a). To a solution of 13 (122.6 mg, 0.2 mmol, 1eq) and MgSO₄ (36 mg, 0.3 mmol, 1.5 eq) in dry MeOH (2 mL) was added 5 (61 mg, 0.22 mmol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH3CN (37 mg, 0.6 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8a ( 45.8 mg, 26 %) as yellow oil. 1H NMR (400 MHz, Acetone-d₆) d 9.02 (s, 1H), 8.62 (d, J = 5.0 Hz, 1H), 8.45 (d, J = 1.2 Hz, 1H), 6.27 (d, J = 2.1 Hz, 1H), 6.25 – 6.17 (m, 1H), 5.64 (td, J = 6.7, 2.1 Hz, 1H), 5.28 – 5.19 (m, 1H), 5.15 (dd, J = 6.3, 3.1 Hz, 1H), 4.45 – 4.28 (m, 1H), 4.28 – 3.99 (m, 1H), 3.98 – 3.75 (m, 1H), 2.99 – 2.13 (m, 10H), 2.02 – 1.65 (m,3H), 1.65 – 1.56 (m, 4H), 1.54 (s, 9H), 1.45 (2 x s,18H), 1.43 (s, 3H), 1.42 – 1.38 (m, 9H). 1³C NMR (101 MHz, Acetone-d₆) d 173.04, 172.81, 155.37 and 155.30, 153.09, 151.97, 151.50, 151.21, 144.08, 124.47, 114.68 and 114.63, 91.89, 91.77, 86.71, 84.91, 84.89, 84.80, 81.67, 81.47 and 81.40, 79.45 and 79.38, 79.20, 59.88, 59.66, 57.97, 57.52, 53.96, 52.39, 35.53, 30.68, 28.96, 28.92 and 28.90, 28.55, 28.49, 27.77, 25.99. R_f : 0.30 (95:5 CH₂Cl₂/MeOH). HRMS (ESI): m/z [M + H]⁺ calcd. for C₄₂H₆₉N₈O₁₁: 861.50 found: 861.50. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-ylmethyl)amino)butanoic acid (9a). The tertiary amine 8a (45.8 mg, 0.053 mmol) were dissolved in 2.6 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9a (54.5 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (400 MHz, Deuterium Oxide) d 8.50 (d, J = 1.7 Hz, 1H), 8.48 (d, J = 2.7 Hz, 1H), 6.22 (dd, J = 3.4, 1.6 Hz, 1H), 4.97–4.84 (m, 1H), 4.62–4.47 (m, 3H), 4.13–4.08 (m, 1H), 3.80 (d, J = 6.2 Hz, 2H), 3.74–3.38 (m, 3H), 3.38–3.27 (m, 2H), 2.98–2.90 (m, 1H), 2.87–2.71 (m, 1H), 2.56–2.23 (m, 1H), 2.19–1.84 (m, 3H), 1.77–1.65 (m, 1H), 1.51–1.20 (m, 2H). HRMS (ESI) : m/z [M + H]⁺ calcd. for C₂₀H₃₃N₈O₅ : 455.25 found: 465.26. Synthesis of the compound 9b methyl 5-vinylnicotinate (14).To a solution of methyl 5-bromo-nicotinate (668 mg, 3.09 mmol, 1 eq) in anhydrous toluene (7.8 ml), a few crystals of 2,6-di-tert.-butyl-4- methylphenol, Pd(PPh₃)₄ (142 mg, 0.12 mmol, 0.04 eq) and vinyl tri-n-butylstannane (4751.35 mL, 4.6 mmol, 1.5 eq) were added under argon. The mixture was refluxed for 3 h. After cooling, the residue was filtered using celite and the filtrate was treated with ethyl acetate (10 ml), water (20 ml), and saturated aqueous KF solution. The organic layer was separated, dried and concentrated in vacuo. The residue was purified on silica gel column eluting with 90:10 to 70:30 cyclohexane/AcOEt to afford the desired product as colorless needles. M.p.: 50-60 °C.³ ¹H NMR (300 MHz, Chloroform-d) d = 9.09 (d, J = 2.0 Hz, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.33 (dd, J = 2.0 Hz, J = 2.2Hz, 1H), 6.75 (dd, J = ll.0 Hz, J = 17.6Hz, 1H), 5.93 (d, J = 17.6 Hz, 1H), 5.48 (d, J = ll.0 Hz, 1H,), 3.97 (s, 3H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₉H₁₀NO₂ : 164.06 found: 164.07. methyl 5-ethylpiperidine-3-carboxylate (15). The compound 14 (168 mg, 1 mmol) and Platinum oxide (29 mg, 15 % mol w/w) was solubilised in acetic acid (1.7 ml) and placed in a autoclave. The atmosphere was replaced twice with argon before the introduction of the hydrogen gas. The autoclave was pressurised with H₂ gas (40 bar) and the solution stirred at 40 °C for 48 h. The atmosphere was repalced with argon, the mixture filtered over celiteand the filtrate was concentrated in vacuo to afford the corresponding piperidine as acetic acid salt (67.5 mg, 38%) which was used without purification. 1H NMR (300 MHz, Chloroform-d) d 3.71 (s, 3H) and 3.67 (s, 3H), 3.30 (s, 2H) and 3.25 (s, 2H), 3.03 (t, J = 14.8 Hz, 3H), 2.80 (d, J = 3.7 Hz, 1H) and 2.75 (d, J = 3.8 Hz, 1H), 2.47 (tt, J = 11.7, 3.7 Hz, 2H), 2.30 (m, 1H), 1.44–1.13 (m, 8H), 0.90 (t, J = 3.7 Hz, 6H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₉H₁₈NO₂ : 172.13 found: 172.13. 1-(tert-butyl) 3-methyl 5-ethylpiperidine-1,3-dicarboxylate (16). The crude of 15 (67.5 mg, 0.39 mmol, 1 eq) was stirred with DMAP (0.96 mg, 7.9 ^mol, 0.02 eq) in dichloromethane (0.7 mL) at 0°C was added di-tert-butyl dicarbonate (86 mg, 0.39 mmol, 1 eq) very slowly. The mixture was stirred at rt for 16 h.The solution was quenched with brine, extracted with AcOEt, dried with Na₂SO₄ and purified on silica gel column eluting with 95:5 to 90:10 petrolium ether/AcOEt) to afford the desired product as a light yellow oil (47.7 mg, 45%).⁴ ¹H NMR (500 MHz, Chloroform-d) d 4.32 (d, J = 13.2 Hz, 1H), 4.23–4.05 (m, 1H), 3.68 (s, 3H), 2.68 (dd, J = 13.2, 11.6 Hz, 1H), 2.45 (tt, J = 11.9, 4.0 Hz, 1H), 2.27–2.10 (m, 2H), 1.46 (s, 9H), 1.31–1.10 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₁₄H₂₆NO₄ : 272.18 found: 272.18. tert-butyl 3-ethyl-5-formylpiperidine-1-carboxylate (17). Compound 16 (47.7 mg, 0.17 mmol, 1 eq) was dissolved in dichloromethane (0.6 mL ) under argon atmosphere and treated dropwise with diisobutylöaluminium hydride (24 ^l of a 1 M DCM solution, 0.21 mmol, 1.2 eq) at -78 °C. After stirring for 2 h at -78°C, the reaction was quenched by cautions with a saturated solution of Rochelle´s salt and stirred 1 h at room temperature and then extracted with AcOEt , dried over Na₂SO₄, filtered and evaporated to afford the desired compound (55,4 mg) used without further purification.⁵ ¹H NMR (300 MHz, Chloroform-d) d 9.66 (d, J = 0.9 Hz, 1H), 4.36 (br s, 1H), 4.26 (br s, 1H), 2.64 (t, J = 12.4 Hz, 1H), 2.54–2.37 (m, 1H), 2.37–2.13 (m, 2H), 1.46 (d, J = 1.3 Hz, 9H), 1.40–1.22 (m, 4H), 0.93 (t, J = 7.4 Hz, 3H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₁₃H₂₄NO₃ : 242.17 found: 242.17 tert-butyl 3-(((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)methyl)-5-ethylpiperidine-1-carboxylate (8b). To a solution of 6 (139 mg, 0.21 mmol, 1eq) and MgSO₄ (39 mg, 0.32 mmol, 1.5 eq) in dry MeOH (2.1 mL) was added 17 (55.4 mg, 0.23 mmol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (40 mg, 0.63 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8b ( 11.5 mg, 6 %) as yellow oil. 1H NMR (300 MHz, Acetone-d₆) d 8.73–8.51 (m, 1H), 8.45 (s, 1H), 6.36–6.06 (m, 2H), 5.62 (s, 1H), 5.29–4.96 (m, 2H), 4.45–4.19 (m, 2H), 4.12 (s, 1H), 3.59 (s, 1H), 2.72–2.36 (m, 4H), 2.34–2.15 (m, 12H), 1.77–1.08 (m, 41H), 1.08–0.77 (m, 3H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₄₄H₇₃N₈O₁₁ : 889.53 found: 889.54. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-ethylpiperidin-3-yl)methyl)amino)butanoic acid (9b). The tertiary amine 8b (11.5 mg, 13 ^mol) were dissolved in 0.6 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9b (21.4 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.49 (d, J = 3.7 Hz, 1H), 8.48 (s, 1H), 6.20 (d, J = 4.2 Hz, 1H), 4.67–4.35 (m, 2H), 4.35–4.11 (m, 1H), 4.05–3.89 (m, 1H), 3.89–3.67 (m, 2H), 3.67–3.25 (m, 3H), 2.99 (d, J = 11.9 Hz, 2H), 2.86–2.53 (m, 1H), 2.38 (s, 4H), 2.28–2.01 (m, 1H), 1.48–1.11 (m, 3H), 1.05– 0.70 (m, 5H). HRMS (ESI) : m/z [M - h]⁺ calcd. for C₂₂H₃₅N₈O₅ : 491.28 found: 491.27. Synthesis of the compound 9c Methylenecyclohexane (18). Sodium hydride (555 mg, 193.9 mmol, 1 eq) as a 60% dispersion in mineral oil) already washed with several portions of petroleum ether to remove the mineral oil. The flask then was equipped with rubber stopples, a reflux condenser connected to the vacuum line, and a magnetic stirrer. The system was alternatively evacuated and filled with argon for three times; 7 mL dry dimethylsulfoxide was introduced, and the mixture was heated at 75-80°C for 45, until the evolution of ydrogen ceased. The resulting solution was cooled in an ice-water bath, and (5.21g, 13.9 mmol, 1 eq) methyltriphenylphosphonium bromide in 13.9 mL warm dimethyl sulfoxide was added. The resulting yellow solution was stirred at room temperature for 10 min before use. Cyclohexanone (1.5 g, 15.3 mmol, 1.1 eq), was added to the ylide solution, and the reaction mixture was stirred at room temperature for 30 min. followed immediately by the distillation under reduced pressure ((b.p.48~56°C at 100 mmHg pressure, collected in an ice water/salt bath) to give 526.5 mg of 18 (39% yield) as a clear liquid.⁵ ¹H NMR (300 MHz, CDCl3) d 4.58 (s, 2H), 2.20 – 2.06 (m, 4H), 1.54 (m, 6H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₇H₁₃ ^M+H ^⁺: 97.09 found: 97.10. methyl 5-(cyclohexylmethyl)nicotinate (19).9-BBN (0,5 M in THF, 6.64 mL, 3.32 mmol, 2 eq) was slowly added to the alkene 18 (160 mg, 1.66 mmol, 1 eq) in a dry flask at 0°C under argon. The mixture was warmed to room temperature and stirred for 4 h. Then K₃PO₄ (3 M in H₂O, 1.8 mL, 5 mmol, 3 eq) was added slowly followed by the addition of methyl 5-bromo-nicotinate (395 mg, 1.8 mmol, 1.1 eq) in dry degassed DMF/THF 3 :1 (20 mL) and finally PdCl₂(dppf) (121 mg, 5 mol%). The reaction mixture was stirred for 16 h at 70°C, cooled to room temperature, and then diluted with AcOEt and saturated NaHCO₃. The aqueous layer was reextracted with AcOEt.The organic layer was washed with brine, dried over Na2SO4 and evaporated to give crude product which was purified using silica gel column eluting with 90:10 to 70:30 petrolium ether/AcOEt to afford the desired product 23 (221.4 mg, 57%) as yellow oil.⁶ ¹H NMR (300 MHz, Chloroform-d) d 9.08 (s, 1H), 8.54 (s, 1H), 8.07 (s, 1H), 3.98 (s, 3H), 2.53 (d, J = 7.0, 2H), 1.89 (m, 1H), 1.71 (m, 5H), 1.24 (m, 2H), 1.01 (m, 2H). HRMS (ESI) : m/z [M + h]⁺ calcd. for C₁₄H₂₀NO₂ ^M+H ^⁺: 234.14 found: 234.15. methyl 5-(cyclohexylmethyl)piperidine-3-carboxylate (20). The compound 19 (221.4 mg, 0.95 mmol) and Platinum oxide (39 mg,15 % mol w/w) was solubilised in acetic acid (2.4 ml) and placed in a autoclave. The atmosphere was replaced twice with argon before the introduction of the hydrogen gas. The autoclave was pressurised with H₂ gas (40 bar) and the solution stirred at 40 °C for 48 h. The atmosphere was repalced with argon, the mixture filtered over celiteand the filtrate was concentrated in vacuo to afford the corresponding piperidine as acetic acid salt which was washed with NaHCO₃, extracted with DCM, dried over Na₂SO₄, filtrated and evaporated to afford the desired compound 20 (182 mg, 80%) which was used without purification. 1H NMR (300 MHz, Chloroform-d) d 3.71 (s, 3H) and 3.67 (s, 3H), 3.27 (d, J = 11.6 Hz, 2H), 2.98 (t, J = 15.6 Hz, 2H), 2.81–2.70 (m, 1H), 1.88–1.81 (m, 5H), 1.69–1.61 (m, 2H), 1.59–1.37 (m, 6H), 1.37–1.11 (m, 3H), 1.11–0.98 (m, 2H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₄H₂₆NO₂ : 240.19 found: 240.19. 1-(tert-butyl) 3-methyl 5-(cyclohexylmethyl)piperidine-1,3-dicarboxylate (21). The crude of 20 (182 mg, 0.76 mmol, 1 eq) was stirred with DMAP (1.8 mg, 0.015 mmol, 0.02 eq) in dichloromethane (1.2 mL) at 0°C was added di-tert-butyl dicarbonate (166 mg, 0.76 mmol, 1 eq) very slowly. The mixture was stirred at rt for 16 h. The solution was quenched with brine, extracted with AcOEt, dried with Na₂SO₄ and purified on silica gel column eluting with 95:5 to 50:50 petrolium ether/AcOEt) to afford the desired product as a light yellow oil (60.6 mg, 25%).⁴ ¹H NMR (300 MHz, Chloroform-d) d 4.30 (s, 1H), 4.10 (s, 1H), 3.68 (s, 3H), 2.68 (t, J = 12.5 Hz, 1H), 2.46 (ddd, J = 11.5, 7.9, 3.9 Hz, 1H), 2.24–2.05 (m, 2H), 1.69 (d, J = 12.2 Hz, 3H), 1.46 (s, 9H), 1.41– 0.76 (m, 14H). HRMS (ESI) : m/z ^M+Na ^⁺ calcd. for C₁₉H₃₃NO₄ + Na: 362.23 found: 362.23. tert-butyl 3-(cyclohexylmethyl)-5-formylpiperidine-1-carboxylate (22). Compound 21 (54.9 mg, 0.16 mmol, 1 eq) ) was dissolved in dichloromethane (0.6 mL ) under argon atmosphere and treated dropwise with diisobutylöaluminium hydride (22 ^l of a 1 M DCM solution, 0.19 mmol, 1.2 eq) at -78 °C. After stirring for 2 h at -78°C, the reaction was quenched by cautions with a saturated solution of Rochelle´s salt and stirred 1 h at room temperature and then extracted with AcOEt , dried over Na₂SO₄, filtered and evaporated to afford the desired compound (57.8 mg) used without further purification.⁵ ¹H NMR (300 MHz, Chloroform-d) d 9.66 (t, J = 1.3 Hz, 1H), 4.35 (s, 1H), 4.15 (s, 1H), 2.70–2.30 (m, 1H), 1.94–1.79 (m, 1H), 1.75–1.56 (m, 11H), 1.46 (d, J = 35.1 Hz, 9H), 1.39–0.67 (m, 6H). HRMS (ESI) : m/z ^M-H ^⁺ calcd. for C₁₈H₃₀NO₃: 308.23 found:308.22 tert-butyl 3-(((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)methyl)-5-(cyclohexylmethyl)piperidine-1-carboxylate (8c). To a solution of 6 (112 mg, 0.17 mmol, 1eq) and MgSO₄ (31 mg, 0.25 mmol, 1.5 eq) in dry MeOH (1.9 mL) was added 22 (55.4 mg, 0.19 mmol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (32 mg, 0.51 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8c ( 46.9 mg, 28 %) as yellow oil. 1H NMR (300 MHz, Acetone-d₆) d 8.97 (s, 1H), 8.63–8.58 (m, 1H), 8.45 (td, J = 3.3, 2.1 Hz, 1H), 6.26 (t, J = 2.2 Hz, 1H), 5.61 (s, 1H), 5.20–5.08 (m, 1H), 4.22 (d, J = 13.0 Hz, 5H), 3.65 (s, 5H), 3.50– 3.41 (m, 5H), 3.35 (t, J = 8.7 Hz, 5H), 2.67–2.53 (m, 1H), 2.46 (ddt, J = 12.9, 6.0, 3.1 Hz, 1H), 1.88– 1.58 (m, 3H), 1.54 (d, J = 1.4 Hz, 12H), 1.43 (s, 30H), 1.31–0.68 (m, 8H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₄₉H₈₁N₈O₁₁ : 957.59 found: 957.60. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-(cyclohexylmethyl)piperidin-3-yl)methyl)amino)butanoic acid (9c). The tertiary amine 8c (26 mg, 27 ^mol) were dissolved in 1.3 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9c (16.6 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.51–8.46 (m, 2H), 6.25–6.19 (m, 1H), 4.64–4.46 (m, 1H), 3.62–3.57 (m, 3H), 3.57–3.26 (m, 8H), 2.99 (s, 1H), 2.72–2.64 (m, 3H), 2.57 (t, J = 12.3 Hz, 2H), 2.38 (s, 1H), 2.11–1.85 (m, 5H), 1.43–1.24 (m, 2H), 1.18–1.02 (m, 3H), 0.98–0.89 (m, 6H). HRMS (ESI) : m/z ^M-H ^⁺ calcd. for C₂₇H₄₃N₈O₅ : 559.34 found: 559.34. Synthesis of the compound 9d methyl 5-benzylnicotinate (23). LiCl (212 mg, 5 mmol, 2.5 eq) and InCl₃ (146 mg, mg, 0.66 mmol, 0.33 eq) were added in a Schlenk-flask, and dried for 5min in high vacuum and then dissolved in 4 mL dry THF. The organic halide benzyl bromide (0.238 mL, 2 mmol,1 eq) was added and the mixture was stirred for 2 min at 25°C. Magnesium turnings (121.5 mg, 5 mmol, 2.5 eq) were added and the reaction mixture was stirred for 2 h at 25°C. Then, the supernatant solution was added to a solution of Pd(OAc)₂ (9 mg, 0.04 mmol), S-Phos (32 mg, 0.08 mmol) and the organic halide methyl 5-bromo-nicotinate (346 mg, 1.6 mmol, 0.8 eq) in dry THF (2 mL). The mixture was stirred for 16 h at 50°C. Then, sat. aq. NH4Cl was added and the aqueous layer was extracted with AcOEt, dried over Na2SO4, filtered evaporated and purified using silica gel column eluting with 80:20 cylohexane/AcOEt to afford the desired compounds 28 (189 mg, 52%) as yellow oil.⁷ ¹H NMR (400 MHz, Chloroform-d) d 9.07 (d, J = 2.0 Hz, 1H), 8.65 (d, J = 2.2 Hz, 1H), 8.11 (t, J = 2.2 Hz, 1H), 7.37–7.29 (m, 2H), 7.24–7.12 (m, 3H), 4.04 (s, 2H), 3.93 (s, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₄H₁₄NO₂ : 228.09 found: 228.10. methyl 5-benzylpiperidine-3-carboxylate (24). The compound 23 (189 mg, 0.86 mmol) and Platinum oxide (3.8 mg, 2 % mol w/w) was solubilised in acetic acid (2 ml). The atmosphere was replaced twice with argon before the introduction of the hydrogen gas using normal ballon (1 bar) and the solution stirred at room temperature for 48 h. The mixture was filtered over celite and the filtrate was concentrated in vacuo to afford the corresponding piperidine as acetic acid salt (193 mg, quant) which was used directly for the next step. 1H NMR (300 MHz, Chloroform-d) d 7.29 (dt, J = 6.8, 1.7 Hz, 1H), 7.24–7.19 (m, 1H), 7.15–7.08 (m, 2H), 3.74 (s, 3H), 3.59–3.48 (m, 1H), 3.48–3.38 (m, 1H), 3.29–3.14 (m, 1H), 3.07 (d, J = 4.0 Hz, 1H), 3.03 (d, J = 4.0 Hz, 1H), 2.92–2.73 (m, 3H), 2.66–2.49 (m, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₄H₂₀NO₂: 234.14 found: 234.15. 1-(tert-butyl) 3-methyl 5-benzylpiperidine-1,3-dicarboxylate (25). The crude 24 (193 mg, 0.83 mmol, 1 eq) was dissolved in THF (5.2 mL) under argon and Et₃N (0.115 mL, 0.83 mmol, 1 eq) was added and the reaction stirred for 10 min at room temperature. Then di-tert-butyldicarbonate 235 mg, 1 mmol, 1.3 eq) were added and the mixture was stirred for 48 h at room temperature. The mixture was quenched with brine, extracted with AcOEt. The combined organics dried over Na₂SO₄ and concentrated in vacuo. The residue purified using silica gel column eluting with 90:10 to 50:50 cyclohexane/AcOEt to afford the desired compound 25 (88 mg, 32%) as yellow oil.⁸ ¹H NMR (500 MHz, Chloroform-d) d 7.31–7.26 (m, 2H), 7.22–7.12 (m, 3H), 4.31 (s, 1H), 3.66 (2 x s, 3H), 3.27 (s, 1H), 2.76–2.48 (m, 2H), 2.47–2.40 (m, 1H), 2.31 (t, J = 12.3 Hz, 1H), 2.18–2.04 (m, 1H), 1.96 (s, 1H), 1.75 (s, 1H), 1.43 (2 x s, 9H), 1.34–1.19 (m, 1H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₉H₂₈NO₄: 334.19 found: 334.20. tert-butyl 3-(cyclohexylmethyl)-5-formylpiperidine-1-carboxylate (26). Compound 25 (59.1 mg, 0.17 mmol, 1 eq) was dissolved in dichloromethane (0.6 mL ) under argon atmosphere and treated dropwise with diisobutylaluminium hydride (24 ^l of a 1 M DCM solution, 0.21 mmol, 1.2 eq) at -78 °C. After stirring for 2 h at -78°C, the reaction was quenched by cautions with a saturated solution of Rochelle´s salt and stirred 1 h at room temperature and then extracted with AcOEt , dried over Na₂SO₄, filtered and evaporated to afford the desired compound (61.7 mg) used without further purification.⁵ ¹H NMR (300 MHz, Chloroform-d) d 9.69 and 9.61 (2 x s, 1H), 7.30 (ddd, J = 6.6, 2.8, 1.5 Hz, 2H), 7.23–7.08 (m, 3H), 4.42–4.27 (m, 1H),4.22–4.10 (m, 1H), 2.80–2.37 (m, 6H), 2.38–2.23 (m, 1H), 2.21– 1.64 (m, 1H), 1.42 (q, J = 2.9 Hz, 9H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₈H₂₆NO₃: 304.18 found: 304.19. tert-butyl 3-benzyl-5-(((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4- oxobutyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)methyl)piperidine-1-carboxylate (8d). To a solution of 6 (82 mg, 0.12 mmol, 1eq) and MgSO₄ (22 mg, 0.18 mmol, 1.5 eq) in dry MeOH (0.5 mL) was added 26 (45.2 mg, 0.15 mmol, 1.2 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH3CN (23 mg, 0.37 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solvent was evaporated and the product was dissolved in DCM and purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8d ( 52.8 mg, 45 %) as yellow oil. 1H NMR (500 MHz, Acetone-d₆) d 8.85 (s, 1H), 8.62 (s, 1H), 8.44–8.40 (m, 1H), 7.29 (ddd, J = 8.5, 5.4, 1.7 Hz, 2H), 7.24–7.18 (m, 3H), 6.27 (dt, J = 4.6, 2.1 Hz, 1H), 5.20–5.10 (m, 1H), 4.36 (s, 2H), 4.22 (d, J = 12.8 Hz, 2H), 4.09 (d, J = 23.3 Hz, 1H), 3.67–3.59 (m, 2H), 3.55 (t, J = 5.5 Hz, 2H), 3.46–3.40 (m, 4H), 3.38–3.32 (m, 2H), 1.75–1.69 (m, 2H), 1.59 (d, J = 3.5 Hz, 5H), 1.54 (dd, J = 3.2, 2.2 Hz, 9H), 1.45 (s, 12H), 1.42–1.38 (m, 21H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₄₉H₇₅N₈O₁₁ : 951.55 found: 951.55. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-benzylpiperidin-3-yl)methyl)amino)butanoic acid (9d). The tertiary amine 8d (34.8 mg, 36 ^mol) were dissolved in 1.8 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9d (35 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.45 (s, 1H), 8.40 (s, 1H), 7.56–7.12 (m, 5H), 6.22–6.10 (m, 1H), 3.54–3.42 (m, 6H), 3.21 (dd, J = 12.8, 4.2 Hz, 3H), 3.13 (dd, J = 12.9, 6.7 Hz, 3H), 3.08–2.93 (m, 3H), 2.38–2.03 (m, 7H), 1.97 (dddd, J = 17.3, 10.6, 7.9, 4.7 Hz, 2H), 1.86 (dtt, J = 13.3, 3.6, 1.8 Hz, 3H), 1.64 (qdd, J = 14.0, 7.4, 4.6 Hz, 6H). HRMS (ESI) : calcd. for C27H38N8O5 ^M+H ^⁺: 555.30 found: 555.30. Synthesis of the compound 9e methyl (E)-5-styrylnicotinate (27). To a solution of methyl 5-bromo-nicotinate (473 mg, 2.19 mmol, 1 eq) in Et₃N 2.2 mL in schlenk tube were added Pd(OAc)₂ (4.9 mg, 1% mol, 21.9 ^mol), P(O-Tol)₃ (53 mg, 8% mol, 0.17 mmol) and styrene (274 mg, 2.63 mmol, 1.2 eq). The reaction was stirred at 125 °C for 16 h. Then the reaction was quenched with water, extracted with AcOEt, washed with brine, dried over Na₂SO₄, filtered and evaporate to give the crude. The crude was purified using silica gel column eluting with 90:10 to 50:50 cyclohexane/AcOEt to afford the desired compound as yellow oil (126 mg, 24%).⁹ ¹H NMR (500 MHz, Chloroform-d) d 9.05 (d, J = 1.9 Hz, 1H), 8.84 (d, J = 2.2 Hz, 1H), 8.44 (t, J = 2.1 Hz, 1H), 7.57–7.47 (m, 2H), 7.37 (dd, J = 8.4, 6.9 Hz, 2H), 7.32–7.28 (m, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.08 (d, J = 16.4 Hz, 1H), 3.96 (s, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₅H₁₄NO₂ : 240.09 found: 240.10. methyl 5-phenethylpiperidine-3-carboxylate (28). The compound 27 (114.8 mg, 0.48 mmol) and Platinum oxide (2.3 mg, 2 % mol w/w) was solubilised in acetic acid (1.2 ml). The atmosphere was replaced twice with argon before the introduction of the hydrogen gas using normal ballon (1 bar) and the solution stirred at room temperature for 48 h. The mixture was filtered over celite and the filtrate was concentrated in vacuo to afford the corresponding piperidine as acetic acid salt (118 mg, quant) which was used directly for the next step. 1H NMR (300 MHz, Chloroform-d) d 7.31 (s, 2H), 7.27–7.10 (m, 3H), 3.95 (s, 3H), 3.49 (s, 2H), 3.22–2.50 (m, 7H), 2.36 (d, J = 40.6 Hz, 1H), 1.29 (dd, J = 14.0, 6.9 Hz, 2H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₅H₂₂NO₂: 248.16 found: 248.16. 1-(tert-butyl) 3-methyl 5-phenethylpiperidine-1,3-dicarboxylate (29). The crude 28 (118 mg, 0.48 mmol, 1 eq) was dissolved in THF (3 mL) under argon and Et₃N (67 ^L, 0.48 mmol, 1 eq) was added and the reaction stirred for 10 min at room temperature. Then di-tert-butyldicarbonate (136 mg, 0.6 mmol, 1.3 eq) were added and the mixture was stirred for 48 h at room temperature. The mixture was quenched with brine, extracted with AcOEt. The combined organics dried over Na₂SO₄ and concentrated in vacuo. The residue purified using silica gel column eluting with 90:10 to 50:50 cyclohexane/AcOEt to afford the desired compound 29 (90.8 mg, 55%) as yellow oil.⁸ ¹H NMR (500 MHz, Chloroform-d) d 7.28 (dd, J = 8.1, 6.9 Hz, 2H), 7.23–7.13 (m, 3H), 4.33 (s, 1H), 4.19 (s, 1H), 3.68 (2 x s, 3H), 2.77–2.59 (m, 3H), 2.46 (tt, J = 11.9, 3.9 Hz, 1H), 2.27 (t, J = 11.6 Hz, 1H), 2.20 (d, J = 13.2 Hz, 1H), 1.53 (dt, J = 8.8, 6.6 Hz, 1H), 1.46 (s, 9H), 1.23 (q, J = 12.3 Hz, 1H). HRMS (ESI) : m/z ^M+H ^⁺calcd. for C₂₀H₃₀NO₄: 348.21 found: 348.22. tert-butyl 3-formyl-5-phenethylpiperidine-1-carboxylate (30). Compound 29 (65.2 mg, 0.18 mmol, 1 eq) ) was dissolved in dichloromethane (0.7 mL ) under argon atmosphere and treated dropwise with diisobutylöaluminium hydride (32 ^l of a 1 M DCM solution, 0.22 mmol, 1.2 eq) at - 78 °C. After stirring for 2 h at -78°C, the reaction was quenched by cautions with a saturated solution of Rochelle´s salt and stirred 1 h at room temperature and then extracted with AcOEt , dried over Na₂SO₄, filtered and evaporated to afford the desired compound (58.5 mg) used without further purification.⁵ ¹H NMR (300 MHz, Chloroform-d) d 9.72 (d, J = 0.7 Hz, 1H), 9.66 (d, J = 0.8 Hz, 1H), 7.29 (q, J = 1.6 Hz, 2H), 7.19 (t, J = 1.9 Hz, 3H), 4.36 (s, 1H), 4.11 (br s, 1H), 2.67 (q, J = 6.7 Hz, 7H), 2.55– 2.44 (m, 1H), 2.23 (s, 1H), 2.18 (s, 1H), 1.47 (s, 9H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₉H₂₈NO₃: 318.20 found:318.21. tert-butyl 3-(((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)methyl)-5-phenethylpiperidine-1-carboxylate (8e). To a solution of 6 (90 mg, 0.14 mmol, 1eq) and MgSO₄ (25 mg, 0.2 mmol, 1.5 eq) in dry MeOH (0.6 mL) was added 30 (52 mg, 0.16 mmol, 1.2 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (26 mg, 0.4 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solvent was evaporated and the product was dissolved in DCM and purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8e (40.7 mg, 31 %) as yellow oil. 1H NMR (500 MHz, Acetone-d₆) d 8.84 (d, J = 7.7 Hz, 1H), 8.64–8.57 (m, 1H), 8.47–8.40 (m, 1H), 7.32–7.20 (m, 3H), 7.16 (ddt, J = 6.5, 4.7, 1.6 Hz, 2H), 6.26 (t, J = 2.6 Hz, 1H), 5.68–5.57 (m, 1H), 5.22–5.12 (m, 1H), 4.36 (q, J = 6.3, 4.7 Hz, 1H), 4.29–4.01 (m, 4H), 3.63 (d, J = 5.4 Hz, 1H), 3.46 (dt, J = 10.4, 5.1 Hz, 1H), 3.36 (ddd, J = 10.7, 7.2, 5.7 Hz, 1H), 2.72–2.63 (m, 4H), 2.50 (tt, J = 20.9, 10.4 Hz, 1H), 1.95–1.89 (m, 1H), 1.79 (d, J = 13.6 Hz, 1H), 1.57 (q, J = 4.8, 4.0 Hz, 3H), 1.53 (s, 9H), 1.48–1.38 (m, 37H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₅₀H₇₇N₈O₁₁ : 965.56 found: 965.57. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-phenethylpiperidin-3-yl)methyl)amino)butanoic acid (9e). The tertiary amine 8e (31.9 mg, 33 ^mol) were dissolved in 1.65 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9e (41 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.53–8.13 (m, 2H), 7.32–6.90 (m, 5H), 6.13–6.07 (m, 1H), 4.48–4.38 (m, 2H), 4.04–3.91 (m, 1H), 3.75–3.62 (m, 2H), 3.56–3.45 (m, 2H), 3.45–3.21 (m, 5H), 3.15–3.03 (m, 1H), 2.98–2.89 (m, 1H), 2.69–2.50 (m, 4H), 2.28–2.15 (m, 1H), 1.94–1.83 (m, 1H), 1.73– 1.63 (m, 1H), 1.56 (ddt, J = 15.6, 13.8, 6.9 Hz, 2H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₂₈H₄₁N₈O₅ : 569.31 found: 569.32. Synthesis of the compound 9f pent-1-en-3-amine (31). 2.3 mL of liquid ammonia (6M) was stirred in a round bottom flask at - 78°C.2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (374 mg, 2.78 mmol, 1.2 eq) in ethanol (2.3 mL) was added to liquid ammonia) and a colorless precipitate was formed. Then solution was stirred at room tempeature for 30 min. After that the propionaldehyde (135 mg, 2.3 mmol, 1 eq) in 2.3 mL was added to the solution and the reaction was stirred for 2 h at room temperature. The excess of NH₃ was evaporated in vacuo and 1M aqueous solution of HCl was added to acidify the solution (pH 1). The mixture was washed with diethylether alkalized with 6 M NaOH and extraced with DCM to afford the desired amine 31 (272 mg, quant) which was used without further purification.¹⁰ ¹H NMR (300 MHz, Chloroform-d) d 5.87–5.55 (m, 1H), 5.08 (dq, J = 6.2, 1.1 Hz, 1H), 5.04 (t, J = 1.2 Hz, 1H), 2.68 (tt, J = 7.7, 4.9 Hz, 1H), 2.22 (dddd, J = 12.4, 6.1, 4.8, 3.4 Hz, 2H), 1.95 (dtt, J = 13.8, 7.9, 1.1 Hz, 1H), 1.37–1.26 (m, 1H), 0.97–0.86 (m, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₆H₁₄N : 100.10 found: 100.11. tert-butyl pent-1-en-3-ylcarbamate (32). The crude product obtained above 31 (294 mg, 2.97 mmol) was dissolved in THF (5.9 mL). To the reaction mixture was added di-tert-butyl dicarbonate (777 mg, 3.6 mmol, 1.1 eq) at room temperature under argon atmosphere. After stirring overnight, the reaction was quenched adding N, N-dimethylethylenediamine (0.287 mL, 2.7 mmol, 0.9 eq). After stirring at room temperature for 3 h, AcOEt was addes and the mixture was washed with brine, and dried over Na₂SO₄ and evaporated. The resulting crude product was purified by silica gel column eluting with 90 :10 to 50 :50 cyclohexane/AcOEt to afford the desired compound (189 mg, 32%).¹¹ ¹H NMR (300 MHz, Chloroform-d) d 5.90–5.65 (m, 1H), 5.15–5.08 (m, 1H), 5.08–5.01 (m, 1H), 4.31 (s, 1H), 3.55 (s, 1H), 2.34–2.09 (m, 2H), 1.64–1.50 (m, 1H), 1.44 (s, 9H), 1.39–1.28 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₁H₂₂NO₂: 200.16 found: 200.16. tert-butyl 2-ethyl-3,4-dihydropyridine-1(2H)-carboxylate (33).1 mL of dry THF was added to the flask containing Rh(acac)(CO)₂ (2.3 mg, 9 ^mol, 0.01 eq) and BIPHEPHOS (14.16 mg, 18 ^mol, 0.02 eq). The air was replaced with argon before the addition of 32 (179.7 mg, 0.9 mmol, 1 eq) in 2 mL of THF. The reaction flask was placed into a stainless steel autoclave. The air was replaced by CO/H₂ (4 bar) and stirred at 65 °C for 16 h.. The autoclave was subsequently cooled at 0 °C and the pressure of CO/H₂ was released. The reaction was filtrate using celite and chromatographed on a silica gel column using 95:5 to 80:20 cyclohexane / AcOEt as eluent to afford the desired compound (187.1 mg, 98%) as yellow oil.¹² ¹H NMR (300 MHz, Chloroform-d) d 6.90–6.46 (m, 1H), 4.74 (d, J = 26.2 Hz, 1H), 4.06 (p, J = 7.1, 6.7 Hz, 1H), 1.96–1.86 (m, 2H), 1.68–1.44 (m, 2H), 1.42 (s, 9H), 1.40 (s, 1H), 1.38–1.28 (m, 1H), 0.83 (t, J = 7.5 Hz, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₂H₂₂NO₂: 212.16 found: 212.16. tert-butyl 2-ethyl-5-oxopiperidine-1-carboxylate (34). To a solution of compound 33 (153 mg, 0.7 mmol) in THF (7.2 mL) at -78 °C was added BH₃.SMe₂ (1.3 mL, 13.8 mmol, 19 eq), and the solution was stirred at -78 °C for 1 h. The mixture was allowed to warm up to room temperature and stirred overnight. The following day BH₃.SMe₂ (0.6 mL, 9 eq) was added at room temperature and the reaction mixture was stirred for 1 h. Subsequently, aqueous NaOH solution (3 M, 1.1 mL) and 30 % H₂O₂ (1.1 mL) were added at 0 °C, after which the reaction mixture was allowed to warm up to room temperature. After 1 h, water was added, and the reaction mixture was extracted with AcOEt. The combined organic layers were dried over Na₂SO₄. The solution was filtered, and concentrated under reduced pressure to afford the crude alcohol product. To a solution of the above crude product in DCM (7.2 mL) was added DMP (492 mg, 1.16 mmol, 1.6 eq) at room temperature. The reaction mixture was stirred for 2 h before being quenched with saturated NaHCO₃ solution and saturated Na₂S₂O₃ solution. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na₂SO₄. The solution was filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 90:10 to 70:30 petrolium ether/EtOAc to give compound 34 (85.3 mg, 52%) as a yellow oil.¹³ ¹H NMR (300 MHz, Chloroform-d) d 4.12 (q, J = 7.1 Hz, 2H), 2.29–2.17 (m, 1H), 1.80–1.49 (m, 4H), 1.46 (s, 9H), 1.42–1.30 (m, 2H), 0.97–0.91 (t, J = 7.4 Hz, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₁₂H₂₃NO₃ : 228.15 found: 228.16. tert-butyl 5-((((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2-ethylpiperidine-1-carboxylate (35). A mixture of 4 (127 mg, 0.31 mmol, 1 eq) and 34 (85.3 mg, 0.37 mmol, 1.2 eq) in dry DCE (1.56 mL) under argon, was stirred for 5 min before adding AcOH (28 ^L, 0.5 mmol, 1.5 eq). The mixture was stirred for 3h then NaBH₃CN (59 mg, 0.94 mmol, 3 eq) was added and the reaction was stirred for 16 h at room temperature. The reaction mixture was washed with NaHCO₃, extracted with DCM, dried over MgSO₄, and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel eluting with 99:1 to 90:10 DCM/MeOH to afford the desired compound (32.3 mg, 17%) as yellow foam.¹H NMR (300 MHz, Acetone-d₆) d 8.55–8.46 (m, 1H), 8.32 (s, 1H), 6.09 (d, J = 3.1 Hz, 1H), 5.61–5.53 (m, 1H), 5.42 (dd, J = 6.3, 3.2 Hz, 1H), 5.16–4.95 (m, 5H), 4.09–3.83 (m, 3H), 2.46–2.31 (m, 1H), 2.24–2.11 (m, 2H), 1.69–1.64 (m, 2H), 1.41 (s, 3H), 1.35 (s, 9H), 1.30 (s, 9H), 1.27 (s, 3H), 0.78 (d, J = 2.2 Hz, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₃₀H₄₈N₇O₇ : 618.35 found: 618.36. tert-butyl 5-((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6-(6- ((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-ethylpiperidine-1-carboxylate (8f). To a solution of 35 (32.3 mg, 52 ^mol, 1eq) and MgSO₄ (9.4 mg, 78 ^mol, 1.5 eq) in dry MeOH (0.5 mL) was added 5 (15 mg, 57 ^mol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (9.8 mg, 0.15 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 97:3 CH₂Cl₂/MeOH to afford the tertiary amine 8f ( 37.4 mg, 90 %) as yellow oil. 1H NMR (500 MHz, Acetone-d₆) d 8.62 (d, J = 11.4 Hz, 1H), 8.44 (d, J = 2.1 Hz, 1H), 6.27 (d, J = 16.5 Hz, 3H), 5.61 (ddd, J = 18.9, 14.6, 6.6 Hz, 3H), 4.81–4.74 (m, 1H), 4.16 (td, J = 8.5, 4.5 Hz, 4H), 2.63–2.47 (m, 2H), 2.43–2.25 (m, 1H), 1.85–1.74 (m, 9H), 1.62–1.53 (m, 12H), 1.47 (s, 9H), 1.45 (s, 9H), 1.44–1.40 (m, 13H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₄₃H₇₁N₈O₁₁: 875.52 found: 875.53. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(6-ethylpiperidin-3-yl)amino)butanoic acid (9f). The tertiary amine 8f (34 mg, 38.8 ^mol) were dissolved in 1.9 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9f (17.1 mg) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.59–8.36 (m, 2H), 6.26–6.09 (m, 1H), 4.43–4.26 (m, 2H), 4.26–4.16 (m, 2H), 3.76–3.37 (m, 2H), 3.13–3.03 (m, 2H), 3.03–2.87 (m, 2H), 2.87–2.68 (m, 3H), 2.32–2.21 (m, 4H), 2.05–1.85 (m, 2H), 1.63–1.46 (m, 2H), 1.31–1.11 (m, 2H), 0.97–0.85 (m, 3H). HRMS (ESI) : m/z ^M+H ^⁺ calcd. for C₂₁H₃₅N₈O₅ : 479.27 found: 479.27. Synthesis of the compound 9g tert-butyl 3-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate (36).¹⁴ To a solution of tert- butyl 3-(hydroxymethyl)piperidine-1-carboxylate (537 mg, 2.5 mmol) in dry CH₂Cl₂ (4 mL) under nitrogen at 5°C was added triethylamine (0.5 mL, 3.75 mmol, 1.5 eq) as a small stream over 5 min. The mixture was stirred for 10 min, and methanesulfonylchloride (0.23 mL, 3 mmol, 1.2 eq) was slowly added while the internal temperature was held below 12°C. The mixture was warmed to 20°C and stirred for 16 h. The suspension was filtered, and the solid was washed with CH₂Cl₂ and discarded. The combined filtrates were washed with water, and the solution was concentrated. The crude was purified on silica gel column eluting with 90:10 CH₂Cl₂/ AcOEt to give the desired product 36 (602 mg, 82%). 1H NMR (500 MHz, Chloroform-d) d 4.13–4.05 (m, 2H), 3.92 (dd, J = 13.3, 3.9 Hz, 1H), 3.79 (dt, J = 13.3, 4.5 Hz, 1H), 3.00 (s, 3H), 2.95 (ddd, J = 13.4, 10.3, 3.4 Hz, 1H), 2.82 (dd, J = 13.2, 9.2 Hz, 1H), 1.96 (ddddd, J = 13.4, 9.7, 7.3, 5.9, 3.9 Hz, 1H), 1.83 (ddt, J = 13.4, 5.4, 3.9 Hz, 1H), 1.70–1.63 (m, 1H), 1.53–1.48 (m, 1H), 1.46 (s, 9H), 1.33 (dtd, J = 13.9, 10.2, 4.0 Hz, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₂H₂₄NO₅S : 294.14 found: 294.18. R_f : 0.66 (80:20 CH₂Cl₂/ AcOEt). tert-butyl 3-(cyanomethyl)piperidine-1-carboxylate (37).¹⁵The compound 36 (542 mg, 1.84 mmol, 1 eq) and NaCN (135 mg, 2.76 mmol, 1.5 eq) are dissolved in 6.4 mL DMSO, and then heated at 100 ºC for 2.5 hours. After cooling down, it is diluted with Et₂O, washed with water, brine, dried over Na₂SO₄. Filtration and concentration afford the crude cyanide 61 (327 mg, 79%) slightly yellow oil, which is used in the next step without further purifications. 1H NMR (400 MHz, Chloroform-d) d 3.92 (d, J = 13.2 Hz, 1H), 3.81 (dt, J = 13.5, 4.4 Hz, 1H), 2.91 (ddd, J = 13.5, 10.3, 3.2 Hz, 1H), 2.83–2.67 (m, 1H), 2.30 (qd, J = 16.9, 6.6 Hz, 2H), 1.90 (dddq, J = 19.9, 9.9, 6.5, 3.8, 3.3 Hz, 2H), 1.67 (ddt, J = 12.6, 8.2, 4.2 Hz, 1H), 1.56–1.48 (m, 1H), 1.45 (s, 9H), 1.43–1.23 (m, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₂H₂₁N₂O₂: 225.15 found: 225.16. tert-butyl 3-(2-oxoethyl)piperidine-1-carboxylate (38). The cyanide 37 (115.9 mg, 0.52 mmol, 1 eq) is dissolved in 1.8 mL ether and then cooled down to -78 ºC. DIBAL-H (71 µL, 0.6 mmol, 1.2 eq) is added and the reaction mixture is gradually warmed up to room temperature over 4 h. The reaction was then quenched at -78 ºC by MeOH and saturated aqueous sodium potassium tartrate solution and stirred for 2 hours at room temperature until the two layers are well separated. The aqueous phase is extracted with Et₂O, the combined organic phase was washed with brine, and dried over Na₂SO₄. Filtration and concentration affords the crude aldehyde 38 (67.8 mg, 58%) which was used without further purification. 1H NMR (300 MHz, Chloroform-d) d 9.80 (t, J = 1.9 Hz, 1H), 3.95 (s, 1H), 3.84 (d, J = 13.4 Hz, 1H), 2.97–2.68 (m, 3H), 2.46–2.19 (m, 2H), 2.05–1.79 (m, 1H), 1.79–1.55 (m, 2H), 1.48 (d, J = 2.0 Hz, 9H), 1.38 (dt, J = 10.8, 3.4 Hz, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₂H₂₂NO₃: 228.15 found: 228.16. tert-butyl 3-(2-((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)ethyl)piperidine-1-carboxylate (8g). To a solution of 6 (133 mg, 0.19 mmol, 1eq) and MgSO₄ (36 mg, 0.29 mmol, 1.5 eq) in dry MeOH (2 mL) was added 37 (50 mg, 0.22 mmol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (37 mg, 0.59 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the tertiary amine 8g (20.3 mg, 11 %) as yellow oil. R_f: 0.57 (90:10 CH₂Cl₂/MeOH). 1H NMR (400 MHz, Acetone-d₆) d 8.75–8.54 (m, 2H), 8.54–8.42 (m, 1H), 6.39–6.08 (m, 1H), 5.58 (tdd, J = 15.4, 6.2, 2.4 Hz, 1H), 5.24–4.97 (m, 1H), 4.40–4.23 (m, 1H), 4.21–3.96 (m, 1H), 2.95–2.68 (m, 3H), 2.53 (ddtd, J = 54.5, 25.7, 13.4, 12.8, 7.2 Hz, 2H), 2.23 (s, 1H), 1.99–1.87 (m, 1H), 1.86–1.69 (m, 2H), 1.59–1.56 (m, 4H), 1.53 (s, 15H), 1.50–1.10 (m, 42H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₄₃H₇₁N₈O₁₁: 875.52 found: 875.52. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-(piperidin-3-yl)ethyl)amino)butanoic acid (9g). The tertiary amine 8g (20.3 mg, 23 µmol) were dissolved in 1.2 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9g (23 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.55–8.40 (m, 2H), 6.21–6.16 (m, 1H), 4.95–4.85 (m, 2H), 4.60–4.45 (m, 2H), 4.42 (dt, J = 8.8, 4.6 Hz, 2H), 4.20–3.95 (m, 2H), 3.87–3.30 (m, 4H), 2.98 (s, 2H), 2.90–2.66 (m, 1H), 2.41 (dt, J = 15.1, 6.9 Hz, 2H), 2.38–2.19 (m, 2H), 2.01–1.47 (m, 2H), 1.45–1.12 (m, 2H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₂₁H₃₅N₈O₅: 479.27 found: 479.27. Synthesis of the compound 9h 1-phenylhex-5-en-3-amine (39).3.1 mL of liquid ammonia (6M) was stirred in a round bottom flask at -78°C. The 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (503 mg, 3.7 mmol, 1.2 eq) in ethanol (3.1 mL) was added to liquid ammonia and a colorless precipitate was formed. Then solution was stirred at room temperature for 30 min. After that the 3-phenylpropanal (524 mg, 3.12 mmol, 1 eq) in 3.1 mL ethanol was added to the solution and the reaction was stirred for 2 h at room temperature. The excess of NH₃ was evaporated in vacuo and 1M aqueous solution of HCl was added to acidify the solution (pH 1). The mixture was washed with diethylether alkalized with 6 M NaOH and extracted with DCM to afford the desired amine 39 (514.8 mg, 78%) which was used without further purification.¹⁰ ¹H NMR (300 MHz, Chloroform-d) d 7.33–7.27 (m, 2H), 7.23–7.14 (m, 3H), 5.88–5.71 (m, 1H), 5.15–5.09 (m, 1H), 5.08 (t, J = 1.2 Hz, 1H), 2.90–2.55 (m, 4H), 2.36–2.22 (m, 1H), 2.05 (dtt, J = 13.8, 7.9, 1.0 Hz, 1H), 1.77 (dddd, J = 13.6, 10.1, 6.3, 5.0 Hz, 1H). HRMS (ESI) : m/z [M+H+H]⁺ calcd. for C₁₂H₁₈N : 176.14 found: 176.14. tert-butyl (1-phenylhex-5-en-3-yl)carbamate (40). The crude product obtained above 39 (443 mg, 2.5 mmol) was dissolved in THF (5 mL). To the reaction mixture was added di-tert-butyl dicarbonate (600 mg, 2.7 mmol, 1.1 eq) at room temperature under argon atmosphere. After stirring overnight, the reaction was quenched adding N, N-dimethylethylenediamine (0.242 mL, 2.3 mmol, 0.9 eq). After stirring at room temperature for 3 h, AcOEt was added and the mixture was washed with brine, and dried over Na₂SO₄ and evaporated. The resulting crude product was purified by silica gel column eluting with 90:10 CH₂Cl₂/AcOEt to afford the desired compound (515 mg, 75%) as a white solid.¹¹ ¹H NMR (400 MHz, Chloroform-d) d 7.33–7.27 (m, 2H), 7.18 (ddd, J = 6.1, 2.9, 1.7 Hz, 3H), 5.78 (ddt, J = 19.1, 9.5, 7.2 Hz, 1H), 5.13–5.08 (m, 1H), 5.07 (d, J = 1.3 Hz, 1H), 4.37 (s, 1H), 3.71 (s, 1H), 2.67 (qdd, J = 13.8, 10.1, 6.0 Hz, 2H), 2.25 (qt, J = 14.0, 6.6 Hz, 2H), 1.81 (dddd, J = 13.8, 10.2, 6.4, 5.1 Hz, 1H), 1.74–1.63 (m, 1H), 1.46 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₇H₂₆NO₂ : 276.19 found: 276.19. Mp.52-54 °C. R_f : 0.47 (90:10 CH₂Cl₂/AcOEt). tert-butyl (1-oxo-5-phenylpentan-3-yl)carbamate (41). The compound 40 (274 mg, 0.99 mmol, 1 eq) was dissolved in dry MeOH (9.9 mL) under Argon and ozone was bubbled directly in the solution stirred at -78 °C. After the reaction showed a blue color, the reaction vessel was degassed with nitrogen until disappearance of the blue color occurred. Then Me₂S (2 mL) was added and the solution was stirred for 30 min at room temperature then concentrated under reduced pressure to afford the desired aldehyde 41 (388 mg, quant) used without further purification. 1H NMR (300 MHz, Chloroform-d) d 9.76 (t, J = 1.9 Hz, 1H), 7.34–7.29 (m, 2H), 7.25–7.14 (m, 3H), 4.66–4.48 (m, 1H), 3.61–3.53 (m, 1H), 3.46 (d, J = 2.7 Hz, 1H), 3.44–3.30 (m, 2H), 2.82–2.68 (m, 1H), 2.03–1.64 (m, 1H), 1.59–1.37 (m, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₆H₂₄NO₃ : 278.17 found: 278.17. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-((tert-butoxycarbonyl)amino)-5- phenylpentyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (8h). To a solution of 6 (155 mg, 0.23 mmol, 1eq) and MgSO₄ (42 mg, 0.35 mmol, 1.5 eq) in dry MeOH (2.3 mL) was added 41 (97 mg, 0.35 mmol, 1.5 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (44 mg, 0.7 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the tertiary amine 8h (25 mg, 11 %) as yellow oil. 1H NMR (400 MHz, Acetone-d6) d 8.82 (s, 1H), 8.62 (q, J = 2.3 Hz, 1H), 8.45 (td, J = 5.1, 2.2 Hz, 1H), 7.43–7.06 (m, 5H), 6.36–6.16 (m, 1H), 5.60 (td, J = 6.6, 5.9, 3.2 Hz, 1H), 5.26–5.09 (m, 1H), 4.38 (t, J = 7.5 Hz, 1H), 4.11 (d, J = 12.8 Hz, 1H), 2.90–2.77 (m, 1H), 2.73–2.40 (m, 2H), 1.96–1.86 (m, 1H), 1.86–1.66 (m, 1H), 1.59 (d, J = 1.5 Hz, 3H), 1.54 (s, 11H), 1.50–1.34 (m, 27H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₄₇H₇₃N₈O₁₁ : 925.53 found: 925.54. R_f: 0.61 (95:5 CH₂Cl₂/MeOH). (S)-2-amino-4-((3-amino-5-phenylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (9h). The tertiary amine 8h (25 mg, 27 µmol) were dissolved in 1.4 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9h (27 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.57–8.28 (m, 2H), 7.49–7.16 (m, 3H), 7.05–6.92 (m, 2H), 6.21–6.15 (m, 1H), 4.70–4.67 (m, 2H), 4.62–4.58 (m, 2H), 4.55–4.44 (m, 2H), 4.14–4.02 (m, 2H), 3.90–3.29 (m, 4H), 2.84–2.58 (m, 2H), 2.53–1.93 (m, 3H), 1.87–1.60 (m, 1H), 1.40–1.16 (m, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₂₅H₃₈N₈O₅ : 529.28 found: 529.29. Synthesis of the compound 9i methyl 3-(phenylamino)propanoate (42).¹⁶ To a solution of aniline (1.47 mL, 16 mmol, 1 eq) in AcOH (4 ml, 4 M) was added methyl acrylate (1.45 mL, 16 mmol, 1 equiv) at 25°C. After being stirred for 4 h at 70 °C, the reaction mixture was cooled to 25 °C and water was added. The product was extracted with CH₂Cl₂, dried over Na₂SO₄, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (20:80 EtOAc / n-Hexane) to give the desired compound 69 (2.84 g, 99%) as a light yellow solid. Mp : 35-36°C. 1H NMR (CDCl3, 400 MHz) d 2.63(t, J = 6.4 Hz,2H), 3.46(t, J = 6.4 Hz,2H), 3.70(s, 3H),6.63(dd, J = 8.6, 1.0Hz,2H), 6.72(t,J = 7.2Hz, 1H),7.18(dd, J = 8.4, 7.6 Hz,2H). 1³C NMR (CDCl3, 100 MHz) d33.6, 39.3, 51.6, 112.9, 117.6, 129.2, 147.5, 172.7. HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₀H₁₄NO₂ : 180.09 found: 180.10. methyl 3-((tert-butoxycarbonyl)(phenyl)amino)propanoate (43). The ester 42 (615 mg, 3.4 mmol, 1 eq) was mixed with di-tert-butyl carbonate (2.99 g, 13.7 mmol, 4 eq) in the absence of solvent. The mixture was heated at 100°C for 18 h. The mixture was partitioned between H₂O and petroleum ether. The organic phase was washed with water, dried, evaporated and purified using silica gel column eluting with 95:5 to 85:15 Petrolium ether/AcOEt to give the ester 43 as an oil (713 mg, 74%). 1H NMR (500 MHz, Chloroform-d) d 7.36–7.30 (m, 2H), 7.23–7.15 (m, 3H), 3.94 (m, t, J = 7.8 Hz, 2H), 3.60 (s, 3H), 2.59 (t, J = 7.8 Hz, 2H), 1.42 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C15H22NO4 : 280.15 found: 280.15. R_f : 0.47 (80:20 Petrolium ether/AcOEt). tert-butyl (3-oxopropyl)(phenyl)carbamate (44). Compound 43 (355 mg, 1.23 mmol, 1 eq) was dissolved in dichloromethane (6 mL) under argon atmosphere and treated dropwise with diisobutylaluminium hydride (0.176 ml of a 1 M DCM solution, 1.5 mmol, 1.2 eq) at -78 °C. After stirring for 2 h at -78°C, the reaction was quenched by cautions with a saturated solution of Rochelle´s salt and stirred 1 h at room temperature and then extracted with AcOEt , dried over Na₂SO₄, filtered and evaporated to afford the desired compound (302 mg, 95%) used without further purification.⁵ ¹H NMR (300 MHz, Chloroform-d) d 9.76 (t, J = 1.9 Hz, 1H), 7.38–7.31 (m, 2H), 7.25–7.11 (m, 3H), 3.85–3.77 (m, 1H), 3.74–3.64 (m, 1H), 2.69 (td, J = 6.9, 1.9 Hz, 2H), 1.41 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₄H₂₀NO₃ : 250.14 found: 250.14. tert-butyl (3-aminohex-5-en-1-yl)(phenyl)carbamate (45). 1.82 mL of liquid ammonia (6M) was stirred in a round bottom flask at -78°C. The 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (292 mg, 2.18 mmol, 1.2 eq) in ethanol (1.82 mL) was added to liquid ammonia and a colorless precipitate was formed. Then solution was stirred at room temperature for 30 min. After that compound 44 (453 mg, 1.82 mmol, 1 eq) in 1.82 mL ethanol was added to the solution and the reaction was stirred for 2 h at room temperature. The excess of NH₃ was evaporated in vacuo and 1M aqueous solution of HCl was added to acidify the solution (pH 1). The mixture was washed with diethylether alkalized with 6 M NaOH and extraced with DCM to afford the desired amine 45 (420 mg, 79%) which was used without further purification.¹⁰ ¹H NMR (300 MHz, Chloroform-d) d 7.42–7.28 (m, 2H), 7.22–7.12 (m, 3H), 5.87–5.64 (m, 1H), 5.09 (qt, J = 2.1, 1.2 Hz, 1H), 5.05 (tt, J = 2.1, 1.2 Hz, 1H), 3.87 (dt, J = 15.0, 7.7 Hz, 1H), 3.78–3.58 (m, 1H), 2.85 (tt, J = 8.4, 4.7 Hz, 1H), 2.31–2.17 (m, 1H), 2.03 (dt, J = 14.5, 7.9 Hz, 1H), 1.87–1.62 (m, 1H), 1.55–1.44 (m, 1H), 1.41 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₇H₂₇N₂O₂ : 291.20 found: 291.21. tert-butyl (3-((tert-butoxycarbonyl)amino)hex-5-en-1-yl)(phenyl)carbamate (46). The crude product obtained above 45 (326 mg, 1.12 mmol) was dissolved in THF (2.3 mL). To the reaction mixture was added di-tert-butyl dicarbonate (269 mg, 1.24 mmol, 1.1 eq) at room temperature under argon atmosphere. After stirring overnight, the reaction was quenched adding N, N- dimethylethylenediamine (0.108 mL, 1.08 mmol, 0.9 eq). After stirring at room temperature for 3 h, AcOEt was added and the mixture was washed with brine, and dried over Na₂SO₄ and evaporated. The resulting crude product was purified by silica gel column eluting with 90:10 cycohexane/AcOEt to afford the desired compound (355.5 mg, 81%) as a white oil.¹¹ ¹H NMR (500 MHz, Chloroform-d) d 7.39–7.27 (m, 2H), 7.23–7.12 (m, 3H), 5.82–5.66 (m, 1H), 5.05 (ddt, J = 15.4, 3.5, 1.7 Hz, 2H), 4.42 (s, 1H), 3.68 (ddddd, J = 23.7, 18.8, 15.3, 9.5, 5.1 Hz, 2H), 3.33 (s, 1H), 2.32–2.16 (m, 2H), 1.87–1.74 (m, 1H), 1.68–1.60 (m, 1H), 1.44 (d, J = 20.3 Hz, 18H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₂₂H₃₅N₂O₄ : 391.25 found: 391.26. R_f : 0.5 (90:10 cyclohexane/AcOEt). tert-butyl (3-((tert-butoxycarbonyl)amino)-5-oxopentyl)(phenyl)carbamate (47). The compound 46 (161.7 mg, 0.44 mmol, 1 eq) was dissolved in dry MeOH (4.1 mL) under Argon and ozone was bubbled directly in the solution stirred at -78 °C. After the reaction showed a blue color, the reaction vessel was degassed with nitrogen until disappearance of the blue color occured. Then Me2S (1 mL) was added and the solution was stirred for 30 min at room temperature then concentrated under reduced pressure to afford the desired aldehyde 47 (108 mg, 63%) used without further purification. 1H NMR (300 MHz, Chloroform-d) d 9.72 (t, J = 1.8 Hz, 1H), 7.38–7.29 (m, 3H), 7.19–7.12 (m, 2H), 4.42 (dd, J = 6.5, 4.9 Hz, 1H), 3.81–3.57 (m, 2H), 2.66 (dd, J = 6.1, 1.8 Hz, 2H), 1.85–1.69 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C21H33N2O5 : 393.23 found: 393.24. tert-butyl (S)-4-((5-((tert-butoxycarbonyl)(phenyl)amino)-3-((tert- butoxycarbonyl)amino)pentyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9- yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (8i). To a solution of 6 (102 mg, 0.18 mmol, 1eq) and MgSO₄ (33 mg, 0.27 mmol, 1.5 eq) in dry MeOH (1.8 mL) was added 47 (108 mg, 0.27 mmol, 1.5 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (35 mg, 0.55 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the tertiary amine 8i (23.9 mg, 12 %) as yellow oil. 1H NMR (500 MHz, Acetone-d₆) d 8.85 (s, 1H), 8.61 (s, 1H), 8.51–8.40 (m, 1H), 7.37–7.32 (m, 5H), 7.19 (t, J = 7.3 Hz, 2H), 6.25 (dd, J = 5.7, 2.3 Hz, 1H), 5.89 (d, J = 8.9 Hz, 1H), 5.63–5.54 (m, 1H), 5.18–5.07 (m, 1H), 4.40–4.31 (m, 1H), 3.71 (dd, J = 8.3, 6.9 Hz, 5H), 2.57–2.42 (m, 1H), 1.73 (dddd, J = 24.4, 14.8, 8.0, 4.7 Hz, 6H), 1.58 (d, J = 1.7 Hz, 4H), 1.54 (s, 9H), 1.41 (d, J = 2.9 Hz, 18H), 1.40 (s, 21H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₅₂H₈₂N₉O₁₃ : 1040.60 found: 1040.60. R_f: 0.57 (95:5 CH₂Cl₂/MeOH). (S)-2-amino-4-((3-amino-5-(phenylamino)pentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (9i). The tertiary amine 8i (23 mg, 22 µmol) were dissolved in 1.1 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9i (23 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (400 MHz, Deuterium Oxide) d 8.57–8.43 (m, 2H), 7.68–7.58 (m, 4H), 7.58–7.52 (m, 3H), 6.22 (dd, J = 7.2, 4.0 Hz, 1H), 4.61–4.46 (m, 2H), 3.80 (tdd, J = 11.6, 9.4, 5.8 Hz, 4H), 3.73–3.37 (m, 7H), 2.44 (s, 1H), 2.07–1.83 (m, 2H), 1.55–1.08 (m, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₂₅H₃₈N₉O₅ : 544.29 found: 544.29. Synthesis of the compound 9j (tert-butoxycarbonyl)-L-homoserine (48).¹⁷ To a solution of L-homoserine (932 mg, 7.75 mmol, 1 eq) in 7.6 mL of a mixture of dioxane/H₂O (0.6:0.4) and NaHCO₃ (1.34g, 16 mmol, 2.1 eq) at 0°C was added Boc₂O (2.03 g, 9.3 mmol, 1.2 eq) in 5 mL dioxane dropwise. Then the reaction was stirred at room temperature for 18 h. The solution was then neutralized with 5% aq. Citric acid solution, extracted with AcOEt. The organic layers was washed with water, brine, dried oved Na₂SO₄ and evaporated to afford the desired compound 48 (425 mg, 28%) which was used for the next step. benzyl (tert-butoxycarbonyl)-L-homoserinate (49). The crude 48 was dissolved in 8 mL dry acetone with Et₃N (1.17 mL, 8.4 mmol, 1.4 eq) and benzylbromid (1,73 g, 10.1 mmol, 1.3 eq). After refluxing for 3 h, the solvent was removed and the residue dissolved in AcOEt. The organic layer was washed with 0.5 N HCl, and dried. After evaporating the solvent, petroleum ether was added and shaken well. The compound was purified on silica gel column eluting with 90 :10 CH₂Cl₂/acetone to give 49 as a yellow oil (1.17 g, 45%).¹⁷ ¹H NMR (300 MHz, Chloroform-d) d 7.45–7.31 (m, 5H), 5.38 (d, J = 7.9 Hz, 1H), 5.19 (d, J = 1.5 Hz, 2H), 4.61–4.47 (m, 1H), 3.77–3.54 (m, 2H), 2.24–2.08 (m, 1H), 1.62 (dd, J = 12.4, 8.9 Hz, 1H), 1.44 (s, 9H). benzyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (50). To a solution of oxalyl chloride (0.115 mL, 1.35 mmol, 1.5 eq) in dry CH₂Cl₂ (3 mL) at -78 °C was added DMSO (0.159 mL, 2.25 mmol, 2.5 eq) in CH₂Cl₂ (1 mL). After 20 min, 49 (277 mg, 0.89 mmol, 1 eq.) in CH₂Cl₂ (1 mL) was added and the reaction stirred for 45 min at -78°C. Then Et₃N was added (0.625 mL, 4.5 mmol, 5 eq) and the mixture was stirred for 1 h at room temperature. The organic phase was washed with a solution of citric acid (5% w/w), then aqueous saturated NaHCO₃, brine, dried over Na₂SO₄, evaporated to afford the desired product (267 mg, 97%) as a yellow oil, which was used without purification. 1H NMR (300 MHz, Chloroform-d) d 9.72 (t, J = 0.7 Hz, 1H), 7.42–7.28 (m, 5H), 5.39 (d, J = 8.3 Hz, 1H), 5.17 (s, 2H), 4.63 (t, J = 4.3 Hz, 1H), 3.17–2.93 (m, 2H), 1.43 (s, 9H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₆H₂₂NO₅ : 308.14 found: 308.15. benzyl (S,S)-4-((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (51). To a solution of 6 (168 mg, 0.25 mmol, 1eq) and MgSO₄ (45 mg, 0.37 mmol, 1.5 eq) in dry MeOH (2.5 mL) was added 50 (85 mg, 0.28 mmol, 1.1 eq) and stirred 30 min at rt. After that, the solution was cooled at 0 °C, and NaBH₃CN (47 mg, 0.75 mmol, 3 eq) was added and the mixture was stirred at rt for 16 h. The solution was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organics were washed with brine, dried over Na₂SO₄ and the residue purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the tertiary amine 51 (101 mg, 42 %) as yellow oil. 1H NMR (500 MHz, Acetone-d₆) d 8.87 (s, 1H), 8.58 (d, J = 5.1 Hz, 1H), 8.41 (dd, J = 7.6, 5.2 Hz, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.33–7.23 (m, 3H), 6.39–6.27 (m, 1H), 6.23 (dd, J = 7.3, 2.2 Hz, 1H), 6.12 (d, J = 9.0 Hz, 1H), 5.53 (dd, J = 23.6, 6.3 Hz, 1H), 5.20–5.04 (m, 3H), 4.37–4.12 (m, 2H), 3.64 (d, J = 2.0 Hz, 1H), 2.86 (dd, J = 13.4, 7.9 Hz, 1H), 2.69–2.54 (m, 2H), 2.54–2.40 (m, 3H), 1.97–1.85 (m, 1H), 1.85–1.70 (m, 1H), 1.58–1.52 (m, 3H), 1.50 (s, 9H), 1.44–1.27 (m, 30H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₄₇H₇₂N₈O₁₃ : 955.51 found: 855.51. R_f: 0.51 (95:5 CH₂Cl₂/MeOH). (S,S)-4-((4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6-(6- ((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoic acid (52). To a solution of 51 (77.6 mg, 81 µmol, 1eq) in AcOEt/MeOH (1:1, 1 mL) was added Pd/C (38 mg, 50 % w/w). The suspension was put under H₂ and stirred for 16 h at room temperature. The solution was then filtrated on celite and evaporated to afford the desired product which was purified on silica gel column eluting with 99:1 to 95:5 CH2Cl2/MeOH to afford 52 (34.5 mg, 49 %) as white foam. 1H NMR (400 MHz, Chloroform-d) d 8.73 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 14.2 Hz, 1H), 6.21–6.02 (m, 1H), 5.86–5.66 (m, 1H), 5.44–5.40 (m, 1H), 5.14 (br s, 1H), 4.57–4.38 (m, 1H), 4.00 (s, 2H), 3.15– 2.51 (m, 2H), 2.06–1.77 (m, 3H), 1.59 (d, J = 2.5 Hz, 3H), 1.55 (s, 9H), 1.44–1.34 (m, 33H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₄₀H₆₅N₈O₁₃ : 865.46 found: 865.46. R_f: 0.41 (95:5 CH₂Cl₂/MeOH). tert-butyl (S,S)-4-((4-amino-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)(((3aR,4R,6R,6aR)-6-(6- ((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (53).¹⁶ DMT-MM (13 mg, 48 µmol, 1.2 eq) was added to a stirred solution of NH₄Cl (3.21 mg, 60 µmol, 1.5 eq), Et₃N (10 µL, 60 µmol, 1.5 eq), and 52 (34.8 mg, 40 µmol) in methanol (0.5 mL). The resulting mixture was stirred at room temperature for 4 h. After the solvent was removed by rotary evaporator, the resulting residue was dissolved in CH₂Cl₂, and washed successively with saturated sodium carbonate, water, and brine, and dried over MgSO4. The crude product was purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the desired amide 53 (10.3 mg, 30 %) as white foam and the corresponding methyl ester 54. 1H NMR (500 MHz, Acetone-d₆) d 8.86 (s, 1H), 8.64 (s, 1H), 8.46 (s, 1H), 6.87 (s, 1H), 6.36 (s, 1H), 6.32–6.20 (m, 2H), 5.59 (td, J = 6.3, 2.2 Hz, 1H), 5.13 (ddd, J = 16.9, 6.3, 3.2 Hz, 1H), 4.39 (td, J = 7.0, 3.1 Hz, 1H), 4.20–4.00 (m, 2H), 3.73–3.51 (m, 1H), 2.90 (dd, J = 13.5, 7.6 Hz, 1H), 2.67 (dt, J = 14.1, 7.3 Hz, 2H), 2.54 (ddd, J = 23.0, 13.4, 6.1 Hz, 3H), 2.01–1.90 (m, 2H), 1.90–1.70 (m, 1H), 1.59 (s, 3H), 1.54 (s, 9H), 1.44 (s, 9H), 1.42 (2 x s, 18H), 1.39 (s, 3H). HRMS (ESI) for 53 : m/z [M+H]⁺ calcd. for C₄₀H₆₆N₉O₁₂ : 864.48 found: 864.48. HRMS (ESI) for 54 : m/z [M+H]⁺ calcd. for C₄₁H₆₇N₈O₁₃ : 879.47 found: 879.48. R_f: 0.59 (90:10 CH₂Cl₂/MeOH). The oil 54 ( 16.5 mg, 19 µmol, 1 eq) was dissolved in 6M liquid MeOH–NH₃(0.1 mL, 38 eq) and kept for 72 h at r.t. under TLC control. The volatiles were evaporated under reduced pressure yielding to the desired compound 53 which was purified on silica gel column eluting with 99:1 to 95:5 CH₂Cl₂/MeOH to afford the desired amide 53 (11.8 mg, 72 %) as white foam. (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((S)-3,4-diamino-4-oxobutyl)amino)butanoic acid (9j). The tertiary amine 53 (11.8 mg, 13.6 µmol) were dissolved in 0.7 mL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9j (20.5 mg, quant) as TFA salts as a light yellow foam which was used without purification. 1H NMR (500 MHz, Deuterium Oxide) d 8.49 (s, 1H), 8.47 (s, 1H), 6.21 (d, J = 3.8 Hz, 1H), 4.83 (dd, J = 5.1, 3.7 Hz, 1H), 4.58–4.46 (m, 2H), 4.13 (t, J = 6.4 Hz, 1H), 3.96 (dd, J = 9.2, 3.9 Hz, 1H), 3.85– 3.74 (m, 2H), 3.68–3.55 (m, 2H), 3.47 (td, J = 7.2, 3.1 Hz, 2H), 2.39 (dq, J = 10.5, 7.1 Hz, 3H), 2.31– 2.20 (m, 1H). HRMS (ESI) : m/z [M+H]⁺ calcd. for C₁₈H₃₀N₉O₆ : 468.22 found: 468.23. Synthesis of the compound 9k 5'-Azido-N⁶,N⁶-bis(tert-butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylideneadenosine (55). To a solution of 2 (0.50 g, 1.5 mmol, 1.0 eq) in dry DCM (5 mL), DMAP (37 mg, 0.30 mmol, 0.2 eq), TEA (0.52 mL, 0.38 g, 3.8 mmol, 2.5 eq) and Boc2O (0.97 mL, 0.98 g, 4.5 mmol, 3.0 eq) were added and the reaction mixture was stirred at rt for 90 min. The mixture was washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (50:50 PE/EA). The desired product 83 was obtained as a colourless solid (687 mg, 1.29 mmol, 86%).¹⁸ Mp: 118-119 °C. 1H NMR (400 MHz, CDCl3): d = 1.41 (d, J = 0.8 Hz, 3H), 1.46 (s, 18H), 1.64 (d, J = 0.7 Hz, 3H), 3.60 (m_c, 2H), 4.41 (ddd, J = 5.8 Hz, J = 4.9 Hz, J = 3.6 Hz, 1H), 5.06 (dd, J = 6.4 Hz, J = 3.6 Hz, 1H), 5.44 (dd, J = 6.5 Hz, J = 2.5 Hz, 1H), 6.19 (d, J = 2.6 Hz, 1H), 8.21 (s, 1H), 8.88 (s, 1H). ¹³C NMR (101 MHz, CDCl₃): d = 25.5, 27.3, 28.0, 52.4, 81.9, 84.1, 84.2, 85.6, 90.9, 115.2, 129.7, 143.9, 150.5, 151.0, 152.5, 152.6. Analytical data matches with literature.¹⁸ 5'-Amino-N⁶,N⁶-bis(tert-butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylideneadenosine (56). To a solution of 5'-azido-N⁶,N⁶-bis(tert-butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylidene-adenosine 55 (650 mg, 1.22 mmol, 1.0 equiv) in EA/MeOH (4 mL, 1:1) Pd/C (65 mg, 10% w/w) was added. The reaction mixture was stirred overnight under hydrogen atmosphere at rt. The mixture was filtered over celite, concentrated in vacuo and purified by column chromatography (DCM/MeOH, 20:1). The desired compound 56 was obtained as a grey solid (253 mg, 0.499 mmol, 41%).¹⁸ Mp: 70-73 °C. 1H NMR (500 MHz, CDCl₃): d = 1.40 (d, J = 0.7 Hz, 3H), 1.46 (s, 18H), 1.63 (s, J = 0.6 Hz, 3H), 2.01 (br. s, 2H), 3.06 (mc, 2H), 4.31 (ddd, J = 5.8 Hz, J = 4.3 Hz, J = 3.5 Hz, 1H), 5.06 (dd, J = 6.4 Hz, J = 3.5 Hz, 1H), 5.42 (dd, J = 6.5 Hz, J = 3.1 Hz, 1H), 6.11 (d, J = 3.2 Hz, 1H), 8.22 (s, 1H), 8.87 (s, 1H). 1³C NMR (126 MHz, CDCl₃): d = 25.5, 27.4, 28.0, 28.3, 28.7, 43.7, 81.4, 81.9, 83.9, 84.1, 87.3, 91.1, 115.0, 129.7, 144.1, 150.6, 150.9, 152.4, 152.7. Analytical data matches with literature.¹⁸ di-tert-butyl 4,4'-((((3aR,4R,6R,6aR)-6-(6-(bis(tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)azanediyl)bis(2-((tert- butoxycarbonyl)amino)butanoate) and di-tert-butyl 4,4'-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)azanediyl)bis(2-((tert-butoxycarbonyl)amino)butanoate) (57) and (58). tert-Butyl (S)-2- ((tert-butoxycarbonyl)amino)-4-oxobutanoate 5 (357 mg, 1.31 mmol, 4.0 equiv) and MgSO₄ (118 mg, 0.978 mmol, 3.0 eq) were added to a solution of 5'-Amino-N⁶,N⁶-bis(tert- butoxycarbonyl)-5'-deoxy-2',3'-O-isopropylidene-adenosine 56 (165 mg, 0.326 mmol, 1.0 eq) in dry MeOH (3.3 mL) at 0 °C and stirred for 30 min before NaBH₃CN (82 mg, 1.31 mmol, 4.0 eq) was added. The reaction mixture was stirred overnight at rt. The solvent was removed in vacuo, water was added and the aqueous phase was extracted three times with EA. The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography (PE/EA, 1:1). The bis-Boc protected title compound 57 was obtained as a colourless oil (110 mg, 0.108 mmol, 33%) and the mono-Boc protected title compound 58 was obtained as a colourless foam (173 mg, 0.188 mmol, 58%). 1H-NMR (500 MHz, CDCl₃): d = 1.44 (s, 30H), 1.46 (s, 30H), 2.14 (ddt, J = 14.5 Hz, J = 9.6 Hz, J = 3.2 Hz, 4H), 2.39-2.69 (m, 3H), 2.79 (m_c, 1H), 3.31-3.50 (m, 3H), 3.58-3.76 (m, 7H), 4.35 (ddd, J = 11.0 Hz, J = 8.1 Hz, J = 3.6 Hz, 4H), 4.97 (m_c, 1H), 5.33 (d, J = 7.6 Hz, 4H), 6.11 (d, J = 2.3 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 8.86 (s, 1H). 1³C-NMR (126 MHz, CDCl₃): d = 21.0, 24.0, 28.1, 28.4, 36.8, 50.7, 51.0, 52.9, 58.4, 80.5, 81.4, 82.5, 84.0, 85.4, 92.5,115.1, 129.7, 144.2, 150.6, 152.2, 152.3, 156.8, 172.2. HRMS (pos. ESI): [M + H]⁺ calc. for C₄₉H₈₁O₁₅N₈: 1021.5816; found: 1021.5829. (2S,2'S)-4,4'-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)azanediyl)bis(2-aminobutanoic acid) (9k). The tertiary amine 57 (equiv) were dissolved in 2.2 mL freshly prepared TFA/H2O (4:1) solution and stirred at rt for 16 h, then evaporated to remove the TFA and dried using freeze dryer to give the desired products 9k (71 mg, quant) as TFA salts as a colorless foam which was used without purification. ¹H-NMR (400 MHz, D₂O): d = 2.04-2.14 (m, 2H), 2.15-2.24 (m, 2H), 2.40 (m_c, 1H), 2.75 (m_c, 1H), 3.40-3.68 (m, 2H), 3.72-3.79 (m, 5H), 4.10 (dd, J = 8.0 Hz, J = 5.0 Hz, 1H), 4.17 (dd, J = 7.1 Hz, J = 5.4 Hz, 2H), 4.31-4.53 (m, 2H), 4.56 (td, J = 9.3 Hz, J = 1.2 Hz, 1H), 6.12 (dd, J = 10.7 Hz, J = 4.3 Hz, 1H), 8.40 (s, 1H), 8.41 (s, 1H). 1³C-NMR (101 MHz, D2O): d = 24.2, 26.7, 41.2, 50.2, 50.5, 51.2, 55.5, 57.8, 67.3, 71.5, 90.3, 111.8, 114.7, 117.6, 119.3, 120.5, 143.5, 144.4, 148.0, 149.9, 161.9, 162.3, 162.7, 163.0, 170.3, 171.7. HRMS (ESI) : m/z [M+H]⁺ calc. for C₁₈H₂₇O₇N₈: 467.20 found: 467.20. For the synthesis of the following compounds up to 75c and from 161a to 200, the following analytic methods were used: Flash column chromatography was performed on a Biotage® Isolera Prime/One purification system using 40–60 µm pre-packed silica gel columns from Biotage or HP-spherical silica 50 µm from Interchim (Jumbo Pack). NMR spectroscopy and mass spectrometry were used for product identification.1H-NMR spectral data were recorded on a Bruker Advance II+ 400 MHz spectrometer using DMSO-d6 as solvent. The 1H assignment resulted from COSY experiments. Mass spectra were recorded on an Advion expression CMS using an ASAP® (Atmospheric Solids Analysis Probe; aka APCI: Atmospheric Pressure Chemical Ionization) as ion source, on a Thermo Scientific Exactive mass spectrometer using electrospray ionization (ESI) as ion source and on a 6200 series TOF/6500 series Q-TOF B.09.00 using ESI as ion source. General Procedure for the 2^nd reductive amination (8l to 8x) and the final deprotection (9l to 9x). To a stirred solution of 6 (1.1 eq.) and an aldehyde 7 (1 eq.) in dry DCE (0.12 ^M based on 7) was added AcOH (1.1 eq.). The solution was stirred for 4 h at rt, then NaBH(OAc)₃ (2.6 eq.) was added and the mixture was stirred for 4 h at rt and 12 h at 70 °C. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (mostly 99.5:0.5–94:6) to afford the tertiary amines 8 as yellow oils. Tertiary amines 8 were dissolved (0.02 M) in freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired products 9 as foams (2 or 3 TFA salt). tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(methyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (8l) & (S)-2-amino-4-((((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (methylamino)propyl)amino)butanoic acid (9l). Reductive amination (8l): yield: 88 mg, 0.105 mmol, 39 %. C₄₀H₆₆N₈O₁₁ (835.01 g/mol). HRMS (ESI): calcd. for C₄₀H₆₇N₈O₁₁ ^M+H ^⁺: 835.4924, found: 835.4921. Deprotection (9l): yield: 82 mg, 0.105 mmol, 100 % (3 TFA salt). C₁₈H₃₀N₈O₅ (438.49 g/mol).¹H- NMR (400 MHz; DMSO-d6): d 8.67 (bs, 3H, NH3⁺), 8.54 (s, 1H, H2), 8.53–8.35 (m, 4H, H8, NH3⁺), 6.01 (d, ³J = 4.8 Hz, 1H, H1'), 4.63 (t, ³J = 4.8 Hz, 1H, H2'), 4.40–4.31 (m, 1H, H4'), 4.22 (t, ³J = 4.8 Hz, 1H, H3'), 4.02 (t, ³J = 6.0 Hz, 1H, Ha), 3.69–3.59 (m, 1H, H5'_A), 3.56–3.47 (m, 1H, H5'_B), 3.39–3.22 (m, 2H, Hg), 3.22–3.13 (m, 2H, H1''), 3.02–2.84 (m, 2H, H3''), 2.57–2.52 (m, 3H, CH₃), 2.27–2.19 (m, 1H, Hb_A), 2.13–2.06 (m, 1H, Hb_B), 2.01–1.87 (m, 2H, H2''); HRMS (ESI): calcd. for C₁₈H₃₁N₈O₅ ^M+H ^⁺: 439.2412, found: 439.2416. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(phenethyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (8m) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (phenethylamino)propyl)amino)butanoic acid (9m). Reductive amination (8m): yield: 66 mg, 0.071 mmol, 24 %. C₄₇H₇₂N₈O₁₁ (925.14 g/mol). HRMS (ESI): calcd. for C₄₇H₇₃N₈O₁₁ ^M+H ^⁺: 925.5393, found: 925.5391. Deprotection (9m): yield: 62 mg, 0.071 mmol, 100 % (3 TFA salt). C₂₅H₃₆N₈O₅ (528.61 g/mol). ¹H- NMR (400 MHz; DMSO-d6): ^ 8.86 (bs, 2H, NH2⁺), 8.73–8.23 (m, 5H, H2, H8, NH3⁺), 8.05 (bs, 3H, NH₃ ⁺), 7.33 (t, ³J = 7.2 Hz, 2H, m-H), 7.29–7.20 (m, 3H, o-H, p-H), 5.98 (d, ³J = 4.8 Hz, 1H, H1'), 4.63 (t, ³J = 4.8 Hz, 1H, H2'), 4.38–4.28 (m, 1H, H4'), 4.21 (t, ³J = 4.8 Hz, 1H, H3'), 3.98 (t, ³J = 5.8 Hz, 1H, Ha), 3.64–3.52 (m, 1H, H5'_A), 3.52–3.41 (m, 1H, H5'_B), 3.25–3.20 (m, 2H, Hg), 3.20– 3.05 (m, 4H, H1'', CH₂–N), 3.03–2.92 (m, 2H, H3''), 2.92–2.77 (m, 2H, CH₂–Ph), 2.27–2.13 (m, ³J = 6.0 Hz, 1H, Hb_A), 2.13–2.01 (m, 1H, Hb_B), 2.00–1.94 (m, 2H, H2''); HRMS (ESI): calcd. for C₂₅H₃₇N₈O₅ ^M+H ^⁺: 529.2881, found: 529.2881. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(3-phenylpropyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6- ((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (8n) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenylpropyl)amino)propyl)amino)butanoic acid (9n). Reductive amination (8n): yield: 104.6 mg, 0.111 mmol, 41 %. C₄₈H₇₄N₈O₁₁ (939.17 g/mol). HRMS (ESI): calcd. for C₄₈H₇₅N₈O₁₁ ^M+H ^⁺: 939.5550, found: 939.5550. Deprotection (9n): yield: 101.8 mg, 0.115 mmol, 100 % (3 TFA salt). C₂₆H₃₈N₈O₅ (542.64 g/mol). ¹H-NMR (400 MHz; DMSO-d₆): ^ 8.68 (bs, 2H, NH₂ ⁺), 8.49 (s, 1H, H2), 8.33 (s, 1H, H8), 8.18 (bs, 3H, NH₃ ⁺), 7.33–7.29 (m, 2H, m-H), 7.22–7.19 (m, 3H, o-H, p-H), 6.00 (d, ³J = 4.9 Hz, 1H, H1'), 4.64 (t, ³J = 4.9 Hz, 1H, H2'), 4.38–4.31 (m, 1H, H4'), 4.23 (t, ³J = 4.9 Hz, 1H, H3'), 4.00 (t, ³J = 6.4 Hz, 1H, Ha), 3.64–3.58 (m, 1H, H5'_A), 3.55–3.44 (m, 1H, H5'_B), 3.31–3.13 (m, 4H, Hg, H1''), 3.00–2.90 (m, 2H, H3''), 2.90–2.78 (m, 2H, CH₂–N), 2.63 (t, ³J = 7.6 Hz, 2H, CH₂–Ph), 2.27–2.18 (m, 1H, Hb_A), 2.11–2.06 (m, 1H, Hb_B), 1.94–1.90 (m, 2H, H2''), 1.90–1.80 (m, 2H, C–CH₂–C); HRMS (ESI): calcd. for C₂₆H₃₇N₈O₅ ^M–H ^^–: 541.2892, found: 541.2894. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(3-phenoxyphenethyl)amino)propyl)(((3aR,4R,6R,6aR)- 6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (8o) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoic acid (9o). Reductive amination (8o): yield: 32.6 mg, 0.032 mmol, 24 %. C₅₃H₇₆N₈O₁₂ (1017.24 g/mol). HRMS (ESI): calcd. for C₅₃H₇₇N₈O₁₂ ^M+H ^⁺: 1017.5655, found: 1017.5651. Deprotection (9o): yield: 18.5 mg, 0.019 mmol, 63 % (3 TFA salt). C31H40N8O6 (620.71 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 8.75 (bs, 3H, NH₃ ⁺), 8.45 (s, 1H, H2), 8.28 (s, 1H, H8), 7.92 (bs, 2H, NH₂ ⁺), 7.42–7.36 (m, 3H, m-H, m-H²), 7.15 (tt, ³J = 7.4 Hz and ⁴J = 1.0 Hz, 1H, p-H²), 7.04–7.00 (m, 3H, o-H, o-H²), 6.94 (t, ⁴J = 1.8 Hz, 1H, o-H'), 6.90–6.87 (m, 1H, p-H), 5.99 (d, ³J = 4.8 Hz, 1H, H1'), 4.65 (t, ³J = 4.8 Hz, 1H, H2'), 4.33–4.32 (m, 1H, H4'), 4.22 (t, ³J = 4.8 Hz, 1H, H3'), 3.98 (m, 1H, Ha), 3.61–3.52 (m, 1H, H5'_A), 3.52–3.42 (m, 1H, H5'_B), 3.31–3.18 (m, 2H, Hg), 3.18–3.04 (m, 4H, H1'', CH₂– N), 3.03–2.92 (m, 2H, H3''), 2.92–2.84 (m, 2H, CH₂–Ph), 2.22–2.16 (m, 1H, Hb_A), 2.05–2.01 (m, 1H, HbB), 1.96–1.91 (m, 2H, H2''); HRMS (ESI): calcd. for C31H41N8O6 ^M+H ^⁺: 621.3144, found: 621.3142. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)((R)-3((tert-butoxycarbonyl)amino)butyl)amino)butanoate (8p) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((R)-3- aminobutyl)amino)butanoic acid (9p). Reductive amination (8p): yield: 79 mg, 0.095 mmol, 35 %. C₄₀H₆₆N₈O₁₁ (835.01 g/mol). HRMS (ESI): calcd. for C40H67N8O11 ^M+H ^⁺: 835.4924, found: 835.4920. Deprotection (9p): yield: 80 mg, 0.102 mmol, 100 % (3 TFA salt). C₁₈H₃₀N₈O₅ (438.49 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 8.62–8.49 (m, 7H, H2, 2 x NH₃ ⁺), 8.40 (s, 1H, H8), 8.02 (m, 3H, NH₃ ⁺), 6.02 (d, ³J = 4.8 Hz, 1H, H1'), 4.64 (t, ³J = 4.8 Hz, 1H, H2'), 4.43–4.32 (m, 1H, H4'), 4.22 (t, ³J = 4.8 Hz, 1H, H3'), 4.04–4.01 (m, 1H, Ha), 3.68–3.62 (m, 1H, H5'_A), 3.55–3.51 (m, 1H, H5'_B), 3.34– 3.19 (m, 5H, H1'', H3'', Hg), 2.31–2.18 (m, 1H, Hb_A), 2.18–2.05 (m, 1H, Hb_B), 1.98–1.80 (m, 2H, H2''_A&B), 1.14 (d, ³J = 6.4 Hz, 3H, CH₃); HRMS (ESI): calcd. for C₁₈H₃₁N₈O₅ ^M+H ^⁺: 439.2412, found: 439.2413. tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((3-((tert-butoxycarbonyl)amino)-4,4,4- trifluorobutyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (8q) & (2S)-2-amino-4- ((3-amino-4,4,4-trifluorobutyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (9q). Reductive amination (8q): yield: 42 mg, 0.048 mmol, 25 %. C₄₀H₆₃N₈O₁₁ (888.98 g/mol). HRMS (ESI): calcd. for C₄₀H₆₄N₈O₁₁F₃ ^M+H ^⁺: 889.4641, found: 889.4639. Deprotection (9q): yield: 36 mg, 0.073 mmol, 100 % (3 TFA salt). C₁₈H₂₇F₃N₈O₅ (492.46 g/mol). ¹H-NMR (400 MHz; DMSO-d₆): ^ 8.48 (s, 1H, H2), 8.31 (s, 1H, H8), 8.15 (bs, 2H, NH₂), 5.98 (d, ³J = 5.1 Hz, 1H, H1'), 4.65 (t, ³J = 5.1 Hz, 1H, H2'), 4.32–4.30 (m, 1H, H4'), 4.20–4.19 (m, 1H, H3'), 4.16–4.03 (m, 1H, H3''), 3.99 (t, ³J = 6.6 Hz, 1H, Ha), 3.54–3.45 (m, 1H, H5'_A), 3.41–3.37 (m, 1H, H5'_B), 3.28–3.19 (m, 2H, Hg), 3.14–3.11 (m, 2H, H1''), 2.23–1.90 (m, 4H, Hb, H2''); HRMS (ESI): calcd. for C₁₈H₂₈N₈O₅F₃ ^M+H ^⁺: 493.2129, found: 493.2130. tert-butyl (S)-4-((4-((tert-butoxycarbonyl)(methyl)amino)butyl)(((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (8r) & (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(4-(methylamino)butyl)amino)butanoic acid (9r). Reductive amination (8r): yield: 88.9 mg, 0.105 mmol, 39 %. C₄₁H₆₈N₈O₁₁ (849.04 g/mol). HRMS (ESI): calcd. for C₄₁H₆₉N₈O₁₁ ^M+H ^⁺: 849.5080, found: 849.5077. Deprotection (9r): yield: 73.1 mg, 0.092 mmol, 100 % (3 TFA salt). C₁₉H₃₂N₈O₅ (452.52 g/mol).¹H- NMR (400 MHz; DMSO-d6): ^ 8.63 (bs, 3H, NH2⁺), 8.56 (s, 1H, H2), 8.48 (bs, 3H, NH3⁺), 8.38 (s, 1H, H8), 6.02 (dd, ³J = 4.8, 2.0 Hz, 1H, H1'), 4.64 (t, ³J = 4.8 Hz, 1H, H2'), 4.42–4.31 (m, 1H, H4'), 4.22 (t, ³J = 4.8 Hz, 1H, H3'), 4.07–3.98 (m, 1H, Ha), 3.72–3.60 (m, 1H, H5'_A), 3.59–3.49 (m, 1H, H5'_B), 3.39– 3.30 (m, 1H, Hg_A), 3.30–3.19 (m, 1H, Hg_B), 3.19–3.06 (m, 2H, H1''), 2.86–2.75 (m, 2H, H4''), 2.55–2.50 (m, 3H, CH₃), 2.29–2.17 (m, 1H, Hb_A), 2.17–2.04 (m, 1H, Hb_B), 1.64–1.57 (m, 2H, H2''), 1.57–1.51 (m, 2H, H3''); HRMS (ESI): calcd. for C₁₉H₃₃N₈O₅ ^M+H ^⁺: 453.2568, found: 453.2569. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)(((1s,3S)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)amino)butanoate (8s) & (S)- 2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(((1s,3S)-3-aminocyclobutyl)methyl)amino)butanoic acid (9s). Reductive amination (8s): yield: 146 mg, 0.172 mmol, 56 %. C₄₁H₆₆N₈O₁₁ (847.02 g/mol). Deprotection (9s): yield: 100 mg, 0.126 mmol, 82 % (3 TFA salt). C₁₉H₃₀N₈O₅ (450.50 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 8.53 (s, 1H, H2), 8.51–8.33 (m, 4H, H8, NH₃ ⁺), 8.08 (bs, 3H, NH₃ ⁺), 6.00 (d, ³J = 4.8 Hz, 1H, H1'), 4.63 (t, ³J = 4.8 Hz, 1H, H2'), 4.39–4.29 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.01 (t, ³J = 6.0 Hz, 1H, Ha), 3.66–3.56 (m, 1H, H5'_A), 3.56–3.45 (m, 2H, H4'', H5'_B), 3.35–3.19 (m, 4H, Hg_A, Hg_B, H1''), 2.45–2.38 (m, 2H, H2'', H3''_A1), 2.28–2.20 (m, 2H, Hb_A, H3''_A2), 2.12–2.08 (m, 1H, Hb_B), 1.95–1.77 (m, 2H, H3''_B1, H3''_B2); HRMS (ESI): calcd. for C₁₉H₃₁N₈O₅ ^M+H ^⁺: 451.2412, found: 451.2412. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)(((1r,3R)-3-((tert-butoxycarbonyl)amino)cyclobutyl)methyl)amino)butanoate (8t) & (S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(((1r,3R)-3-aminocyclobutyl)methyl)amino)butanoic acid (9t). Reductive amination (8t): yield: 160 mg, 0.189 mmol, 61 %. C₄₁H₆₆N₈O₁₁ (847.02 g/mol). Deprotection (9t): yield: 127 mg, 0.160 mmol, 86 % (3 TFA salt). C₁₉H₃₀N₈O₅ (450.50 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 8.50 (s, 1H, H2), 8.33 (s, 1H, H8), 8.17 (bs, 2H, NH₃ ⁺), 8.09 (bs, 2H, NH₃ ⁺), 5.99 (d, ³J = 4.8 Hz, 1H, H1'), 4.64 (t, ³J = 4.8 Hz, 1H, H2'), 4.38–4.29 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.00 (t, ³J = 6.2 Hz, 1H, Ha), 3.60–3.47 (m, 3H, H5', H4''), 3.29–3.18 (m, 3H, Hg, H1''), 2.55–2.39 (m, 2H, H2'', H3''_A1), 2.25–2.19 (m, 2H, Hb_A, H3''_A2), 2.11–2.07 (m, 1H, Hb_B), 1.93– 1.80 (m, 2H, H3''_B1, H3''_B2); HRMS (ESI): calcd. for C₁₉H₃₁N₈O₅ ^M+H ^⁺: 451.2412, found: 451.2415. tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-(((S)-3-((tert-butoxycarbonyl)amino)-4- methylpentyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (8u) & (S)-2-amino-4- (((S)-3-amino-4-methylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (9u). Reductive amination (8u): yield: 179 mg, 0.205 mmol, 75 %. C₄₂H₇₀N₈O₁₁ (863.07 g/mol). HRMS (ESI): calcd. for C42H71N8O11 ^M+H ^⁺: 863.5237, found: 863.5236. Deprotection (9u): yield: 191 mg, 0.236 mmol, 100 % (3 TFA salt). C₂₀H₃₄N₈O₅ (466.54 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 8.65–8.41 (m, 4H, H2, NH₃ ⁺), 8.38 (s, 1H, H8), 7.97 (bs, 3H, NH₃ ⁺), 6.02 (d, ³J = 4.8 Hz, 1H, H1'), 4.65 (t, ³J = 4.8 Hz, 1H, H2'), 4.38–4.35 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.03 (t, ³J = 5.8 Hz, 1H, Ha), 3.68–3.54 (m, 2H, H5'), 3.35–3.18 (m, 4H, Hg, H1''), 3.03 (bs, 1H, H3''), 2.26–2.22 (m, 1H, Hb_A), 2.15–2.10 (m, 1H, Hb_B), 1.92–1.78 (m, 3H, H2'', CH- iPr), 0.87 (s, 3H, CH3-iPr), 0.85 (s, 3H, CH3-iPr). tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((3-((tert-butoxycarbonyl)amino)-5- methylhexyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (8v) & (2S)-2-amino-4-((3- amino-5-methylhexyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methyl)amino)butanoic acid (9v). Reductive amination (8v): yield: 143 mg, 0.163 mmol, 69 %. C₄₃H₇₂N₈O₁₁ (877.09 g/mol). HRMS (ESI): calcd. for C43H73N8O11 ^M+H ^⁺: 877.5393, found: 877.5392. Deprotection (9v): yield: 147 mg, 0.179 mmol, 100 % (3 TFA salt). C₂₁H₃₆N₈O₅ (480.57 g/mol). ¹H- NMR (400 MHz; DMSO-d₆): ^ 8.55 (s, 1H, H2), 8.55–8.38 (m, 6H, 2 x NH₃ ⁺), 8.38 (s, 1H, H8), 7.96 (bs, 3H, NH₃ ⁺), 6.02 (d, ³J = 4.4 Hz, 1H, H1'), 4.66–4.57 (m, 1H, H2'), 4.38–4.36 (m, 1H, H4'), 4.28– 4.19 (m, 1H, H3'), 4.02 (t, ³J = 5.6 Hz, 1H, Ha), 3.72–3.63 (m, 1H, H5'_A), 3.58–3.48 (m, 1H, H5'_B), 3.36–3.19 (m, 5H, Hg, H1'', H3''), 2.31–2.19 (m, 1H, Hb_A), 2.16–2.08 (m, 1H, Hb_B), 1.91–1.84 (m, 2H, H2''), 1.64–1.44 (m, 1H, CH-iPr), 1.43–1.27 (m, 1H, H4''_A), 1.25–1.15 (m, 1H, H4''_B), 0.81–0.71 (m, 6H, 2 x CH3-iPr). tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-4-((3-((tert-butoxycarbonyl)amino)-3- methylbutyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (8w) & (S)-2-amino-4-((3- amino-3-methylbutyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran- 2-yl)methyl)amino)butanoic acid (9w). Reductive amination (8w): yield: 60 mg, 0.071 mmol, 26 %. C₄₁H₆₈N₈O₁₁ (849.04 g/mol). HRMS (ESI): calcd. for C₄₁H₆₉N₈O₁₁ ^M+H ^⁺: 849.5080, found: 849.5077. Deprotection (9w): yield: 58 mg, 0.073 mmol, 100 % (3 TFA salt). C₁₉H₃₂N₈O₅ (452.52 g/mol). ¹H- NMR (400 MHz; DMSO-d₆): ^ 8.53 (s, 1H, H2), 8.51–8.25 (m, 4H, H8, NH₃ ⁺), 8.08 (bs, 3H, NH₃ ⁺), 6.01 (d, ³J = 4.8 Hz, 1H, H1'), 4.67 (t, ³J = 4.8 Hz, 1H, H2'), 4.38–4.34 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.03–4.00 (m, 1H, Ha), 3.66–3.61 (m, 1H, H5'_A), 3.57–3.47 (m, 1H, H5'_B), 3.40– 3.14 (m, 4H, Hg, H1''), 2.28–2.20 (m, 1H, Hb_A), 2.15–2.06 (m, 1H, Hb_B), 1.97–1.85 (m, 2H, H2''), 1.16 (s, 3H, CH₃), 1.13 (s, 3H, CH₃). tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-4-((((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)(3-((tert-butoxycarbonyl)amino)hexyl)amino)butanoate (8x) & (2S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- aminohexyl)amino)butanoic acid (9x). Reductive amination (8x): yield: 61.2 mg, 0.071 mmol, 35 %. C₄₂H₇₀N₈O₁₁ (863.07 g/mol). HRMS (ESI): calcd. for C₄₂H₇₁N₈O₁₁ ^M+H ^⁺: 863.5237, found: 863.5237. Deprotection (9x): yield: 60.5 mg, 0.075 mmol, 100 % (3 TFA salt). C₂₀H₃₄N₈O₅ (466.54 g/mol). ¹H-NMR (400 MHz; DMSO-d₆): ^ 8.78–8.30 (m, 8H, H2, H8, 2 x NH₃ ⁺), 7.95 (bs, 3H, NH₃ ⁺), 6.01 (d, J = 4.8 Hz, 1H, H1'), 4.66–4.60 (m, 1H, H2'), 4.37–4.34 (m, 1H, H4'), 4.26–4.20 (m, 1H, H3'), 4.02 (t, J = 5.4 Hz, 1H, Ha), 3.70–3.61 (m, 1H, H5'_A), 3.54–3.50 (m, 1H, H5'_B), 3.32–3.08 (m, 5H, Hg, H1'', H3''), 2.30–2.19 (m, 1H, Hb_A), 2.15–2.06 (m, 1H, Hb_B), 1.93–1.80 (m, 2H, H2''), 1.43–1.36 (m, 2H, H4''), 1.24–1.16 (m, 2H, H5''), 0.87–0.72 (m, 3H, H6''); HRMS (ESI): calcd. for C₂₀H₃₅N₈O₅ ^M+H ^⁺: 467.2725, found: 467.2725. methyl (tert-butoxycarbonyl)-L-homoserinate (59) To a solution of (S)-4-(methoxy)-3-((tert- butoxycarbonyl)amino)-4-oxobutanoic acid (1 eq.) and Et3N (1.1 eq.) in dry THF (0.25 ^M based on (S)-4-(methoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid) was added isobutyl chloroformate (1.1 eq.) at -5 °C. The mixture was stirred for 30 min then the white precipitate was filtered off. The solution containing the corresponding anhydride was recovered, and MeOH (0.25 M based on (S)-4-(methoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutanoic acid) and NaBH₄ (2 eq.) were added portionwise at 0 °C. The solution was then stirred at rt for 2 h. The reaction was quenched by the addition of a 1 M NH₄Cl solution then extracted three times with AcOEt and the combined organics were washed once with brine, before being dried over Na₂SO₄, filtered and evaporated. The resulting residue was purified on silica gel column eluting with CyHex/AcOEt to afford the desired product. yield: 1.95 g, 8.37 mmol, 70 %) as a colorless oil. C₁₀H₁₉NO₅ (233.26 g/mol).¹H-NMR (400 MHz, DMSO-d₆): ^ 7.19 (d, ³J = 7.6 Hz, 1H, NH carbamate), 4.59 (t, ³J = 5.0 Hz, 1H, OH), 4.11–4.05 (m, 1H, Ha), 3.61 (s, 3H, CH₃), 3.47–3.37 (m, 2H, Hg), 1.82–1.75 (m, 1H, Hb_A), 1.72–1.64 (m, 1H, Hb_B), 1.37 (s, 9H, CH₃ tBu). methyl (S)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (60) To a solution of oxalyl chloride (1.5 eq.) in dry CH₂Cl₂ (0.3 M) at -78 °C was added DMSO (2 eq.) in CH₂Cl₂. After 15 min the alcohol 59 (1 eq.) in CH₂Cl₂ was added. After 30 min, Et₃N was added (5 eq.) and the mixture was allowed to warm up to rt. The organic phase was washed with a freshly prepared citric acid solution (5 % w/w), then an aq. sat. NaHCO₃ solution and brine, before being dried over Na₂SO₄, filtered and evaporated. The crystalline residue was pure enough to be used without further purification. yield: 1.65 g, 7.13 mmol, 86 %). C₁₀H₁₇NO₅ (231.25 g/mol). ¹H-NMR (400 MHz, DMSO-d₆): ^ 9.59 (t, ³J = 1.4 Hz, 1H, CHO), 7.34 (d, ³J = 6.8 Hz, 1H, NH carbamate), 4.54–4.46 (m, 1H, Ha), 3.62 (s, 3H, CH₃), 2.84 (ddd, ²J = 17.4 Hz, ³J = 5.2 H and ⁴J = 1.4 Hz, 1H, Hb_A), 2.72 (ddd, ²J = 17.4 Hz, ³J = 8.4 Hz and ⁴J = 1.4 Hz, 1H, Hb_A), 1.37 (s, 9H, CH₃ tBu). General procedure for the preparation of extended N-Boc protected amino-alcohols. To a mixture of aldehyde 7a (2-phenylacetaldehyde), 7b (3-phenylpropionaldehyd), and 7c (2-(3- phenoxyphenyl)acetaldehyde), respectively (1 eq.) and 3-amino-1-propanol (1 eq.) in anhydrous CH₂Cl₂ (0.2 M) was added Et₃N (2.5 eq.) at rt, and the resulting solution was stirred vigorously for 1 h. Then, Boc₂O (1.2–3 eq.) followed by NaBH(OAc)₃ (2 eq.). The reaction was stirred for an additional 16 h at rt, quenched with saturated NaHCO₃ solution, and extracted with CH₂Cl₂. The combined organics were dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (CH₂Cl₂/MeOH 99:1–95:5). tert-butyl (3-hydroxypropyl)(phenethyl)carbamate (61). yield: 111 mg, 0.39 mmol, 8 %. C₁₆H₂₅NO₃ (279.38 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 7.33–7.25 (m, 2H, m-H), 7.23–7.16 (m, 3H, o-H, p-H), 4.41 (t, ³J = 5.4 Hz, 1H, OH), 3.37 (q, ³J = 5.9 Hz, 2H, CH₂–O), 3.34–3.29 (m, 2H, Ph–C–CH₂– N), 3.21–3.08 (m, 2H, N–CH₂), 2.75 (t, ³J = 7.4 Hz, 2H, CH₂–Ph), 1.59 (quint, ³J = 6.8 Hz, 2H, C– CH2–C), 1.43–1.28 (m, 9H, CH3 tBu); APCI-MS(+): m/z 180.1 [M–Boc+2H]⁺. tert-butyl (3-hydroxypropyl)(3-phenylpropyl)carbamate (62). yield: 302 mg, 1.69 mmol, 23 %. C₁₇H₂₇NO₃ (293.41 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 7.29–7.25 (m, 2H, m-H), 7.21–7.14 (m, 3H, o-H, p-H), 4.43–4.41 (m, 1H, OH), 3.38 (q, ³J = 5.9 Hz, CH₂–O, 2H), 3.18–3.10 (m, 4H, 2 x CH₂– N), 2.58–2.49 (m, 2H, Ph–CH₂), 1.75–1.70 (m, 2H, Ph–C–CH₂–N), 1.61–1.58 (m, 2H, O–C–CH₂–C–N), 1.41–1.36 (m, 9H, CH₃ tBu); APCI-MS(+): m/z 194.2 [M–Boc+2H]⁺. tert-butyl (3-hydroxypropyl)(3-phenoxyphenethyl)carbamate (63). yield: 71 mg, 191 mmol, 12 %. C₂₂H₂₉NO₄ (371.48 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 7.38 (dd, ³J = 8.4 Hz and J = 7.6 Hz, 2H, m''-H), 7.30 (dd, ³J = 8.0 Hz and ³J = 7.6 Hz, 1H, m-H), 7.13 (t, ³J = 7.4 Hz, 1H, p''-H), 7.00–6.96 (m, 3H, o''-H, o-H), 6.84 (d, ³J = 7.2 Hz, 2H, p-H, o'-H), 4.40 (t, ³J = 5.0 Hz, 1H, OH), 3.39–3.33 (m, 2H, CH₂–O), 3.33–3.27 (m, 2H, Ph–C–CH₂–N), 3.13–3.07 (m, 2H, N–CH₂), 2.73 (t, ³J = 7.2 Hz, 2H, CH₂–Ph), 1.57 (quintet, ³J = 6.8 Hz, 2H, C–CH₂–C), 1.40–1.26 (m, 9H, CH₃ tBu); APCI- MS(+): m/z 270.3 [M–Boc+2H]⁺. General procedure for the preparation of extended N-Boc protected amino-aldehydes. To a solution of oxalyl chloride (1.5 eq.) in dry CH₂Cl₂ (0.3 ^M) at -78 °C was added DMSO (2 eq.) in CH₂Cl₂. After 15 min, N-Boc protected amino-alcohol (61-63) (1 eq.) in CH₂Cl₂ was added. After 30 min, Et₃N was added (5 eq.) and the mixture was allowed to warm up to rt. The organic phase was washed with a freshly prepared citric acid solution (5 % w/w), then an aq. sat. NaHCO₃ solution and brine, before being dried over Na₂SO₄, filtered and evaporated. The corresponding residue was pure enough to be used without further purification. tert-butyl (3-oxopropyl)(phenethyl)carbamate (7d). yield: 84.2 mg, 0.3 mmol, 77 %. C16H23NO3 (277.36 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 9.64 (t, ³J = 1.6 Hz, 1H, CHO), 7.33–7.25 (m, 2H, m-H), 7.22–7.18 (m, 3H, o-H, p-H), 3.39–3.38 (m, 2H, N–CH₂), 3.36–3.28 (m, 2H, CH₂–N), 2.74 (t, ³J = 7.6 Hz, 2H, CH₂–Ph), 2.60 (td, ³J = 6.7 Hz and ³J = 1.6 Hz, 1H, CH₂–CHO), 1.36–1.32 (m, 9H, CH₃ tBu). tert-butyl (3-oxopropyl)(3-phenylpropyl)carbamate (7e). yield: 235 mg, 0.806 mmol, 80 %. C₁₇H₂₅NO₃ (291.39 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 9.65 (s, 1H, CHO), 7.29–7.26 (m, 2H, m-H), 7.21–7.14 (m, 3H, o-H, p-H), 3.43 (t, ³J = 6.6 Hz, 2H, CHO–C–CH₂–N), 3.23–3.06 (m, 2H, CH₂–N), 2.61 (t, ³J = 6 Hz, 2H, CH₂–CHO), 2.57–2.49 (m, 2H, CH₂–Ph), 1.77–1.73 (m, 2H, C–CH₂–C), 1.41–1.36 (m, 9H, CH₃ tBu); APCI-MS(+): m/z 192.2 [M–Boc+2H]⁺. tert-butyl (3-oxopropyl)(3-phenoxyphenethyl)carbamate (7f). yield: 49.8 mg, 0.135 mmol, 72 %. C₂₂H₂₇NO₄ (369.46 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 9.63 (s, 1H, CHO), 7.38 (dd, ³J = 8.4 Hz and ³J = 7.6 Hz, 2H, m''-H), 7.30 (t, ³J = 8.0 Hz, 1H, m-H), 7.13 (t, ³J = 7.4 Hz, 1H, p''-H), 7.00–6.96 (m, 3H, o''-H, o-H), 6.84 (d, ³J = 6.8 Hz, 2H, p-H, o'-H), 3.42–3.34 (m, 2H, CHO–C–CH₂– N), 3.34–3.26 (m, 2H, CH₂–N), 2.73 (t, ³J = 7.2 Hz, 2H, CH₂–Ph), 2.59 (td, ³J = 6.6 Hz and ³J = 1.6 Hz, 2H, CH₂–CHO), 1.40–1.22 (m, 9H, CH₃ tBu). Synthesis of deaza and deoxy compounds 72a and 72b (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2- diol (64). To a solution of (1R,2S,3R,5R)-3-amino-5-(hydroxymethyl)cyclopentane-1,2-diol hydrochloride (5.0 g, 27 mmol, 1 eq.) in Abs. grade EtOH (234 mL) was added 4,6- dichloropyrimidin-5-acetaldehyde (5.15 g, 27 mmol, 1 eq.) and Et₃N (12.5 mL, 53.9 mmol, 2 eq.). The reaction mixture was refluxed (90 °C) for 16 h. Volatiles were then evaporated in vacuo and the corresponding residue was purified by silica gel flash column chromatography (CH2Cl2/MeOH 99:1–90:10) to afford compound 64 as a yellow solid (7.39 g, 26 mmol, 97 %). C₁₂H₁₄N₃O₃Cl (283.71 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 8.61 (s, 1H, H2), 7.91 (d, ³J = 3.6 Hz, 1H, H8), 6.68 (d, ³J = 3.6 Hz, 1H, H7), 5.04 (dt, ³J = 10.2 Hz and ³J = 8.9 Hz, 1H, H1'), 4.89–4.75 (m, 3H, 3 x OH), 4.23 (dd, ³J = 8.9 Hz and ³J = 5.2 Hz, 1H, H2'), 3.83 (dd, ³J = 5.2 Hz and ³J = 2.8 Hz, 1H, H3'), 3.52– 3.43 (m, 2H, H5'), 2.22 (dt, ³J = 12.8 Hz ³J = 8.9 Hz, 1H, H6'_A), 2.09–2.02 (m, 1H, H4'), 1.61 (ddd, ³J = 12.8 Hz, ³J = 10.2 Hz and ³J = 7.6 Hz, 1H, H6'B); APCI-MS(+): m/z 284.0 [M+H]⁺. ((3aR,4R,6R,6aS)-6-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)methanol (65). To a solution of 64 (7.39 g, 25.8 mmol, 1 eq.) in acetone (685 mL) was added CH(OEt)₃ (21.6 mL, 128.9 mmol, 5 eq.) followed by pTsOH (24.7 g, 128.9 mmol, 5 eq.) and the mixture was stirred at rt for 16. After quenching with 5 % NaHCO₃, most of acetone was evaporated and the remaining aqueous solution was extracted 3 times with CH₂Cl₂. The combined organic layer were dried over Na₂SO₄, filtered and evaporated to afford the crude product subjected to flash column chromatography (CH2Cl2/MeOH 99.6:0.4–97.5:2.5). The pure compound 65 was obtained as a beige foam (4.81 g, 14.8 mmol, 58 %). C₁₅H₁₈N₃O₃Cl (323.78 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 8.65 (s, 1H, H2), 7.96 (d, ³J = 3.8 Hz, 1H, H8), 6.72 (d, ³J = 3.8 Hz, 1H, H7), 5.12–5.06 (m, 1H, H1'), 4.91 (t, ³J = 7.0 Hz, 1H, H2'), 4.81 (t, ³J = 5.4 Hz, 1H, OH-5'), 4.55 (dd, ³J = 7.0 Hz and ³J = 4.4 Hz, 1H, H3'), 3.52 (td, ³J = 5.2 Hz and ⁴J = 0.8 Hz, 2H, H5'), 2.28–2.21 (m, 2H, H4', H6'_A), 2.13–2.08 (m, 1H, H6'_B), 1.48 (s, 3H, CH₃), 1.22 (s, 3H, CH₃); APCI- MS(+): m/z 324.1 [M+H]⁺. ((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro- 4H-cyclopenta[d][1,3]dioxol-4-yl)methanol (66). To a solution of 65 (4.81 g, 14.7 mmol) in n-BuOH (37 mL), in a µ-waves reactor, was added 37 mL of a 33 % CH₃NH₂ solution in EtOH. The reaction mixture was stirred under µ-waves irradiation at 120 °C (100 W, 6–7 bar) for 15 min. After completion of the reaction, the volatiles were evacuated and the crude product was used without further purification (4.46 g, 14.0 mmol, 95 %). C₁₆H₂₂N₄O₃ (318.38 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 8.14 (s, 1H, H2), 7.66 (bs, 1H, NH), 7.32 (d, ³J = 3.6 Hz, 1H, H8), 6.60 (d, ³J = 3.6 Hz, 1H, H7), 4.97–4.89 (m, 1H, H1'), 4.86 (t, ³J = 6.6 Hz, 1H, H2'), 4.81–4.79 (m, 1H, OH-5'), 4.51 (dd, ³J = 6.8 Hz and ³J = 4.4 Hz, 1H, H3'), 3.49 (s, 2H, H5'), 2.95 (d, ³J = 4.4 Hz, 3H, N-CH₃), 2.20–2.14 (m, 2H, H4', H6'_A), 2.09–1.97 (m, 1H, H6'_B), 1.46 (s, 3H, CH₃), 1.21 (s, 3H, CH₃); APCI- MS(+): m/z 319.4 [M+H]⁺. 7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)- N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (67). To a suspension of 66 (4.5 g, 13.9 mmol, 1 eq.) in dry dioxane (55 mL) at 0 °C were added DPPA (12.0 mL, 55.5 mmol, 4 eq.) and DBU (12.6 mL, 83.3 mmol, 6 eq.). The mixture was stirred at rt for 16 h. NaN₃ (4.6 g, 69.4 mmol, 5 eq.) and 15-crown-5 (2.9 mL, 13.9 mmol, 1 eq.) were added and the mixture was heated at 110 °C for 6 h. The organic phase was evaporated, water was added and the aqueous phase was extracted three times with AcOEt. The combined organic phase were dried over Na₂SO₄, filtered and evaporated. The residue was purified on silica gel column eluting with CH₂Cl₂/MeOH (99.5:05– 96.5:3.5) to afford 67 (1.3 g, 3.9 mmol, 28 %) as a yellow foam. C₁₆H₂₁N₇O₂ (343.39 g/mol).¹H- NMR (400 MHz, DMSO-d₆): ^ 8.14 (s, 1H, H2), 7.47 (d, ³J = 4.6 Hz, 1H, NH), 7.29 (d, ³J = 3.6 Hz, 1H, H8), 6.56 (d, ³J = 3.6 Hz, 1H, H7), 4.95 (dt, ³J = 12.4 Hz and ³J = 6.4 Hz, 1H, H1'), 4.89 (t, ³J = 6.4 Hz, 1H, H2'), 4.51 (dd, ³J = 7.2 Hz and ³J = 5.2 Hz, 1H, H3'), 3.57–3.44 (m, 2H, H5'), 2.95 (d, ³J = 4.6 Hz, 3H, N–CH3), 2.35–2.20 (m, 2H, H4', H6'A), 2.12–1.97 (m, 1H, H6'B), 1.47 (s, 3H, CH3), 1.22 (s, 3H, CH₃); APCI-MS(+): m/z 344.4 [M+H]⁺. tert-butyl (7-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (68). To a solution of 67 (566 mg, 1.63 mmol, 1 eq.) in dry THF (7.1 mL) with traces of DMF at 0 °C was added 60 % suspended in oil NaH (163 mg, 4.08 mmol, 2.5 eq.). After 45 min stirring at rt, the solution was cooled down to 0 °C and Boc2O (380 µL, 1.63 mmol, 1 eq.) was added. The mixture was stirred at rt for an extra 1.5 h. The mixture was cooled again to 0 °C and same amount of 60 % suspended in oil NaH and Boc₂O were added sequentially. After 3 h at rt, full conversion was observed according to TLC. Cold brine was added and the aqueous phase was extracted three times with AcOEt. The combined organic phase were dried over Na₂SO₄, filtered and evaporated. The residue was purified on silica gel column eluting with CH₂Cl₂/MeOH (99.5:0.5– 97.5:2.5) to afford 68 (537 mg, 1.21 mmol, 74 %) as a orange oil. C₂₁H₂₉N₇O₄ (443.51 g/mol).¹H- NMR (400 MHz, DMSO-d6): ^ 8.62 (s, 1H, H2), 7.72 (d, ³J = 3.6 Hz, 1H, H8), 6.45 (d, ³J = 3.6 Hz, 1H, H7), 5.12 (dt, ³J = 12.4 Hz and ³J = 6.2 Hz, 1H, H1'), 4.92 (dd, ³J = 7.2 Hz and ³J = 6.2 Hz, 1H, H2'), 4.53 (dd, ³J = 7.2 Hz and ³J = 5.2 Hz, 1H, H3'), 3.60–3.46 (m, 2H, H5'), 3.35 (s, 3H, N–CH₃), 2.39– 2.27 (m, 2H, H4', H6'_A), 2.17–2.05 (m, 1H, H6'_B), 1.49 (s, 3H, CH₃), 1.44 (s, 9H, CH₃ tBu), 1.23 (s, 3H, CH₃); APCI-MS(+): m/z 388.5 [M–tBu+2H]⁺, 444.6 [M+H]⁺. tert-butyl (7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (69). To a solution of 68 (1.38 g, 3.08 mmol, 1 eq.) in AcOEt/MeOH (1:1, 10 mL) was added Pd/C (103 mg, 10 % w/w). The suspension was put under H₂ and stirred at rt for 6 h, then filtered on celite® pad and evaporated to afford the desired product (1.19 g, 2.84 mmol, 92 %) as a dark grey oil. C₂₁H₃₁N₅O₄ (417.51 g/mol).¹H-NMR (400 MHz, DMSO-d₆): ^ 8.62 (s, 1H, H2), 7.75 (d, ³J = 3.6 Hz, 1H, H8), 6.43 (d, ³J = 3.6 Hz, 1H, H7), 5.08 (dt, ³J = 12.4 Hz and ³J = 6.2 Hz, 1H, H1'), 4.88 (t, ³J = 6.8 Hz, 1H, H2'), 4.50 (dd, ³J = 6.8 Hz and ³J = 4.8 Hz, 1H, H3'), 3.34 (s, 3H, N–CH₃), 2.77–2.69 (m, 1H, H5'_A), 2.68–2.59 (m, 1H, H5'_B), 2.26 (dt, ³J = 12.4 Hz and ³J = 6.2 Hz, 1H, H6'_A), 2.18–2.07 (m, 1H, H4'), 2.06–1.95 (m, 1H, H6'_B), 1.47 (s, 3H, CH₃), 1.44 (s, 9H, CH₃ tBu), 1.22 (s, 3H, CH₃); APCI- MS(+): m/z 318.5 [M–Boc+2H]⁺, 362.5 [M–tBu+H]⁺, 418.7 [M+H]⁺. tert-butyl (S)-4-((((3aR,4R,6R,6aS)-6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydrofuro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2- ((tert-butoxycarbonyl)amino)butanoate (70).

To a stirred solution of 69 (400 mg, 0.96 mmol, 1.1 eq.) and 5 (240 mg, 0.87 mmol, 1 eq.) in dry DCE (7.5 mL) was added AcOH (55 µL, 0.96 mmol, 1.1 eq.). The solution was stirred for 3 h at rt, then NaBH(OAc)₃ (484 mg, 2.26 mmol, 2.6 eq.) was added and the mixture was stirred for 4 h at rt. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.4:0.6–95:5) to afford the secondary amine 70 (180.1 mg, 0.27 mmol, 31 %) as a beige foam. C₃₄H₅₄N₆O₈ (674.84 g/mol).¹H-NMR (400 MHz; DMSO-d₆): ^ 8.61 (s, 1H, H2), 7.74 (d, J = 3.8 Hz, 1H, H8), 7.34 (d, J = 7.2 Hz, 1H, NH Carbamate), 6.44 (d, J = 3.8 Hz, 1H, H7), 5.08 (dt, J = 12.4 Hz and J = 6.2 Hz, 1H, H1'), 4.90 (t, J = 6.6 Hz, 1H, H2'), 4.48–4.45 (m, 1H, H3'), 3.95–3.86 (m, 1H, Ha), 2.76–2.65 (m, 1H, H5'_A), 2.64–2.58 (m, 1H, Hg_A), 2.56–2.50 (m, 2H, H5'_B, Hg_B), 2.33– 2.29 (m, 1H, H6'A), 2.25–2.19 (m, 1H, H4'), 2.07–1.98 (m, 1H, H6'B), 1.77–1.72 (m, 1H, HbA), 1.71–1.64 (m, 1H, Hb_B), 1.47 (s, 3H, CH₃), 1.44 (s, 9H, CH₃ tBu), 1.38 (s, 9H, CH₃ tBu), 1.28 (s, 9H, CH₃ tBu), 1.22 (s, 3H, ; CH₃). General Procedure for the 2^nd reductive amination (71) and the final deprotection (72). To a stirred solution of 70 (1.1 eq.) and an aldehyde 7 or 170d (1 eq.) in dry DCE (0.12 M based on 70) was added AcOH (1.1 eq.). The solution was stirred for 4 h at rt, then NaBH(OAc)3 (2.6 eq.) was added and the mixture was stirred for 4 h at rt and 12 h at 70 °C. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (mostly 99.5:0.5–94:6) to afford the tertiary amines 71 as yellow oils. Tertiary amines 71 (or secondary amines 70) were dissolved (0.02 ^M) in freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired products 72 as foams (2 or 3 TFA salt). (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)cyclopentyl)methyl)amino)butanoic acid (72a). Deprotection (72a): yield: 24.5 mg, 0.04 mmol, 100 % (2 TFA salt). C₁₇H₂₆N₆O₄ (378.43 g/mol). ¹H-NMR (400 MHz; DMSO-d₆): ^ 9.52 (bs, 1H, NH), 8.68 (bs, 2H, NH₂ ⁺), 8.48 (bs, 3H, NH₃ ⁺), 8.36 (s, 1H, H2), 7.61 (s, 1H, H8), 6.90 (s, 1H, H7), 4.97–4.91 (m, 1H, H1'), 4.17 (t, J = 6.6 Hz, 1H, H2'), 4.04 (s, 1H, Ha), 3.88 (t, J = 5.2 Hz, 1H, H3'), 3.28–3.17 (m, 1H, H5'_A), 3.17–2.99 (m, 6H, H5'_B, Hg, CH₃), 2.37–2.29 (m, 1H, H6'_A), 2.27–2.17 (m, 2H, H4', Hb_A), 2.10–2.06 (m, 1H, Hb_B), 1.64–1.56 (m, 1H, H6'_B); HRMS (ESI): calcd. for C₁₇H₂₇N₆O₄ ^M+H ^⁺: 379.2088, found: 379.2092. tert-butyl (S)-4-((((3aR,4R,6R,6aS)-6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)(3-((tert- butoxycarbonyl)(phenethyl)amino)propyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (71b) & (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)cyclopentyl)methyl)(3-(phenethylamino)propyl)amino)butanoic acid (72b).

Reductive amination (71b): yield: 101.5 mg, 0.108 mmol, 54 %. C₅₀H₇₇N₇O₁₀ (936.21 g/mol). HRMS (ESI): calcd. for C₅₀H₇₈N₇O₁₀ ^M+H ^⁺: 936.5805, found: 936.5796. Deprotection (72b): yield: 64 mg, 0.097 mmol, 100 % (1 TFA salt). C₂₈H₄₁N₇O₄ (539.68 g/mol).¹H- NMR (400 MHz; DMSO-d₆): ^ 9.44 (bs, 1H, CH₃–NH), 8.91 (bs, 2H, NH₂ ⁽⁺⁾), 8.35 (s, 1H, H2), 7.58 (s, 1H, H8), 7.39–7.32 (m, 2H, m-H), 7.29–7.25 (m, 3H, o-H, p-H), 6.91 (s, 1H, H7), 5.00–4.89 (m, 1H, H1'), 4.15 (t, J = 6.4 Hz, 1H, H2'), 4.02 (t, J = 6.4 Hz, 1H, Ha), 3.87 (t, J = 5.8 Hz, 1H, H3'), 3.37–3.18 (m, 9H, H5', Hg, H1'', CH₂–N), 3.14–2.99 (m, 5H, H3'', CH₃), 2.97–2.86 (m, 2H, CH₂–Ph), 2.40–2.35 (m, 2H, H4', H6'_A), 2.28–2.21 (m, 1H, Hb_A), 2.18–2.09 (m, 1H, Hb_B), 2.09–1.96 (m, 2H, H2''), 1.68–1.61 (m, 1H, H6'_B); HRMS (ESI): calcd. for C₂₈H₄₂N₇O₄ ^M+H ^⁺: 540.3293, found: 540.3293. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(4-phenoxyphenethyl)amino)propyl)(((3aR,4R,6R,6aS)- 6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (71c) & (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid (72c).

^ Reductive amination (71c): yield: 30.2 mg, 0.029 mmol, 37 %. HRMS (ESI): calcd. for C₅₆H₈₂N₇O₁₁ ^M+H ^⁺: 1028.6067, found: 1028.6046; R_f: 0.83 (CHx₂Cl₂/MeOH 9:1). ^ Deprotection (72c): yield: 21 mg, 0.024 mmol, 100 % (2 TFA salts).¹H-NMR (400 MHz; DMSO- d₆): d 9.57 (bs, 3H, NH₃ ⁺), 8.91 (bs, 2H, NH₂ ⁺), 8.36 (s, 1H, H2), 7.60 (s, 1H, H8), 7.39 (t, ³J = 7.6 Hz, 2H, m-H'), 7.28 (d, ³J = 8.4 Hz, 2H, m-H), 7.14 (t, ³J = 7.2 Hz, 1H, p-H'), 7.00–6.97 (m, 4H, o-H, o- H'), 6.92 (s, 1H, H7), 5.01–4.89 (m, 1H, H1'), 4.14 (t, ³J = 6.2 Hz, 1H, H2'), 4.04 (t, ³J = 6.2 Hz, 1H, Ha), 3.94–3.85 (m, 1H, H3'), 3.47–3.29 (m, 4H, H5', Hg), 3.23–3.17 (m, 4H, H1'', CH₂–N), 3.14–3.00 (m, 5H, H3'', CH₃), 2.96–2.84 (m, 2H, CH₂–Ph), 2.43–2.35 (m, 2H, H4', H6'_A), 2.30–2.18 (m, 1H, Hb_A), 2.16– 2.03 (m, 3H, H2'', Hb_B), 1.74–1.57 (m, 2H, H6'_B); HRMS (ESI): calcd. for C₃₄H₄₆N₇O₅ ^M+H ^⁺: 632.3555, found: 632.3553. Synthesis of methyl ester compounds 75a, 75b, and 75c tert-butyl (3-((((3aR,4R,6R,6aR))-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)propyl)(phenethyl)carbamate (73a) To a stirred solution of 4 (500 mg, 1.22 mmol, 1.1 eq.) and 7d (310 mg, 1.11 mmol, 1 eq.) in dry DCE (9 mL) was added AcOH (70 µL, 1.22 mmol, 1.1 eq.). The solution was stirred for 3 h at rt, then NaBH(OAc)₃ (616 mg, 2.88 mmol, 2.6 eq.) was added and the mixture was stirred for 3 h at rt. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH2Cl2/MeOH (99.5:0.5–95.5:4.5) to afford the target compound (183 mg, 0.27 mmol, 25 %). C₃₄H₄₉N₇O₇ (667.81 g/mol). methyl (S)-4-((3-((tert-butoxycarbonyl)(phenethyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d] [1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (74a)

Compound 73a (181 mg, 0.27 mmol, 1.1 eq.) and 60 (57 mg, 0.24 mmol, 1 eq.) in dry DCE (2 mL) was added AcOH (16 µL, 0.27 mmol, 1.1 eq.). The solution was stirred for 3 h at rt, then NaBH(OAc)₃ (136 mg, 0.63 mmol, 2.6 eq.) was added and the mixture was stirred for 4 h at rt and 12 h at 70 °C. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH2Cl2/MeOH (99.5:0.5–95.5:4.5) to afford the target compound (31 mg, 0.035 mmol, 14 %). C₄₄H₆₆N₈O₁₁ (883.06 g/mol). HRMS (ESI): calcd. for C₄₄H₆₇N₈O₁₁ ^M+H ^⁺: 883.4924, found: 883.4911. methyl (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)(3-(phenethylamino)propyl)amino)butanoate (75a). Compound 74a was then dissolved in 600 µL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 3 h, then evaporated to give the desired product 75a (14 mg, 0.026 mmol, 92 %). C₂₆H₃₈N₈O₅ (542.64 g/mol).¹H-NMR (400 MHz, DMSO-d₆): ^ 8.87 (s, 2H, NH₂), 8.73–8.51 (m, 4H, H2, NH₃ ⁺), 8.50–8.31 (m, 2H, H8, NH), 7.35 (t, J = 7.2 Hz, 2H, m-H), 7.28–7.24 (m, 3H, o-H, p-H), 6.01 (d, J = 4.6 Hz, 1H, H1'), 4.62 (t, J = 4.6 Hz, 1H, H2'), 4.42–4.31 (m, 1H, H4'), 4.24–4.20 (m, 1H, H3'), 4.19–4.14 (m, 1H, Ha), 3.71 (s, 3H, CH₃), 3.68–3.57 (m, 1H, H5'_A), 3.57–3.44 (m, 1H, H5'_B), 3.36– 3.05 (m, 5H, Hg, H1'', CH₂-N), 3.05–2.94 (m, 2H, H3''), 2.94–2.84 (m, 2H, CH₂-Ph), 2.27–2.17 (m, 1H, Hb_A), 2.17–2.05 (m, 1H, Hb_B), 2.04–1.91 (m, 2H, H2''). tert-butyl (7-((3aS,4R,6R,6aR)-6-(((3-((tert-butoxycarbonyl)(3- phenoxyphenethyl)amino)propyl)amino)methyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (73b). To a solution of aldehyde 7f (0.14 g, 0.356 mmol, 1 eq.) in dry MeOH (1.3 mL) was added 69 (0.158 g, 0.356 mmol, 1 eq.) in 0.5 mL of dry MeOH dropwise and the mixture was stirred overnight at rt. After cooling to 0 °C NaBH₄ (0.022 g, 0.54 mmol, 1.5 eq) was added. The reaction was stirred at rt until the bubbling stops, then the solvent was evaporated and the residue was partitioned between water and AcOEt. The aqueous phase was extracted with AcOEt (3 times). The combined organic phases were dried over Na₂SO₄, dryed and the solvent was removed under vacuum. The resulting product was purified via flash chromatography using DCM/MeOH (100/0 to 80/20) to afford the final product as a yellow oil (0.05 g, 0.065 mmol, 17.4 %). C43H58N6O7 (770.97 g/mol).¹H-NMR (400 MHz, DMSO-d₆): ^ 8.61 (s, 1H, H2), 7.73 (d, 1H, H8), 7.37 (t, 2H, m''- H), 7.26 (t, 1H, m-H), 7.11 (t, 1H, p''-H), 6.97 (t, 3H, o''-H, o''-H), 6.82 (d, 2H, p-H, o'-H), 6.43 (d, 1H, H7), 5.10–5.03 (m, 1H, H1'), 4.89 (t, 1H, H2'), 4.48 (t, 1H, H3'), 3.51–3.46 (m, 1H), 3.43-3.37 (m, 2H, CH₂–N), 3.20–3.05 (m, 3H, N-CH₃), 2.76–2.69 (m, 3H, CH₂-Ph, H5'_A), 2.68–2.65 (m, 1H, H5'_B), 2.34– 2.31 (m, 1H, H6'A), 2.29-2.15 (m, 2H, H4',), 2.09–1.93 (m, 2H, H6'B), 1.59 (m, 2H), 1.47 (s, 3H, CH3), 1.43 (s, 9H, CH₃ tBu), 1.32 (d, 9H, CH₃ tBu), 1.23 (s, 1H), 1.21 (s, 3H, CH₃). methyl (S)-4-((3-((tert-butoxycarbonyl)(3-phenoxyphenethyl)amino)propyl)(((3aR,4R,6R,6aS)-6- (4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert butoxycarbonyl)amino)butanoate (74b).

To a stirred solution of 73b (0.050 g, 0.064 mmol, 1 eq.) and 14 (0.015 g, 0.064 mmol, 1 eq.) in dry DCE (1 mL) was added AcOH (4 µL, 0.071 mmol, 1.1 eq.). The solution was stirred for 4 h at rt, then NaBH(OAc)₃ (0.04 g, 0.17 mmol, 2.6 eq.) was added and the mixture was stirred for 4 h at rt and 12 h at 70 °C. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.5:0.5–90:10) to afford the target compound (3 mg, 0.003 mmol, 4.7 %). C₅₃H₇₅N₇O₁₁ (986.22 g/mol). methyl (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((3-phenoxyphenethyl)amino)propyl)amino)butanoate (75b).74b was then dissolved in 500 µL freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired product 74b (5.6 mg, 0.006 mmol, 100 %). C₃₅H₄₇N₇O₅ (645.81 g/mol). ¹H-NMR (400 MHz, DMSO-d₆): ^ 9.00–8.93 (m, 2H), 8.72–8.64 (m, 3H), 8.35–8.27 (m, 1H), 7.55–7.50 (m, 1H), 7.38–7.26 (m, 3H), 7.12–7.05 (m, 2H), 7.01–6.91 (m, 2H), 6.89– 6.85 (m, 1H), 6.85–6.80 (m, 1H), 5.26–5.24 (m, 1H), 4.88–4.85 (m, 1H), 4.18–4.12 (m, 1H), 4.10–4.05 (m, 1H), 3.82–3.78 (m, 1H), 3.69 (s, 3H), 3.24–3.05 (m, 5H), 3.05–2.96 (m, 3H), 2.86–2.82 (m, 2H), 2.30–2.06 (m, 5H), 2.02–1.86 (m, 3H), 1.61–1.54 (m, 2H), 1.41–1.36 (m, 1H). tert-butyl (7-((3aS,4R,6R,6aR)-6-(((3-((tert-butoxycarbonyl)(4- phenoxyphenethyl)amino)propyl)amino)methyl)-2,2-dimethyltetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)(methyl)carbamate (73c). After having stirred a solution of the nucleoside 69 (1 eq.) and aldehyde 170d (1 eq.) in dry MeOH (0.5 M) for 72–96 h at rt, the reaction mixture was cooled down to 0 °C and NaBH₄ (1.5 eq.) was added portionwise. After bubbling stopped, H₂O was added and the aqueous phase was extracted with AcOEt (3 x). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and evaporated and the corresponding crude was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH to afford the secondary amines 73c. yield: 165 mg, 0.214 mmol, 19 %. C₄₃H₅₈N₆O₇ (770.9 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 8.61 (s, 1H, H2), 7.73 (d, ³J = 3.6 Hz, 1H, H8), 7.36 (t, ³J = 8.0 Hz, 2H, m-H'), 7.18 (d, ³J = 8.0 Hz, 2H, m-H), 7.10 (t, ³J = 7.4 Hz, 1H, p-H'), 6.96–6.91 (m, 4H, o-H, o-H'), 6.42 (d, ³J = 3.6 Hz, 1H, H7), 5.07 (dt, ³J = 12.4 Hz and ³J = 6.2 Hz, 1H, H1'), 4.89 (t, ³J = 6.8 Hz, 1H, H2'), 4.48 (dd, ³J = 6.8 Hz and ³J = 4.8 Hz, 1H, H3'), 3.37–3.33 (m, 2H, CH₂-N), 3.23–3.09 (m, 2H, H1''), 2.73 (t, ³J = 7.2 Hz, 2H, CH₂-Ph), 2.69–2.64 (m, 1H, H5'_A), 2.56–2.53 (m, 1H, H5'_B), 2.45–2.42 (m, 2H, H3''), 2.30–2.19 (m, 2H, H4', H6'_A), 2.06–1.98 (m, 1H, H6'_B), 1.64–1.57 (m, 2H, H2''), 1.46 (s, 3H, CH₃), 1.43 (s, 9H, CH₃ tBu), 1.35 (s, 9H, CH₃ tBu), 1.21 (s, 3H, CH₃). HRMS (ESI): calcd. for C₄₃H₅₉N₆O₇ ^M+H ^⁺: 771.4440, found: 771.4429. methyl (S)-4-((3-((tert-butoxycarbonyl)(4-phenoxyphenethyl)amino)propyl)(((3aR,4R,6R,6aS)-6- (4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (74c).

To a stirred solution of 73c (154 mg, 0.198 mmol, 1.1 eq.) and aldehyde 60 (42mg, 0.180 mmol, 1 eq.) in dry DCE (1.5 mL) was added AcOH (11 µL, 0.198 mmol, 1.1 eq.). The solution was stirred for 48 h at rt, then NaBH(OAc)₃ (100 mg, 0.467 mmol, 2.6 eq.) was added and the mixture was stirred for 4 h at rt before adding extra 3–5 eq. of aldehyde 60 and let it stir overnight. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na₂SO₄, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH to afford the tertiary amines 74c as a white foam (70 mg, 0.070 mmol, 39 %). HRMS (ESI): calcd. for C₅₃H₇₆N₇O₁₁ ^M+H ^⁺: 986.5597, found: 986.5587; R_f: 0.68 (CH₂Cl₂/MeOH 9:1). methyl (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((4-phenoxyphenethyl)amino)propyl)amino)butanoate (75c). Tertiary amines 74c were dissolved (0.02 ^M) in freshly prepared TFA/MeOH (4:1) solution and stirred at rt for 4–5 h. The reaction was concentrated under reduced pressure and the obtained compound was used without further purification. yield: 26 mg, 0.030 mmol, 100 % (1 TFA salt). ¹H-NMR (400 MHz; DMSO-d₆): d 9.54 (s, 1H, CH₃–NH), 8.95 (s, 2H, NH₂ ⁺), 8.67 (s, 3H, NH₃ ⁺), 8.36 (s, 1H, H2), 7.60 (s, 1H, H8), 7.39 (t, ³J = 7.6 Hz, 2H, m-H'), 7.28 (d, ³J = 8.4 Hz, 2H, m- H), 7.14 (t, ³J = 7.6 Hz, 1H, p-H'), 7.00-6.97 (m, 4H, o-H, o-H'), 6.92 (s, 1H, H7), 4.96-4.93 (m, 1H, H1'), 4.27–4.18 (m, 1H, Ha), 4.14 (t, J = 6.2 Hz, 1H, H2'), 3.92–3.84 (m, 1H, H3'), 3.78 (s, 3H, CH3), 3.28–3.16 (m, 8H, H5', Hg, H1'', CH₂–N), 3.08–3.06 (m, 5H, H3'', CH₃), 2.96–2.86 (m, 2H, CH₂–Ph), 2.37–2.32 (m, 3H, H4', H6'_A, Hb_A), 2.23–2.13 (m, 1H, Hb_B), 2.09–1.96 (m, 2H, H2''), 1.68–1.60 (m, 1H, H6'_B); HRMS (ESI): calcd. for C₃₅H₄₈N₇O₅ ^M+H ^⁺: 646.3711, found: 646.3702. For the synthesis of the remaining compounds, the following analytic methods were used: ¹H-NMR spectra were recorded on Bruker Avance III 400 MHz and Bruker Fourier 300 MHz and TMS was used as an internal standard. LCMS was taken on a quadrupole Mass Spectrometer on Agilent LC/MSD 1200 Series (Column: ODS 2000 (50 × 4.6 mm, 5 mm) operating in ES (+) or (-) ionization mode; T = 30 oC; flow rate = 1.5 mL/min; detected wavelength: 214 nm. Synthesis of compound 81a (S)-3-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4-oxobutanoic acid (76) To a solution of compound (S)-3-amino-4-(tert-butoxy)-4-oxobutanoic acid (7.0 g, 37 mmol) in 70 mL/70 mL of dioxane/H₂O was added NaHCO₃ (9.3 g, 111 mmol) at room temperature. After stirring for 2 hours, CbzCl (68 mL, 48 mmol) was added at ice-water bath. The reaction mixture was stirred at room temperature overnight. The reaction was diluted with H₂O (50 mL x 2) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated to give compound 76 (2.7 g, 22.5% yield) as yellow oil which was used to the next step without further purification. MS Calcd.: 323; MS Found: 324 [M+H]⁺. (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-4-hydroxybutanoate (77) To a solution of compound 76 (1.7 g, 5.26 mmol) in THF (20 mL) was added BH₃ ^.DMS (10 M, 1.2 mL, 2.3 mmol) at 0 ^oC. The mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with MeOH (10 mL) and concentrated to get the crude product. The residue was purified by flash chromatography on silica gel (PE/EA = 2/1) to give compound 77 (780 mg, 48% yield) as yellow oil. MS Calcd.: 309; MS Found: 310 [M+H]⁺ _. (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-4-oxobutanoate (78) A solution of compound 77 (780 mg, 2.52 mmol) in DCM (10 mL) was added PCC (1.63 g, 7.56 mmol). The reaction was stirred at room temperature for 4 hours. The reaction mixture was diluted with silica gel (2.0 g), filtered and the residue was concentrated to give compound 78 (580 mg, 75% yield) as yellow oil which was used to the next step without further purification. MS Calcd.: 307; MS Found: 308 [M+H]⁺. tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)amino)piperidine-1-carboxylate (79) A solution of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol- 4-yl)-9H-purin-6-amine (500 mg, 1.63 mmol) in 20 mL of MeOH was added tert-butyl 3- oxopiperidine-1-carboxylate (390 mg, 1.96 mmol). After stirring for 5 minutes, NaBH₃CN (205 mg, 3.26 mmol) was added at ice-water bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H2O = 5% - 95%, 254 nm, 30 min) to give compound 79 (347 mg, 44% yield) as a white solid. MS Calcd.: 489; MS Found: 490 [M+H]⁺. tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)(3-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4- oxobutyl)amino)piperidine-1-carboxylate (80) A solution of compound 79 (300 mg, 0.61 mmol) and compound 78 (226 mg, 0.74 mmol) in MeOH (10 mL) and AcOH( 0.1 mL). After stirring for 5 minutes, NaBH3CN (77 mg, 1.22 mmol) was added and the reaction mixture was stirred at 50 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 80 (170 mg, 36% yield) as a white solid. MS Calcd.: 780; MS Found: 781 [M+H]⁺. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-yl)amino)butanoic acid (81a) A solution of compound 80 (170 mg, 0.22 mmol) in AcOH (2 mL) was added HBr (30% in AcOH) (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeOH and adjusted pH = 7 with Na₂CO₃ solution. The residue was concentrated and purified by prep-HPLC (with additive agent of TFA) to give compound 81a (13 mg, 13% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.40 (d, J = 4.8 Hz, 2H), 6.06 (t, J = 4.4 Hz, 1H), 4.74-4.69 (m, 1H), 4.33-4.29 (m, 1H), 4.23-4.19 (m, 1H), 4.09 (t, J = 6.2 Hz, 1H), 3.48 (d, J = 11.6 Hz, 1H), 3.32-3.33 (m, 1H), 3.16-3.10 (m, 1H), 3.06-2.98 (m, 5H), 2.92-2.82 (m, 1H), 2.22-2.12 (m, 1H), 2.10-1.88 (m, 3H), 1.77-1.63 (m, 2H). MS Calcd.: 450; MS Found: 451 [M+H]⁺ _. Synthesis of compound 81b tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)amino)pyrrolidine-1-carboxylate (82) To a solution of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)-9H-purin-6-amine (500 mg, 1.63 mmol) and tert-butyl 3-oxopyrrolidine-1- carboxylate (453 mg, 2.45 mmol) in MeOH (10 mL) and AcOH (0.1 mL) was added NaBH₃CN (154 mg, 2.45 mmol). The reaction mixture was stirred at room temperature for two days. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 82 (200 mg, 26% yield) as yellow oil. MS Calcd.: 475; MS Found: 476 [M+H]⁺. tert-butyl 3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)(3-(((benzyloxy)carbonyl)amino)-4-(tert-butoxy)-4- oxobutyl)amino)pyrrolidine-1-carboxylate (83) To a solution of compound 82 (150 mg, 0.32 mmol) and compound 78 (126 mg, 0.41 mmol) in MeOH (10 mL) and AcOH( 0.1 mL)was added NaBH₃CN (154 mg, 2.45 mmol). The reaction mixture was stirred at 35 ^oC for two days. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 10/1) to give compound 83 (140 mg, 58% yield) as yellow oil. MS Calcd.: 766; MS Found: 767 [M+H]⁺ (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(pyrrolidin-3-yl)amino)butanoic acid (81b) To a solution of compound 83(140 mg, 0.18 mmol) in ACOH (3 mL) was added a solution of HBr (30% in AcOH, 1 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeOH and adjusted pH = 7 with Na₂CO₃ solution. The residue was concentrated and purified by prep-HPLC (with additive agent of TFA) to give compound 81b (15 mg, 18% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.27 (d, J = 7.2 Hz, 2H), 5.93 (d, J = 2.8 Hz, 1H), 4.60-4.56 (m, 1H), 4.22-4.11 (m, 2H), 3.95 (t, J = 6.0 Hz, 1H), 3.70-3.63 (m, 1H), 3.38-3.26 (m, 2H), 3.16-3.03 (m, 2H), 2.96-2.93 (m, 2H), 2.86-2.80 (m, 2H), 2.16-2.03 (m, 2H), 1.96-1.84 (m, 2H). MS Calcd.: 436; MS Found: 437 [M+H]⁺ _. Synthesis of compound 81c tert-butyl (3-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)amino)-1-phenylpropyl)carbamate (84) To a mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)-9H-purin-6-amine (500 mg, 1.6 mmol) in 10 mL of MeOH was added tert-butyl (3-oxo-1-phenylpropyl)carbamate (597 mg, 2.4 mmol). After stirring for 5 minutes, NaBH₃CN (302 mg, 4.8 mmol) was added at ice-water bath. The reaction mixture was stirred at 45 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 84 (200 mg, 23% yield) as a yellow solid. MS Calcd.: 539; MS Found: 540 [M+H]⁺. tert-butyl tert-butyl 4-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)(3-((tert-butoxycarbonyl)amino)-3- phenylpropyl)amino)-2-(((benzyloxy)carbonyl)amino)butanoate (85) To a solution of compound 84 (100 mg, 0.19 mmol) and 78 (74 mg, 0.24 mmol) in MeOH (10 mL) and AcOH ( 0.1 mL) was added NaBH₃CN (36 mg, 0.57 mmol). The reaction mixture was stirred at 35 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 10/1) to give compound 85 (100 mg, 65% yield) as yellow oil. MS Calcd.: 830; MS Found: 831[M+H]⁺. (2S)-2-amino-4-((3-amino-3-phenylpropyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (81c) To a solution of compound 85(100 mg, 0.12 mmol) in AcOH (2 mL) was added HBr (30% in AcOH, 2 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeOH and adjusted pH = 7 with Na₂CO₃ solution. The residue was concentrated and purified by prep-HPLC (with additive agent of TFA) to give compound 81c (12 mg, 20% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.23-818 (m, 2H), 728-7.24 (m, 5H), 5.59 (d, J = 3.6 Hz, 1H), 4.55- 4.50 (m, 1H), 4.31-4.25 (m, 3H), 3.86-3.81 (m, 1H), 3.55-3.32 (m, 3H), 2.89-2.79 (m, 1H), 2.46-2.26 (m, 2H), 2.23-2.08 (m, 1H), 2.02-1.92 (m, 1H), 1.21-1.19 (m, 2H). MS Calcd.: 500; MS Found: 501 [M+H]⁺ _. Synthesis of compound 81d tert-butyl (1-acetylazetidin-3-yl)carbamate (86) To a solution of tert-butyl (azetidin-3-yl)carbamate (1.0 g, 5.81 mmol) in 30 mL of DCM was added TEA (1.17 g, 11.62 mmol) and Ac2O (711 mg, 6.97 mmol) at ice-water bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H₂O (100 mL) and extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated to give compound 86 (1.1 g, 89% yield) as yellow oil which was used to the next step without further purification. MS Calcd.: 214; MS Found: 215 [M+H]⁺. tert-butyl (1-acetylazetidin-3-yl)(3-(benzyloxy)propyl)carbamate (87) To a solution of compound 86 (1.24 g, 5.79 mmol) in DMF (30 mL) was added NaH (463 mg, 11.58 mmol, 60% wt. in mineral oil) at 0 ^oC. After stirring for 0.5 hour, 3-(benzyloxy)propyl 4- methylbenzenesulfonate (2.22 g, 6.95 mmol) was added at ice-water bath. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with H₂O (30 mL) and extracted with EA (30 mL x 2). The combined organic phase was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 214 nm, 30 min) to give compound 87 (1.1 g, 52% yield) as yellow oil. MS Calcd.: 362; MS Found: 363 [M+H]⁺ _. tert-butyl (1-acetylazetidin-3-yl)(3-hydroxypropyl)carbamate (88) To a solution of compound 87 (1.1 g, 3.04 mmol) in MeOH (30 mL) was added Pd/C (110 mg, 10%). The reaction mixture was stirred under H₂ balloon at 50 ^oC overnight. The reaction mixture was filtered, washed with MeOH (20 mL) and concentrated. The residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 214 nm, 30 min) to give compound 88 (0.3 g, 36% yield) as yellow oil. MS Calcd.: 272; MS Found: 273 [M+H]⁺. tert-butyl (1-acetylazetidin-3-yl)(3-oxopropyl)carbamate(89) To a solution of (COCl)₂ (279 mg, 2.20 mmol) in DCM (30 mL) was added DMSO (344 mg, 440 mmol) at -65 ^oC and stirred at this temperature for 1 hour. Compound 88 (300 mg, 1.10 mmol) was added at -65 ^oC and stirred at this temperature for 1.5 hours. TEA (667 mg, 6.60 mmol) was added at -60 ^oC. The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with H₂O (30 mL) and extracted with EA (30 mL x 2). The combined organic phase was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 214 nm, 30 min) to give compound 89 (90 mg, 30% yield) as yellow oil. MS Calcd.: 270; MS Found: 271 [M+H]⁺ _. (S)-tert-butyl 4-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (90) A solution of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol- 4-yl)-9H-purin-6-amine (1.0 g, 3.27 mmol) in 30 mL of MeOH was added compound 78 (0.98 g, 3.59 mmol). After stirring for 5 minutes, NaBH3CN (411 mg, 6.54 mmol) was added at ice-water bath. The reaction mixture was stirred at 65 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 90 (0.66 g, 36% yield) as a white solid. MS Calcd.: 563; MS Found: 564 [M+H]⁺. (S)-tert-butyl 4-((3-((1-acetylazetidin-3-yl)(tert-butoxycarbonyl)amino)propyl)(((3aR,4R,6R,6aR)- 6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2- ((tert-butoxycarbonyl)amino)butanoate (91) A solution of compound 90 (170 mg, 0.30 mmol) and compound 89 (86 mg, 0.32 mmol) in MeOH (15 mL) and AcOH (0.1 mL). After stirring for 5 minutes, NaBH₃CN (38 mg, 0.60 mmol) was added and the reaction mixture was stirred at 50 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 91 (100 mg, 41% yield) as a yellow solid. MS Calcd.: 817; MS Found: 818 [M+H]⁺. (S)-4-((3-((1-acetylazetidin-3-yl)amino)propyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-aminobutanoic acid (81d) To a solution of compound 91 (100 mg, 0.12 mmol) in DCM (5 mL) was added HBr (30% in AcOH) (1 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeOH and adjusted pH = 7 with Na₂CO₃ solution. The mixture was concentrated and purified by prep-HPLC to give compound 81d (15 mg, 17% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.55 (d, J = 4.4 Hz, 2H), 6.26 (d, J = 4.0 Hz, 1H), 4.91 (t, J = 3.8 Hz, 2H), 4.72-4.68 (m, 1H), 4.64-4.60 (m, 2H), 4.47-4.43 (m, 2H), 4.30-4.11 (m, 3H), 3.79-3.69 (m, 2H), 3.45-3.24 (m, 5H), 2.55-2.47 (m, 1H), 2.33-2.28 (m, 3H), 2.09 (s, 3H). MS Calcd.: 521; MS Found: 522 [M+H]⁺. Synthesis of compound 81e tert-butyl 2-(2-hydroxyethyl)pyrrolidine-1-carboxylate (92) To a solution of 2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)acetic acid (500 mg, 2.18 mmol) in 20 mL of THF was added BH₃ ^.BS (10M in DMSO, 0.33 mL, 3.27 mmol) at 0 ^oC. The reaction mixture was stirred at 50 ^oC overnight. The reaction mixture was diluted MeOH (10 mL), concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 214 nm, 30 min) to give compound 92 (305 mg, 65% yield) as yellow oil. MS Calcd.: 215; MS Found: 216 [M+H]⁺. tert-butyl 2-(2-oxoethyl)pyrrolidine-1-carboxylate(93) To a solution of alcohol 92 (305 mg, 451 mmol) in dry DCM (20 mL) was added PCC (451 mg, 2.09 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with H₂O (20 mL) and the phases were separated. The organic phase was washed with brine (20 mL x 2), dried over Na₂SO₄, filtered and concentrated to give compound 93 (300 mg, 100% yield) as a brown solid which was used to the next step without further purification. MS Calcd.: 213; MS Found: 214 [M+H]⁺. tert-butyl 2-(2-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((S)-4-(tert-butoxy)-3-((tert-butoxycarbonyl)amino)-4-oxobutyl)amino)ethyl)pyrrolidine- 1-carboxylate (94) A solution of compound 90 (100 mg, 0.18 mmol) and 93 (49 mg, 0.23 mmol) in MeOH (10 mL) and AcOH (0.1 mL) was stirred for 5 minutes. NaBH3CN (23 mg, 0.36 mmol) was added and stirred at 65 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 94 (68 mg, 50% yield) as a yellow solid. MS Calcd.: 760; MS Found: 761 [M+H]⁺. (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-(pyrrolidin-2-yl)ethyl)amino)butanoic acid (81e) To a solution of compound 94 (68 mg, 0.09 mmol) in DCM (2 mL) was added HBr (30% in AcOH) (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeoH and adjusted pH = 7 with Na₂CO₃ solution. The residue was concentrated and purified by prep-HPLC to give compound 81e (17.3 mg, 28% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.25 (d, J = 6.0 Hz, 2H), 5.98 (d, J = 3.2 Hz, 1H), 4.63 (br s, 2H), 4.36-4.29 (m, 2H), 3.83-3.80 (m, 1H), 3.48-3.36 (m, 3H), 3.15-3.03 (m, 4H), 2.21 (br s, 1H), 2.11-1.81 (m, 7H), 1.6-1.42 (m, 1H). MS Calcd.: 464; MS Found: 465 [M+H]⁺. Synthesis of compound 81f 9-((3aR,4R,6R,6aR)-2,2-dimethyl-6-(((3-morpholinopropyl)amino)methyl)tetrahydrofuro[3,4- d][1,3]dioxol-4-yl)-9H-purin-6-amine (95) To a mixture of 9-((3aR,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)-9H-purin-6-amine (500 mg, 1.63 mmol) in 30 mL of THF was added TEA (494 mg, 4.89 mmol) and 4-(3-chloropropyl)morpholine (1.33 g, 8.17 mmol). The reaction mixture was stirred at 80 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase silica gel (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 95 (70 mg, 10% yield) as a white solid. MS Calcd.: 433; MS Found: 434 [M+H]⁺. (S)-tert-butyl 4-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)(3-morpholinopropyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (96) A solution of compound 95 (70 mg, 0.16 mmol) and (S)-tert-butyl 2-((tert- butoxycarbonyl)amino)-4-oxobutanoate (53 mg, 0.19 mmol) in MeOH (10 mL) and AcOH ( 0.1 mL) was stirred for 5 minutes. NaBH₃CN (20 mg, 0.32 mmol) was added and the reaction mixture was stirred at 65 ^oC overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (DCM/MeOH = 20/1) to give compound 96 (35 mg, 31% yield) as a yellow solid. MS Calcd.: 690; MS Found: 691 [M+H]⁺. (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-morpholinopropyl)amino)butanoic acid (81f) To a solution of compound 96 (35 mg, 0.05 mmol) in DCM (2 mL) was added HBr (30% in AcOH) (0.2 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeoH and adjusted pH = 7 with Na₂CO₃ solution. The residue was concentrated and purified by prep-HPLC to give compound 81f (13.1 mg, 52% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.26 (d, J = 6.4 Hz, 2H), 5.98 (d, J = 4.0 Hz, 1H), 4.62 (t, J = 4.2 Hz, 1H), 4.35-4.28 (m, 2H), 3.86-3.83 (m, 1H), 3.79 (br s, 4H), 3.52-3.39 (m, 2H), 3.32-3.25(m, 2H), 3.14-3.02 (m, 7H), 2.27-2.17 (m, 1H), 2.11-1.91 (m, 4H). MS Calcd.: 494; MS Found: 495 [M+H]⁺. Synthesis of compound 81g 2-(((2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)isoindoline-1,3-dione (97) A solution of 6-chloropurine riboside (3.0 g, 10.5 mmol) in 50 mL of THF was added isoindoline- 1,3-dione (1.85 g, 12.6 mmol), PPh₃ (4.13 g, 15.8 mmol) and DEAD (2.75 g, 15.8 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H₂O (50 mL) and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM/MeOH = 50/1-30/1) to give compound 97 (3.65 g, 84% yield) as a white solid. MS Calcd.: 415; MS Found: 416 [M+H]⁺. 2-(((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(phenylamino)-9H-purin-9-yl)tetrahydrofuran-2- yl)methyl)isoindoline-1,3-dione (98) A solution of compound 97 (1.0 g, 2.41 mmol) and aniline (673 mg, 7.23 mmol) in EtOH (30 mL) was stirred at 80 ^oC for 3 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated and the residue was triturated with MeOH (10 mL), filtered, washed with MeOH (5 mL), then dried to give compound 98 (700 mg, 61% yield) as a white solid. MS Calcd.: 472; MS Found: 473 [M+H]⁺. (2R,3S,4R,5R)-2-(aminomethyl)-5-(6-(phenylamino)-9H-purin-9-yl)tetrahydrofuran-3,4-diol (99) A solution of compound 98 (700 mg, 1.48 mmol) in EtOH (30 mL) was added NH₂NH₂ ^.H₂O (85% in H₂O, 175 mg, 2.96 mmol). The reaction mixture was stirred at 80 ^oC overnight. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 99 (250 mg, 49% yield) as a yellow solid. MS Calcd.: 342; MS Found: 343 [M+H]⁺. tert-butyl (3-((((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(phenylamino)-9H-purin-9- yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)propyl)(methyl)carbamate (100) A solution of compound 99 (200 mg, 0.58 mmol) and tert-butyl methyl(3-oxopropyl)carbamate (130 mg, 0.70 mmol) in MeOH (20 mL) and AcOH (0.1 mL). After 5 min, NaBH₃CN (73 mg, 1.16 mmol) was added and the reaction mixture was stirred at 65 ^oC for 2 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash chromatography on reverse phase (ACN/H₂O = 5% - 95%, 254 nm, 30 min) to give compound 100 (150 mg, 50% yield) as a yellow solid. MS Calcd.: 553; MS Found: 554 [M+H]⁺. (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-4-((3-((tert- butoxycarbonyl)(methyl)amino)propyl)(((3aR,4R,6R,6aR)-2,2-dimethyl-6-(6-(phenylamino)-9H- purin-9-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)butanoate (101) A solution of compound 100 (140 mg, 0.27 mmol) and compound 78 (107.5 mg, 0.35 mmol) in MeOH (20 mL) and AcOH (0.2 mL). After 5 min NaBH₃CN (34 mg, 0.54 mmol) was added and stirred at 65 ^oC overnight. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel (EA) to give compound 101 (173 mg, 82% yield) as a yellow solid. MS Calcd.: 844; MS Found: 845 [M+H]⁺. (S)-2-amino-4-((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6-(phenylamino)-9H-purin-9- yl)tetrahydrofuran-2-yl)methyl)(3-(methylamino)propyl)amino)butanoic acid (81g) A solution of compound 101 (150 mg, 0.18 mmol) in DCM (3 mL) was added HBr (30% in AcOH) (1 mL). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The residue was dissolved in 2 mL of MeoH and adjusted pH = 7 with Na₂CO₃ solution. The mixture was concentrated and the residue was purified by prep-HPLC to give compound 81g (21 mg, 23% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.32 (s, 1H), 8.21 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.04 (t, J = 7.4 Hz, 1H), 5.97 (d, J = 4.0 Hz, 1H), 4.71-4.69 (m, 1H), 4.39-4.32 (m, 2H), 3.85- 3.81 (m, 1H), 3.65-3.59 (m, 1H), 3.47-3.43 (m, 1H), 3.37-3.34 (m, 2H), 3.20-3.12 (m, 2H), 3.19-2.90 (m, 2H), 2.55 (s, 3H), 2.26-2.23 (m, 1H), 2.21-1.98 (m, 3H). MS Calcd.: 514; MS Found: 515[M+H]⁺. Synthesis of 81h (R)-tert-butyl (1-(benzyl(methyl)amino)-4-oxobutan-2-yl)carbamate (102) A solution of (R)-tert-butyl (1-(benzyl(methyl)amino)-4-hydroxybutan-2-yl)carbamate (540 mg, 1.75 mmol) and Dess-Martin periodinane (1.48 g, 3.5 mmol) in DCM (10 mL) was stirred at rt. overnight. The reaction mixture was concentrated and the residue was purified by column (PE:EA = 10:1) to give compound 102 (100 mg, 19% yield) as yellow oil. MS Calcd.:306.2; MS Found: 307.2 [M+H]⁺. (S)-tert-butyl 4-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)((R)-4-(benzyl(methyl)amino)-3-((tert- butoxycarbonyl)amino)butyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (103) A solution of compound 102 (46 mg, 0.0015 mmol) and compound 90 (70 mg, 0.0012 mmol) in DCM (10 mL) was stirred at rt. for 30 min. Then NaBH3CN (16 mg, 0.0024 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give compound 103 (15 mg, 14% yield) as colorless oil. MS Calcd.:853.5; MS Found: 854.5 [M+H]⁺. (S)-tert-butyl 4-((((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4- d][1,3]dioxol-4-yl)methyl)((R)-4-((tert-butoxycarbonyl)(methyl)amino)-3-((tert- butoxycarbonyl)amino)butyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (104) A solution of compound 103 (15 mg, 0.0017 mmol), Pd/C (5 mg, 30%) and (Boc)₂O (5 mg, 0.0023 mmol) in MeOH (5 mL) was stirred at 60 ^oC under H₂ atmosphere overnight. The reaction mixture was filtered and concentrated to give compound 104 (12 mg, 80% yield) as colorless oil. MS Calcd.: 863.5; MS Found: 864.5 [M+H]⁺ _. (S)-2-amino-4-(((S)-3-amino-4-(methylamino)butyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)- 3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid (81h) A solution of compound 104 (12 mg, 0.0014 mmol) and TFA (1.5 mL) in DCM (1.5 mL) and H₂O (0.5 mL) was stirred at rt. for 2h. The reaction mixture was concentrated and purified by prep- HPLC to give compound 81h (3.1 mg, 48% yield) as colorless oil. 1H NMR (400 MHz, CD₃OD) d: 8.14 (d, J = 3.2 Hz, 2H), 5.88 (d, J = 4.4 Hz, 1H), 4.66-4.64 (m, 1H), 4.18-4.11 (m, 2H), 3.53-3.50 (m, 1H), 2.89-2.49 (m, 9H), 2.35 (s, 3H), 1.93-1.92 (m, 1H), 1.84-1.82 (m, 1H), 1.52-1.46 (m, 2H). MS Calcd.: 467.2; MS Found: 468.2 [M+H]⁺. For the synthesis of the following compounds (110 to 155), the following analytic methods were used: 1H NMR spectra were recorded on Bruker Avance III 400 MHz and Bruker Fourier 300 MHz and TMS was used as an internal standard. LCMS was taken on a quadrupole Mass Spectrometer on Agilent LC/MSD 1200 Series (Column: ODS 2000 (50 × 4.6 mm, 5 mm) operating in ES (+) or (-) ionization mode; T = 30 °C; flow rate = 1.5 mL/min; detected wavelength: 214 nm. Prep-HPLC was performed at conditions: (Flash: Welchrom C18, 150 x 20 mm); Wavelength 220 nm; Mobile phase: A MeCN (0.1% TFA); B water (0.1% TFA); Flow rate: 25 mL /min; Injection volume: 2 mL; Run time: 30 min; Equilibration: 5 min. Synthesis of compounds 110, 111, 112, and 120 Synthesis of 4-(4-chlorophenoxy)-3-fluorobenzaldehyde (113)

To a solution of 3,4-difluorobenzaldehyde (5 g, 38.9 mmol) in DMF (30 mL) was added K₂CO₃ (10.7 g, 77.8 mmol) and 4-chlorophenol (5.5 g, 38.9 mmol) at r. t. The mixture was stirred at 80 °C overnight. The reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL). The organic phase was washed with brine (50 mL x 2), dried over Na₂SO₄, and concentrated to provide compound 113 (0.9 g, 93% yield) as a yellow oil. MS Calcd.: 250; MS Found: 251 [M+H]⁺. Synthesis of 3-((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propan-1-ol (114)

To a solution of compound 113 (400 mg, 1.60 mmol) in MeOH (10 mL) was added 3-aminopropan-1-ol (180 mg, 2.40 mmol)), and the mixture was stirred at r. t for 1 h. Then NaBH₃CN (201.6 mg, 3.20 mmol) was added and the mixture was stirred at r. t overnight. Solvent was removed and the residue was purified by flash chromatography (30% EA in PE) to give compound 114 (350 mg, 70.8% yield) as a yellow oil. MS Calcd.: 309; MS Found: 310 [M+H]⁺. Synthesis of tert-butyl (4-(4-chlorophenoxy)-3-fluorobenzyl)(3-hydroxypropyl)carbamate (115)

To a solution of compound 114 (350 mg, 1.13 mmol) in DCM (10 mL) was added TEA (228.8 mg, 2.26 mmol)) and (Boc)₂O (370.4 mg, 1.70 mmol). The mixture was stirred at r. t for 2 h. Solvent was removed and the residue was purified by flash chromatography (25% EA in PE) to give compound 115 (200 mg, 70.8% yield) as a yellow oil. MS Calcd.: 409; MS Found: 410[M+H]⁺. Synthesis of tert-butyl (4-(4-chlorophenoxy)-3-fluorobenzyl)(3-oxopropyl)carbamate (116)

To a mixture of compound 115 (0.8 g, crude, 3.11 mmol) and TEA (0.94 g, 9.33 mmol) in DCM (20 mL) was added DMP (1.02 g, 4.66 mmol) at r. t. After addition the mixture was then stirred for 1 h at r. t. A mixture of sat. NaHCO₃ (10 mL) and sat. Na₂S₂O₃ (10 mL) was added into the reaction mixture, stirred for 5 min and stood. Separated, washed with brine (10 mL), dried and concentrated to provide a crude compound 116 (250 mg, 84% yield), which could be used in the next step. MS Calcd.: 407; MS Found: 408 [M+H]⁺. Synthesis of tert-butyl (4-(4-chlorophenoxy)-3-fluorobenzyl)(3-((((3aR,4R,6R,6aS)-2,2-dimethyl- 6-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)methyl)amino)propyl)carbamate (117)

A mixture of compound 116 (250 mg, 0.61 mmol) and 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (155.4 mg, 0.49 mmol) in MeOH (15 mL) was stirred for 1 h at r. t. Then NaBH₃CN (76.9 mg, 1.22 mmol) was added. The resulting mixture was stirred for additional 14 h at r. t. Solvent was removed and the residue was purified by flash chromatography (5% MeOH in DCM) to give compound 117 (150 mg, 43.2% yield) as a white gum. MS Calcd.: 708; MS Found: 709[M+H]⁺ 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)- N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine was synthesized according to the synthesis of 7- [(3aS,4R,6R,6aR)-6-(Aminomethyl)-2,2-dimethyl-hexahydrocyclopenta[d][l,3]dioxol-4-yl]-N- cyclopropyl-7H-pyrrolo[2,3-d]pyrim amine in WO2012075492. The only difference was that instead of using cyclopropanamine in the chlorine substitution step, methylamine (2.0 M in methanol solution) was used. Synthesis of ethyl (S)-4-((3-((tert-butoxycarbonyl)(4-(4-chlorophenoxy)-3- fluorobenzyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (118)

A mixture of compound 117 (150 mg, 0.21 mmol) and (S)-ethyl 2-((tert-butoxycarbonyl)amino)- 4-oxobutanoate (62.3 mg, 0.25 mmol) in EtOH (15 mL) was stirred for 1 h at r. t. Then NaBH₃CN (26.5 mg, 0.42 mmol) was added. The resulting mixture was stirred for additional 14 h at r. t. Solvent was removed and the residue was purified by flash chromatography (5% EtOH in DCM) to give compound 118 (150 mg, 75.5% yield) as a white gum. MS Calcd.: 937; MS Found: 938[M+H]⁺ (S)-ethyl 2-((tert-butoxycarbonyl)amino)-4-oxobutanoate was synthesized according to compound 3a of Jacob M. Janey, Charles J. Orella, Eugenia Njolito, Jenny M. Baxter, Jonathan D. Rosen, Michael Palucki, Rick R. Sidler, Wenjie Li, Jason J. Kowal, and Ian W. Davies; The Journal of Organic Chemistry 200873 (8), 3212-3217; DOI: 10.1021/jo8000996.

Synthesis of (S)-ethyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate (110)

To a mixture of compound 118 (40 mg, 0.11 mmol) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred for 2 h at r. t. The mixture was concentrated and the residue was purified by prep-HPLC (TFA method) to give compound 110 (4 mg, 13.4% yield) as a white solid. 1H NMR (400 MHz, D₂O) d: 8.16 (s, 1H), 7.39-7.36 (m , 2H), 7.29-7.22 (m, 3H), 7.11 (t, J = 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.77 (s, 1H), 4.95-4.91 (m, 1H), 4.31-4.19 (m, 6H), 4.05 (t, J = 6.2 Hz, 1H), 3.48-3.28 (m, 6H), 3.15-3.09 (m, 5H), 2.45-2.28 (m, 4H), 2.14-2.08 (m, 2H), 1.74-1.69 (m, 1H). MS Calcd.: 697; MS Found: 698 [M+H]⁺. Synthesis of (S)-2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid (111)

To a mixture of compound 110 (25 mg, 0.036 mmol) in MeOH (5 mL) was added LiOH (7.5 mg, 0.179 mmol) and H₂O (0.5 mL). The mixture was stirred for 3 h at r. t. The mixture was concentrated and the residue was purified by prep-HPLC (TFA method) to give compound 111 (10 mg, 41.7% yield) as a white solid. 1H NMR (400 MHz, CD₃OD) d: 8.26 (s, 1H), 7.53-7.47 (m , 2H), 7.38-7.36 (m, 3H), 7.20 (t, J = 8.0 Hz, 1H), 7.00-6.96 (m, 2H), 6.89 (s, 1H), 5.08-5.02 (m, 1H), 4.37-4.32 (m, 1H), 4.28 (d, J = 2.8 Hz, 2H), 4.14-4.09 (m, 1H), 3.99-3.93 (m, 1H), 3.56-3.15 (m, 11H), 2.57-2.36 (m, 3H), 2.25-2.14 (m, 3H), 1.87-1.83 (m, 1H). MS Calcd.: 669; MS Found: 670 [M+H]⁺. Synthesis of methyl (S)-4-((3-((tert-butoxycarbonyl)(4-(4-chlorophenoxy)-3- fluorobenzyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (119)

To a solution of compound 118 (20 mg, 0.021 mmol) in MeOH (5 mL) was added NaOMe (3.5 mg, 0.064 mmol). The resulting mixture was stirred for 4 h at r.t. The reaction mixture was concentrated and extracted with EA (10 mL). The organic phase was washed with brine (10 mL), dried and concentrated to provide compound 119 (20 mg, crude) as a white gum. MS Calcd.: 923; MS Found: 924 [M+H]⁺. Synthesis of (S)-methyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate (112)

To a mixture of compound 119 (20 mg, 0.022 mmol) in DCM (2 mL) was added TFA (1 mL). The resulting mixture was stirred for 2 h at r. t. The mixture was concentrated and the residue was purified by prep-HPLC (TFA method) to give compound 112 (1.5 mg, 9.5% yield) as a white solid. 1H NMR (400 MHz, D₂O) d: 8.16 (s, 1H), 7.38-7.36 (m , 2H), 7.28-7.22 (m, 3H), 7.10 (t, J = 8.4 Hz, 1H), 6.86-6.84 (dd, J = 8.4 Hz, J = 1.6 Hz, 2H), 6.77 (s, 1H), 4.94-4.91 (m, 1H), 4.30-4.19 (m, 4H), 4.02 (t, J = 6.4 Hz, 1H), 3.81 (d, J = 6.0 Hz, 1H), 3.38-3.20 (m, 6H), 3.14-3.05 (m, 5H), 2.42-2.25 (m, 4H), 2.11-2.05 (m, 2H), 1.69-1.65 (m, 1H). MS Calcd.: 683; MS Found: 684 [M+H]⁺. Synthesis of 2-(4-(4-chlorophenoxy)-3-fluorophenyl)-2-hydroxyacetonitrile (121)

To a solution of compound 113 (10.4 g, 41.5 mmol) in DCM (100 mL) was added ZnI₂ (2.6 g, 0.83 mmol) and TMSCN (4.9 g, 49.8 mmol) at r. t. After addition the mixture was stirred for 2 h at r.t. Solvent was removed, treated with 20 mL of HCl (2 M), and stirred for 30 min. The resulting mixture was extracted with DCM (100 mL) and concentrated to provide crude product, which was used directly in the next step. MS Calcd.: 277. Synthesis of 2-chloro-2-(4-(4-chlorophenoxy)-3-fluorophenyl)acetonitrile (122)

To a solution of compound 121 (10.1 g, 36.5 mmol) in toluene (50 mL) was added SOCl2 (8.7 g, 72.9 mmol) dropwise at r. t. After addition the mixture was stirred for 3 h at 65 °C. Solvent was removed and the residue was used directly in the next step. MS Calcd.: 296. Synthesis of 2-(4-(4-chlorophenoxy)-3-fluorophenyl)acetonitrile (123)

To a solution of compound 122 (5.5 g, 18.6 mmol) in MeOH (25 mL) was added AcOH (2 mL) and Zn (2.42 g, 37.2 mmol). The mixture was stirred at 80 °C overnight. Solvent was removed and the residue was purified by flash chromatography (10% EA in PE) to give compound 123 (2.3 g, 47.3% yield) as a yellow solid. MS Calcd.: 261; MS Found: 260 [M-H]⁺. Synthesis of 2-(4-(4-chlorophenoxy)-3-fluorophenyl)acetamide (124)

To a solution of compound 123 (6 g, 23.0 mmol) in DMSO (50 mL) was added K₂CO₃ (6.34 g, 46.0 mmol) and H₂O₂ (5.2 g, mmol) at r. t. The mixture was stirred for 3 h at r.t. The reaction mixture was diluted was water (20 mL) and filtered to give compound 124 (3.5g, 54.6% yield) as a yellow solid. MS Calcd.: 279; MS Found: 280 [M+H]⁺. Synthesis of 2-(4-(4-chlorophenoxy)-3-fluorophenyl)acetic acid (125)

To a solution of compound 124 (3.5 g, 12.5 mmol) in EtOH (20 mL) and H2O (20 mL) was added NaOH (1.0 g, 25.1 mmol) at r. t. After addition the mixture was stirred for 4 h at 80 oC. The reaction mixture was adjusted to pH = 4 with HCl (2M) and extracted with EA (100 mL x 2). The combined organic phases were washed with water (100 mL), dried over Na₂SO₄, and concentrated to give compound 125 (3 g, 85.7% yield) as a yellow solid. MS Calcd.: 280. Synthesis of 2-(4-(4-chlorophenoxy)-3-fluorophenyl)-N-(3-hydroxypropyl)acetamide (126)

To a solution of compound 125 (1 g, 3.57 mmol) in DMF (10 mL) was added HATU (1.63 g, 4.28 mmol), TEA (1.08 g, 10.7 mmol) and 3-aminopropan-1-ol (0.4 g, 5.25 mmol) at r.t. After addition the resulting mixture was stirred for 3 h at r.t. The reaction mixture was diluted with water (20 mL) and extracted with EA (50 mL). The organic phase was washed with brine (50 mL), dried over Na2SO4, and concentrated to give compound 126 (800 mg, crude) as a yellow oil. MS Calcd.: 337; MS Found: 338 [M+H]⁺. Synthesis of 3-((4-(4-chlorophenoxy)-3-fluorophenethyl)amino)propan-1-ol (127)

BH3.THF (1M in THF, 10 mL, 10 mmol) was slowly added into a mixture of compound 126 (800 mg, 2.37 mmol) in THF (4 mL) dropwise at r. t. Then the resulting mixture was heated at 60 °C for 12 h. The reaction mixture was quenched at 0 °C with MeOH (10 mL) dropwise carefully and concentrated to give a white residue which was directly used in the next step. MS Calcd.: 323; MS Found: 324 [M+H]⁺. Synthesis of tert-butyl 4-(4-chlorophenoxy)-3-fluorophenethyl(3-hydroxypropyl)carbamate

(128) To a mixture of compound 127 (1g, crude, 3.09 mmol) and TEA (687 mg, 6.18 mmol) in DCM (20 mL) and MeOH (10 mL) was added (Boc)2O (1.01 g, 4.64 mmol) at r. t. The resulting mixture was then stirred for 4 h at r. t. Solvent was removed and the residue was purified by flash chromatography (30% EA in PE) to give compound 128 (310 mg, 20.7% yield over 3 steps) as a white gum. MS Calcd.: 423; MS Found: 424 [M+H]⁺ Synthesis of tert-butyl 4-(4-chlorophenoxy)-3-fluorophenethyl(3-oxopropyl)carbamate (129)

To a mixture of compound 128 (310 mg, 0.73 mmol) in DCM (20 mL) was added DMP (464 mg, 1.09 mmol) in portions at r. t. After addition the resulting mixture was stirred for 1 h at r. t. A mixture of sat. NaHCO₃ (10 mL) and sat. Na₂S₂O₃ (10 mL) was added into the reaction mixture, stirred for 20 min and stood. Separated, washed with sat. NaHCO3 (10 mL x2), dried and concentrated to give a crude compound 129 (250 mg, 81% yield), which was used directly in the next step. MS Calcd.: 421; MS Found: 422 [M+H]⁺. Synthesis of tert-butyl (4-(4-chlorophenoxy)-3-fluorophenethyl)(3-((((3aR,4R,6R,6aS)-2,2- dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H- cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)propyl)carbamate (130)

A mixture of compound 129 (100 mg, 0.23 mmol) and 7-((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2- dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (60 mg, 0.19 mmol) in EtOH (10 mL) was stirred for 1 h at r. t. Then NaBH₃CN (29 mg, 0.46 mmol) was added. The resulting mixture was stirred for additional 12 h at r. t. Solvent was removed and the residue was purified by flash chromatography (5% MeOH in DCM) to give compound 130 (45 mg, 27% yield) as a white gum. MS Calcd.: 722; MS Found: 723 [M+H]⁺ Synthesis of ethyl (S)-4-((3-((tert-butoxycarbonyl)(4-(4-chlorophenoxy)-3- fluorophenethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (131)

A mixture of compound 130 (45 mg, 0.062 mmol) and B (23 mg, 0.093 mmol) in EtOH (5 mL) was stirred for 1 h at r. t. Then NaBH3CN (8 mg, 0.124 mmol) was added. The resulting mixture was stirred for additional 12 h at 30 oC. Solvent was removed and the residue was purified by flash chromatography (5% EtOH in DCM) to give compound 13 (30 mg, 50.8% yield) as a white gum. MS Calcd.: 952; MS Found: 953[M+H]⁺ Synthesis of (S)-ethyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorophenethyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate (120)

To a mixture of compound 131 (30 mg, 0.032 mmol) in DCM (5 mL) was added TFA (2 mL). The resulting mixture was stirred for 2 h at r. t. The mixture was concentrated and the residue was purified by prep-HPLC (TFA method) to give compound 120 (also referred to as KMI95423512) (17 mg, 83% yield) as a white solid. 1H NMR (400 MHz, D₂O) d: 8.16 (s, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 11.2 Hz, 1H), 7.07 (s, 2H), 6.89(d, J = 8.4 Hz, 2H), 6.77 (s, 1H), 4.96-4.93 (m, 1H), 4.32-4.14 (m, 4H), 4.09-4.06 (t, J = 6.0 Hz, 1H), 3.51-3.43 (m, 4H), 3.35-3.32 (m, 4H), 3.23-3.11 (m, 4H), 3.02-2.96 (m, 2H), 2.45-2.31 (m, 4H), 2.15-2.10 (m, 2H), 1.81-1.74 (m, 1H), 1.26-1.21 (m, 3H). MS Calcd.: 645.4; MS Found: 646.4 [M+H]⁺. Synthesis of compounds 140 and 141 Synthesis of methyl 2-amino-4,5-dichlorobenzoate (142)

To a solution of methyl 2-amino-4-chlorobenzoate (75 g, 0.4 mol) in 500 mL DMF was added NCS (53 g, 0.4 mol), the mixture was stirred at 50 °C overnight. The reaction mixture was added H₂O (1000 mL) and was extracted with EA (1000 mL x 3), the combined organic layers were washed brine (1000 mL), dried over Na2SO4, filtered, the filtrate was concentrated to give crude product. The crude product was purified by flash chromatography (EA in PE = 5 %) to give compound 142 (44 g, 50% yield) as white solid. 1H NMR (400 MHz, CDCl₃) d = 7.91(s, 1H), 6.78 (s, 1H), 5.78 (br s, 2H), 3.86 (s, 3H). Synthesis of 2-amino-4,5-dichlorobenzoic acid (143)

To a solution of compound 142 (44 g, 0.2 mol) and LiOH.H₂O (40 g 1 mol) in MeOH/H₂O (500 mL/100 mL) was stirred at room temperature overnight. The reaction mixture was adjusted pH to 2-3 with HCl (1N/L) and extracted with EA (500 mL x 3), the combined organic layers were dried over Na₂SO₄, filtered, the filtrate was concentrated to give compound 143 (36 g, 87% yield) as white solid. MS Calcd.: 204.9; MS Found: 204 [M-H]-. Synthesis of methyl 6,7-dichloro-2-naphthoate (144)

A solution of compound 143 (36 g, 0.17 mol) and methyl 2-oxo-2H-pyran-5-carboxylate (17.4 g, 0.11 mol; also known as methyl coumalate) in toluene (100 mL) was stirred at 80 °C for 30 min, the mixture was added amylnitrite (38 g, 0.33 mol) and stirred at 100 °C overnight. The reaction mixture was cooled and concentrated to give a residue, which was purified by flash chromatography (EA in PE = 3 %) to give compound 144 (6.4 g, 22 % yield) as yellow solid. Synthesis of (6,7-dichloronaphthalen-2-yl)methanol (145)

To a solution of compound 144 (6.4 g, 0.025 mol) in THF (20 mL) was added LiAlH₄ (950 mg, 0.025 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hrs. TLC showed that the mixture was completed. The mixture was added 1 mL H₂O and 1 mL 15% NaOH aq and 3 mL H₂O, Na₂SO₄ was added and filtered. The mixture was extracted with EA (5 mL x 3), the combined organic layers were dried over Na2SO4, filtered, the filtrate was concentrated to give a residue, which was purified by flash chromatography (EA in PE = 50 %) to give compound 145 (2.2 g, 85 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆) d 8.26 (d, J = 3.6 Hz, 2H), 7.90 (d, J =8.4 Hz, 1H), 7.86 (s, 1H), 7.55 (dd, J = 8.4, 1.6 Hz, 1H), 5.98 (br s, 1H), 4.66 (s, 2H). Synthesis of 2,3-dichloro-6-(chloromethyl)naphthalene (146)

To a solution of compound 145 (2.2 g, 9.7 mmol) in SOCl₂ (15 mL) was stirred at 60 °C for 3 hrs. The mixture was concentrated to give compound 146 (1.89 g, 78 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆) d 8.32 (s, 2H), 8.01-7.97 (m, 2H), 7.66-7.64 (m, 1H), 4.94 (s, 2H). Synthesis of 2-(6,7-dichloronaphthalen-2-yl)acetonitrile (147)

To a solution of compound 146 (1.89 g, 7.6 mmol) and NaCN (0.49 g, 8.36 mmol) in DMF/H₂O (15 mL/3 mL) was stirred at 85 °C overnight. The reaction mixture was added H₂O (20 mL), extracted with EA (20 mL x 3), the combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, the filtrate was concentrated. The residue was purified by flash chromatography (EA/PE = 10 %) to give compound 147 (1.5 g, 88 % yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d₆) d 8.32 (d, J = 9.6 Hz, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.56 (dd, J = 8.4, 1.6 Hz, 1H), 4.26 (s, 2H). MS Calcd.: 234; MS Found: 235 [M+H]⁺. Synthesis of 2-(6,7-dichloronaphthalen-2-yl)acetamide (148)

To a solution of compound 147 (1.5 g, 6.4 mmol) in DMSO (5 mL) was added K2CO3 (2.6 g, 19.2 mmol) and H₂O₂ (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was added saturated solution of sodium sulfite and was filtrated. The filter cake was washed with H₂O to give compound 148 (1.32 g, 82 % yield) as a white solid. MS Calcd.: 253.1; MS Found: 254.1 [M+H]⁺. Synthesis of 2-(6,7-dichloronaphthalen-2-yl)acetic acid (149)

To a solution of compound 148 (1.32 g, 5.2 mmol) in EtOH/H₂O (10 mL / 3 mL) was added NaOH (0.62 g, 15.6 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was cooled, adjusted pH to 2-3 with 2 N HCl, extracted with EA (20 mL x 3), the combined organic layers were dried over Na₂SO₄, filtered, the filtrate was concentrated to give compound 149 (1.2 g, 92 % yield) as a white solid. MS Calcd.: 254.0; MS Found: 255.1 [M+H]⁺. Synthesis of 2-(6,7-dichloronaphthalen-2-yl)-N-(3-hydroxypropyl)acetamide (150)

To a solution of compound 149 (1.2 g, 4.7 mmol), HATU (2.69 g, 7.05 mmol) in DMF (10 mL) was added TEA (1.42 g g, 14.1 mmol), 3-aminopropan-1-ol (0.52 g, 7.05 mmol). The mixture was stirred at room temperature for 2 hrs. The mixture was added H₂O (20 mL), extracted with EA (20 mL x 3), the combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, the filtrate was concentrated to give compound 150 (500 mg, 35 % yield) as a yellow oil. MS Calcd.: 311.05; MS Found: 312.1 [M+H]⁺. Synthesis of 3-((2-(6,7-dichloronaphthalen-2-yl)ethyl)amino)propan-1-ol (151)

To a solution of compound 150 (0.5 g, 1.6 mmol) in THF (5 mL) was added BH₃/THF (3 mL, 1N). The mixture was stirred at 65 °C overnight. The mixture was cooled, quenched with MeOH (25 mL) at 0 °C and concentrated to give crude compound 151 (330 mg, 69 % yield) as yellow oil. MS Calcd.: 297.07; MS Found: 298.11 [M+H]⁺. Synthesis of tert-butyl (2-(6,7-dichloronaphthalen-2-yl)ethyl)(3-hydroxypropyl)carbamate (152)

To a solution of compound 151 (330 mg, 1.11 mmol) in DCM (5 mL) was added TEA (336.3 mg, 3.33 mmol) and Boc₂O (290 mg, 1.33 mmol). The mixture was stirred at room temperature overnight. The mixture was concentrated. The residue was purified by flash chromatography (EA in PE = 9 %) to give compound 152 (135 mg, 30 % yield) as yellow oil. MS Calcd.: 397.07; MS Found: 398.01 [M+H]⁺. Synthesis of tert-butyl (2-(6,7-dichloronaphthalen-2-yl)ethyl)(3-oxopropyl)carbamate (153)

To a solution of compound 152 (135 mg, 0.34 mmol) in DCM (5 mL) was added Dess-Martin periodinane (also known as 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one; 216 mg, 0.51 mmol). The mixture was stirred at room temperature for 1 hr. The mixture was quenched with sat. Na₂SO₃ aq (25 mL), the separated organic layer was washed with sat. NaHCO₃ aq (25 mL), dried over Na₂SO₄, filtered, the filtrate was concentrated to give compound 153 (110 mg, 82 % yield) as yellow oil. MS Calcd.: 395.1; MS Found: 396.1 [M+H]⁺. Synthesis of tert-butyl (2-(6,7-dichloronaphthalen-2-yl)ethyl)(3-((((3aR,4R,6R,6aS)-2,2-dimethyl- 6-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)methyl)amino)propyl)carbamate (154)

To a solution of compound 153 (110 mg, 0.27 mmol) in MeOH (5 mL) was added 7- ((3aS,4R,6R,6aR)-6-(aminomethyl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-N- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.27 mmol) and NaBH₃CN (25 mg, 0.405 mmol). The mixture was stirred at room temperature overnight. The mixture was quenched with sat. NH₄Cl aq (25 mL), the separated organic layer was dried over Na₂SO₄, filtered, the filtrated was concentrated to give crude product, which was purified by flash chromatography (MeOH in DCM = 10 %) to give compound 154 (89 mg, 47 % yield) as yellow oil. MS Calcd.: 696.3; MS Found: 697.1 [M+H]⁺. Synthesis of ethyl (S)-4-((3-((tert-butoxycarbonyl)(2-(6,7-dichloronaphthalen-2- yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (155)

To a solution of compound 154 (89 mg, 0.127 mmol) in EtOH (5 mL) was added (S)-ethyl 2- ((tert-butoxycarbonyl)amino)-4-oxobutanoate (31 mg, 0.127 mmol) and NaBH₃CN (15 mg, 0.19). The mixture was stirred at room temperature overnight. The mixture was quenched with sat. NH₄Cl aq (25 mL), the separated organic layer was dried over Na₂SO₄, filtered, the filtrated was concentrated to give crude product, which was purified by flash chromatography (MeOH in DCM = 10 %) to give compound 155 (48 mg, 41 % yield) as yellow oil. MS Calcd.: 925.1; MS Found: 926.1 [M+H]⁺. Synthesis of ethyl (S)-2-amino-4-((3-((2-(6,7-dichloronaphthalen-2- yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)butanoate (140)

To a solution of compound 155 (48 mg, 0.05 mmol) in DCM/TFA (4 mL/1 mL) was stirred at room temperature overnight. The mixture was concentrated to give crude product, which was purified by prep-HPLC to give compound 140 (17 mg, 50 % yield) as white solid. 1H NMR (400 MHz, D₂O) d 8.04 (s, 1H), 7.92 (s, 1H), 7.82 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 3.2 Hz, 1H), 6.67 (s, 1H), 4.86 - 4.84 (m, 2H), 4.28 - 4.18 (m, 6H), 3.44 - 3.02 (m, 13H), 2.43 - 2.11 (m, 7H), 1.25 - 1.20 (m, 3H). MS Calcd.: 685.25; MS Found: 688.3 [M+H]⁺. Synthesis of (S)-2-amino-4-((3-((2-(6,7-dichloronaphthalen-2- yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)butanoic acid (141)

To a solution of compound 140 (13 mg, 0.018 mmol) in MeOH / H₂O (3 mL/1 mL) was added LiOH (5 mg, 0.054 mmol). The mixture was stirred at room temperature 30 min. The reaction mixture was adjusted pH to 2-3 with HCl (1N/L) and extracted with EA (5 mL x 3), the combined organic layers was concentrated to give crude product, which was purified by prep-HPLC to give compound 141 (3.8 mg, 34 % yield) as white solid. 1HNMR (400 MHz, D₂O): d 8.01- 7.97 (m, 1H), 7.89-7.81 (m, 2H), 7.73-7.66 (m, 1H), 7.58-7.52 (m, 1H), 7.42-7.37 (m, 1H), 7.32-7.26 (m, 1H), 6.64-6.55 (m, 1H), 4.29-4.21 (m, 1H), 4.04 -4.01 (m, 1H), 3.92 -3.89 (m, 1H), 3.57-2.96 (m, 16H), 2.25-2.11 (m, 6H), 1.81-1.75 (m, 1H). MS Calcd.: 657.2; MS Found: 658.3 [M+H]⁺. Synthesis of compounds 190a-f:

General Procedure for the 2^nd reductive amination (180a to 180f) and the final deprotection (190a to 190f). To a stirred solution of 6 (1.1 eq.) and an aldehyde 170 (1 eq.) in dry DCE (0.12 ^M based on 170) was added AcOH (1.1 eq.). The solution was stirred for 4 h at rt, then NaBH(OAc)₃ (2.6 eq.) was added and the mixture was stirred for 4 h at rt and 12 h at 70 °C. After completion, the reaction was quenched by the addition of a 5 % aq. NaHCO₃ solution and the phases were separated. The aqueous phase was then extracted 3 times with CH₂Cl₂ and the combined organic phases once with brine. Drying over Na2SO4, filtration and evaporation afforded the crude product that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (mostly 99.5:0.5–94:6) to afford the tertiary amines 180 as yellow oils. Tertiary amines 180 were dissolved (0.02 M) in freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 6–16 h, then evaporated to give the desired products 190 as foams (2 or 3 TFA salt). tert-butyl (S)-4-((3-(benzyl(tert-butoxycarbonyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6-((tert- butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (180a) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (benzylamino)propyl)amino)butanoic acid (190a). ^ Reductive amination (180a): yield: 27 mg, 0.030 mmol, 21 %. HRMS (ESI): calcd. for C₄₆H₇₁N₈O₁₁ ^M+H ^⁺: 911.5237, found: 911.5222; R_f: 0.8 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190a): yield: 18 mg, 0.024 mmol, 100 % (2 TFA salt).¹H-NMR (400 MHz; DMSO-d₆): d 9.06 (s, 2H, NH₂), 8.52 (s, 1H, H2), 8.45–8.25 (m, 4H, H8, NH₃ ⁺), 7.50–7.36 (m, 5H, H- Ph), 6.01 (d, ³J = 4.8 Hz, 1H, H1'), 4.63 (t, ³J = 4.8 Hz, 1H, H2'), 4.39–4.31 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.11 (s, 2H, CH₂), 4.01 (t, ³J = 6.2 Hz, 1H, Ha), 3.63–3.60 (m, 1H, H5'_A), 3.55– 3.46 (m, 1H, H5'_B), 3.32–3.18 (m, 4H, Hg, H1''), 3.02–2.89 (m, 2H, H3''), 2.26–2.20 (m, 1H, Hb_A), 2.11– 2.05 (m, 1H, Hb_B), 2.06–1.96 (m, 2H, H2''); HRMS (ESI): calcd. for C₂₄H₃₅N₈O₅ ^M+H ^⁺: 515.2725, found: 515.2718. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(3-phenoxybenzyl)amino)propyl)(((3aR,4R,6R,6aR)-6- (6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (180b) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxybenzyl)amino)propyl)amino)butanoic acid (190b). ^ Reductive amination (180b): yield: 42 mg, 0.042 mmol, 28 %. HRMS (ESI): calcd. for C₅₂H₇₄N₈O₁₂Na ^M+H ^⁺: 1025.5318, found: 1025.5295; R_f: 0.82 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190b): yield: 31 mg, 0.037 mmol, 100 % (2 TFA salt).¹H-NMR (400 MHz; DMSO-d₆): d 9.06 (bs, 3H, NH₃ ⁺), 8.50 (s, 1H, H2), 8.34 (s, 1H, H8), 8.20 (bs, 2H, NH₂), 7.48–7.41 (m, 3H), 7.24–7.17 (m, 3H), 7.08–7.03 (m, 3H), 6.01 (d, ³J = 4.8 Hz, 1H, H1'), 4.64 (t, ³J = 4.8 Hz, 1H, H2'), 4.37–4.33 (m, 1H, H4'), 4.23 (t, ³J = 4.8 Hz, 1H, H3'), 4.12 (s, 2H, CH₂), 4.02–3.99 (m, 1H, Ha), 3.64–3.58 (m, 1H, H5'_A), 3.51–3.47 (m, 1H, H5'_B), 3.32–3.15 (m, 4H, Hg, H1''), 2.97–2.95 (m, 2H, H3''), 2.28–2.18 (m, 1H, Hb_A), 2.12–2.05 (m, 1H, Hb_B), 2.03–1.95 (m, 2H, H2''); HRMS (ESI): calcd. for C₃₀H₃₉N₈O₆ ^M+H ^⁺: 607.2987, found: 607.2983. tert-butyl (S)-4-((3-((3-(benzyloxy)benzyl)(tert-butoxycarbonyl)amino)propyl)(((3aR,4R,6R,6aR)- 6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (180c) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid (190c). ^ Reductive amination (180c): yield: 73 mg, 0.072 mmol, 49 %. HRMS (ESI): calcd. for C₅₃H₇₇N₈O₁₂ ^M+H ^⁺: 1017.5655, found: 1017.5627; R_f: 0.73 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190c): yield: 54 mg, 0.064 mmol, 100 % (2 TFA salt).¹H-NMR (400 MHz; DMSO-d₆): d 9.06 (bs, 3H, NH₃ ⁺), 8.50 (s, 1H, H2), 8.33 (s, 1H, H8), 8.20 (bs, 2H, NH₂), 7.46–7.35 (m, 6H, m-H, m-H'', o-H'', p-H''), 7.16 (d, ³J = 2.0 Hz, 1H, o-H'), 7.08 (dd, ³J = 8.0 Hz and ³J = 2.4 Hz, 1H, o-H), 7.03 (d, ³J = 7.2 Hz, 1 00 (d, ³J = 4.8 Hz, 1H, H1'), 5.11 (s, 2H, CH₂), 4.64 (t, ³J = 4.8 Hz, 1H, H2'), 4.36–4.34 (m .23 (t, ³J = 4.8 Hz, 1H, H3'), 4.09 (s, 2H, CH₂), 4.01–3.98 (m, 1H, Ha), 3.61–3.58 (m, 1H, H 47 (m, 1H, H5'_B), 3.31–3.19 (m, 4H, Hg, H1''), 3.04–2.89 (m, 2H, H3''), 2.25–2.18 (m, 1H,

.95 (m, 3H, Hb_B, H2''); HRMS (ESI): calcd. for C₃₁H₄₁N₈O₆ ^M+H ^⁺: 621.3144, found: 621.3128. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(4-phenoxyphenethyl)amino)propyl)(((3aR,4R,6R,6aR)- 6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (180d) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid (190d). ^ Reductive amination (180d): yield: 37.7 mg, 0.037 mmol, 28 %. HRMS (ESI): calcd. for C₅₃H₇₇N₈O₁₂ ^M+H ^⁺: 1017.5655, found: 1017.5641; R_f: 0.85 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190d): yield: 28 mg, 0.029 mmol, 100 % (3 TFA salt).¹H-NMR (400 MHz; DMSO-d₆): d 8.80 (bs, 3H, NH₃ ⁺), 8.68-8.09 (m, 7H, H2, H8, NH₃ ⁺, NH₂ ⁺), 7.39 (dd, ³J = 8.8 Hz and ³J = 7.6 Hz, 2H, m-H'), 7.28–7.26 (m, 2H, m-H), 7.17–7.12 (m, 1H, p-H'), 7.00–6.97 (m, 4H, o-H, o- H'), 6.01 (d, ³J = 4.7 Hz, 1H, H1'), 4.64 (t, ³J = 4.7 Hz, 1H, H2'), 4.39–4.31 (m, 1H, H4'), 4.23 (t, ³J = 4.7 Hz, 1H, H3'), 4.01 (t, ³J = 6.0 Hz, 1H, Ha), 3.68–3.56 (m, 1H, H5'_A), 3.56–3.44 (m, 1H, H5'_B), 3.67–3.22 (m, 2H, Hg), 3.22–3.16 (m, 2H, H1''), 3.16–3.06 (m, 2H, CH₂–N), 3.05–2.95 (m, 2H, H3''), 2.92–2.81 (m, 2H, CH₂–Ph),), 2.28–2.20 (m, 1H, Hb_A), 2.14–2.03 (m, 1H, Hb_B), 2.00–1.96 (m, 2H, H2''); HRMS (ESI): calcd. for C₃₁H₄₁N₈O₆ ^M+H ^⁺: 621.3144, found: 621.3136. tert-butyl (S)-4-((3-((3-(benzyloxy)benzyl)(tert-butoxycarbonyl)amino)propyl)(((3aR,4R,6R,6aR)- 6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl)methyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (180e) & (S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid (190e). ^ Reductive amination (180e): yield: 79 mg, 0.078 mmol, 49 %. HRMS (ESI): calcd. for C₅₃H₇₇N₈O₁₂ ^M+H ^⁺: 1017.5655, found: 1017.5626; R_f: 0.89 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190e): yield: 60 mg, 0.071 mmol, 100 % (2 TFA salt).¹H-NMR (400 MHz; DMSO-d6): d 8.91 (bs, 2H, NH2⁺), 8.48 (s, 1H, H2), 8.42 (bs, 3H, NH3⁺), 8.32 (s, 1H, H8), 8.09 (bs, 2H, NH₂), 7.47–7.42 (m, 2H, m-H'), 7.41–7.36 (m, 4H, o-H, o-H'), 7.36–7.31 (m, 1H, p-H'), 7.08–7.06 (m, 2H, m-H), 5.99 (d, ³J = 4.9 Hz, 1H, H1'), 5.13 (s, 2H, CH₂), 4.63 (d, ³J = 4.9 Hz, 1H, H2'), 4.37– 4.29 (m, 1H, H4'), 4.23 (t, ³J = 4.9 Hz, 1H, H3'), 4.08–3.97 (m, 3H, Ha, CH₂), 3.65–3.54 (m, 1H, H5'_A), 3.53–3.42 (m, 1H, H5'_B), 3.31–3.22 (m, 2H, Hg), 3.18–3.10 (m, 2H, H1''), 2.93–2.91 (m, 2H, H3''), 2.28–2.14 (m, 1H, Hb_A), 2.13–2.01 (m, 1H, Hb_B), 2.02–1.94 (m, 2H, H2''); HRMS (ESI): calcd. for C₃₁H₄₁N₈O₆ ^M+H ^⁺: 621.3144, found: 621.3126. tert-butyl (S)-4-((3-((tert-butoxycarbonyl)(naphthalen-2- ylmethyl)amino)propyl)(((3aR,4R,6R,6aR)-6-(6-((tert-butoxycarbonyl)amino)-9H-purin-9-yl)-2,2- dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl)amino)-2-((tert- butoxycarbonyl)amino)butanoate (180f) & (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin- 9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((naphthalen-2- ylmethyl)amino)propyl)amino)butanoic acid (190f). ^ Reductive amination (180f): yield: 63 mg, 0.066 mmol, 41 %. HRMS (ESI): calcd. for C₅₀H₇₃N₈O₁₁ ^M+H ^⁺: 961.5393, found: 961.5363; R_f: 0.85 (CH₂Cl₂/MeOH 9:1). ^ Deprotection (190f): yield: 51 mg, 0.065 mmol, 100 % (2 TFA salt).¹H-NMR (400 MHz; DMSO-d₆): d 9.17 (bs, 2H, NH₂ ⁺), 8.51–8.27 (m, 7H, H2, H8, NH₃ ⁺, NH₂), 8.03–7.99 (m, 2H, H naphthyl), 7.97 (dd, ³J = 6.2 Hz and ³J = 3.4 Hz, 1H, H naphthyl), 7.93 (dd, ³J = 6.2 Hz and ³J = 3.4 Hz, 1H, H naphthyl), 7.60–7.58 (m, 3H, H naphthyl), 6.00 (d, ³J = 4.7 Hz, 1H, H1'), 4.63 (t, ³J = 4.7 Hz, 1H, H2'), 4.36–4.33 (m, 1H, H4'), 4.29 (s, 2H, CH₂), 4.23 (t, ³J = 4.7 Hz, 1H, H3'), 4.02–3.99 (m, 1H, Ha), 3.66–3.60 (m, 1H, H5'_A), 3.52–3.48 (m, 1H, H5'_B), 3.31–3.19 (m, 4H, Hg, H1''), 3.07–2.96 (m, 2H, H3''), 2.30–2.16 (m, 1H, Hb_A), 2.10–1.99 (m, 3H, Hb_B, H2''). ; HRMS (ESI): calcd. for C₂₈H₃₇N₈O₅ ^M+H ^⁺: 565.2881, found: 565.2885. Synthesis of elongated building blocks for the side chain (170a to 170f):

General procedure for the preparation of extended amino-alcohols (161a to 161f). A mixture of aldehyde 160 (1 eq.) and 3-aminopropan-1-ol (1 eq.) in anhydrous MeOH (0.5 M) was stirred at rt for 48 h. After the formation of the imine was confirmed according to TLC and MS, the mixture was cooled down to 0°C and NaBH₄ (1.5 eq.) was added portionwise and the reaction was stirred at rt O/N. The volatiles were evacuated in vacuo and the crude was extracted with H2O/AcOEt (3 times). The combined organics were dried over Na₂SO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (CH₂Cl₂/MeOH 99.6:0.4–92:8). 3-(benzylamino)propan-1-ol (161a) was commercially available. 3-((3-phenoxybenzyl)amino)propan-1-ol (161b). yield: 892 mg, 3.467 mmol, 76 %. C₁₆H₁₉NO₂ (257.33 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.41–7.35 (m, 2H, m''-H), 7.30 (t, ³J = 8.0 Hz, 1H, m-H), 7.15–7.10 (m, 1H, p''-H), 7.08 (ddd, ³J = 7.6 Hz, ⁴J = 1.6 Hz and ⁴J = 1.2 Hz, 1H, o-H), 7.01– 6.97 (m, 3H, o'-H, o''-H), 6.84 (ddd, J = 8.4, 2.8, 1.2 Hz, 1H, p-H), 3.66 (s, 2H, Ph–CH2–N), 3.43 (t, ³J = 6.7 Hz, 2H, CH₂–O), 2.53 (t, ³J = 6.7 Hz, 2H, CH₂–N), 1.55 (quintet, ³J = 6.7 Hz, 2H, O–CH₂– CH₂–CH₂–N); ¹³C NMR (101 MHz, DMSO-d₆) d 156.7, 156.5, 143.4, 130.0, 129.5, 123.2, 123.0, 118.4, 117.9, 116.7, 59.5, 52.6, 46.0, 32.5; R_f: 0.07 (CH₂Cl₂/MeOH 96:4). 3-((3-(benzyloxy)benzyl)amino)propan-1-ol (161c). yield: 815 mg, 3.003 mmol, 64 %. C₁₇H₂₁NO₂ (271.36 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.47–7.43 (m, 2H, o''-H), 7.41–7.37 (m, 2H, m''- H), 7.35–7.30 (m, 1H, p''-H), 7.20 (dd, ³J = 7.6 Hz and ³J = 7.6 Hz, 1H, m-H), 6.99 (dd, ⁴J = 2.0 Hz and ⁴J = 1.6 Hz, 1H, o'-H), 6.90–6.88 (m, 1H, o-H), 6.85 (ddd, ³J = 8.0 Hz, ⁴J = 2.4 Hz and ⁴J = 0.8 Hz, 1H, p-H), 5.08 (s, 2H, Ph–CH₂–OPh), 3.64 (s, 2H, Ph–CH₂–N), 3.46 (t, ³J = 6.6 Hz, 2H, CH₂–O), 2.52 (t, ³J = 6.6 Hz, 2H, CH₂–N), 1.57 (quintet, ³J = 6.6 Hz, 2H, CH₂–CH₂–CH₂); ¹³C NMR (101 MHz, DMSO-d₆) d 158.3, 142.7, 137.1, 129.0, 128.3, 127.7, 127.6, 120.2, 114.1, 112.6, 69.0, 59.6, 52.9, 46.1, 32.5; R_f: 0.20 (CH₂Cl₂/MeOH 9:1). 3-((4-phenoxyphenethyl)amino)propan-1-ol (161d). yield: 589 mg, 2.171 mmol, 51 %. C₁₇H₂₁NO₂ (271.36 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.39–7.35 (m, 2H, m'-H), 7.23–7.21 (m, 2H, o-H), 7.13–7.09 (m, 1H, p'-H), 6.98–6.96 (m, 2H, o'-H), 6.93–6.91 (m, 2H, m-H), 3.44 (t, ³J = 6.5 Hz, 2H, CH₂–O), 2.74–2.63 (m, 4H, CH₂–N, CH₂–Ph), 2.58 (t, ³J = 6.5 Hz, 2H, CH₂–N), 1.54 (quintet, ³J = 6.5 Hz, 2H, CH₂–CH₂–CH₂). R_f: 0.16 (CH₂Cl₂/MeOH 9:1). 3-((4-(benzyloxy)benzyl)amino)propan-1-ol (161e). yield: 946 mg, 3.486 mmol, 75 %. C₁₇H₂₁NO₂ (271.36 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.45–7.43 (m, 2H, o''-H), 7.40–7.37 (m, 2H, m''- H), 7.34–7.30 (m, 1H, p''-H), 7.21 (d, ³J = 8.6 Hz, 2H, m-H), 6.93 (d, ³J = 8.6 Hz, 2H, o-H), 5.07 (s, 2H, Ph–CH₂–OPh), 3.59 (s, 2H, Ph–CH₂–N), 3.45 (t, ³J = 6.6 Hz, 2H, CH₂–O), 2.52 (t, ³J = 6.6 Hz, 2H, CH₂–N), 1.56 (quintet, ³J = 6.6 Hz, 2H, CH₂–CH₂–CH₂).¹³C NMR (101 MHz, DMSO-d₆) d 157.0, 137.2, 133.1, 129.0, 128.3, 127.7, 127.6, 114.3, 69.0, 59.6, 52.5, 46.1, 32.5; R_f: 0.16 (CH₂Cl₂/MeOH 9:1). 3-((naphthalen-2-ylmethyl)amino)propan-1-ol (161f). yield: 1.016 g, 4.719 mmol, 74 %. C14H17NO (215.30 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.88–7.84 (m, 3H, H naphthyl), 7.79 (s, 1H, H1 naphthyl), 7.51–7.43 (m, 3H, H naphthyl), 3.83 (s, 2H, naphthyl–CH₂–N), 3.47 (t, ³J = 6.6 Hz, 2H, CH₂–O), 2.58 (t, ³J = 6.6 Hz, 2H, CH₂–N), 1.60 (quintet, ³J = 6.6 Hz, 2H, CH₂–CH₂–CH₂).¹³C NMR (101 MHz, DMSO-d₆) d 138.7, 132.9, 132.0, 127.4, 127.4, 126.7, 125.9, 125.8, 125.3, 59.5, 53.2, 46.2, 32.6; R_f: 0.19 (CH₂Cl₂/MeOH 9:1). General procedure for the Boc protection of extended amino-alcohols (162a to 162f). To a solution of amino-alcohol 161(a-f) (1 eq.) was added Et₃N (1.5 eq.) and the mixture was cooled to 0 °C. After few minutes stirring at that temperature, Boc₂O (1.1 eq.) was added dropwise and the reaction mixture was stirred for 1–2 h at rt. After completion according to TLC, the reaction mixture was filtered through a silica pad, the pad was washed with AcOEt and the filtrate was evaporated under vacuum. The corresponding crude was subjected to flash column chromatography eluting with CH₂Cl₂/MeOH (99.7:0.3–98:2). tert-butyl benzyl(3-hydroxypropyl)carbamate (162a). yield: 1117 mg, 4.208 mmol, 70 %. C₁₅H₂₃NO₃ (265.35 g/mol).¹H-NMR (400 MHz; DMSO-d₆): 7.34 (t, ³J = 7.4 Hz, 2H, m-H), 7.28–7.23 (m, 1H, p-H), 7.22–7.20 (m, 2H, o-H), 4.41 (t, ³J = 5.2 Hz, 1H, OH), 4.37 (s, 2H, Ph–CH₂–N), 3.36 (q, ³J = 6.0 Hz, 2H, CH₂–O), 3.18–3.13 (m, 2H, CH₂–N), 1.63–1.56 (m, 2H, C–CH₂–C), 1.42–1.36 (m, 9H, CH₃ tBu). R_f: 0.41 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-hydroxypropyl)(3-phenoxybenzyl)carbamate (162b). yield: 359 mg, 1.004 mmol, 59 %. C₂₁H₂₇NO₄ (357.45 g/mol).¹H-NMR (400 MHz; DMSO-d₆): 7.41–7.33 (m, 3H, m''-H, m-H), 7.16–7.12 (m, 1H, p''-H), 7.02–6.98 (m, 3H, o-H, o''-H), 6.92–6.90 (m, 1H, p-H), 6.82 (s, 1H, o'-H), 4.41 (t, ³J = 5.2 Hz, 1H, OH), 4.34–4.34 (m, 2H, Ph–CH₂–N), 3.37–3.34 (m, 2H, CH₂–O), 3.16–3.11 (m, 2H, CH₂–N), 1.62–1.51 (m, 2H, C–CH₂–C), 1.40–1.27 (m, 9H, CH₃ tBu). R_f: 0.74 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-(benzyloxy)benzyl)(3-hydroxypropyl)carbamate (162c). yield: 829 mg, 2.316 mmol, 78 %. C₂₂H₂₉NO₄ (371.48 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.45–7.42 (m, 2H, o''-H), 7.41– 7.37 (m, 2H, m''-H), 7.35–7.30 (m, 1H, p''-H), 7.25 (t, ³J = 7.8 Hz, 1H, m-H), 6.90 (dd, ³J = 8.0 Hz and ⁴J = 2.0 Hz, 1H, o-H), 6.86–6.82 (m, 1H, o'-H), 6.79 (d, ³J = 7.6 Hz, 1H, p-H), 5.08 (s, 2H, Ph– CH₂–OPh), 4.42 (t, ³J = 5.0 Hz, 1H, OH), 4.34 (s, 2H, Ph–CH₂–N), 3.40–3.34 (m, 2H, CH₂–O), 3.17– 3.11 (m, 2H, CH₂–N), 1.65–1.53 (m, 2H, C–CH₂–C), 1.42–1.35 (m, 9H, CH₃ tBu). R_f: 0.63 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-hydroxypropyl)(4-phenoxyphenethyl)carbamate (162d). yield: 824 mg, 2.22 mmol, 100 %. C₂₂H₂₉NO₄ (371.48 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.38–7.34 (m, 2H, m'-H), 7.21– 7.19 (m, 2H, o-H), 7.13–7.09 (m, 1H, p'-H), 6.98–6.93 (m, 4H, m-H, o'-H), 4.44–4.42 (m, 1H, OH), 3.41–3.37 (m, 2H, CH₂–O), 3.35–3.30 (m, 2H, CH₂–N), 3.16–3.14 (m, 2H, CH₂–N), 2.74 (t, J = 7.4 Hz, 2H, CH₂–Ph), 1.62–1.56 (m, 2H, C–CH₂–C), 1.44–1.26 (m, 9H, CH₃ tBu). R_f: 0.75 (CH₂Cl₂/MeOH 9:1). tert-butyl (4-(benzyloxy)benzyl)(3-hydroxypropyl)carbamate (162e). yield: 1.21 g, 3.257 mmol, 95 %. C₂₂H₂₉NO₄ (371.48 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 7.45–7.42 (m, 2H, o'-H), 7.41– 7.37 (m, 2H, m'-H), 7.34–7.30 (m, 1H, p'-H), 7.15 (d, ³J = 8.6 Hz, 2H, m-H), 6.98 (d, ³J = 8.6 Hz, 2H, o-H), 5.08 (s, 2H, Ph–CH₂–OPh), 4.41 (t, ³J = 5.0 Hz, 1H, OH), 4.29 (s, 2H, Ph–CH₂–N), 3.36 (q, ³J = 5.8 Hz, 2H, CH₂–O), 3.13–3.09 (m, 2H, CH₂–N), 1.58 (quintet, ³J = 6.8 Hz, 2H, C–CH₂–C), 1.41 (s, 9H, CH₃ tBu). R_f: 0.7 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-hydroxypropyl)(naphthalen-2-ylmethyl)carbamate (162f). yield: 1.08 g, 3.43 mmol, 75 %. C19H25NO3 (315.41 g/mol). ¹H-NMR (400 MHz; DMSO-d6): d 7.90–7.86 (m, 3H, H naphthyl), 7.70 (s, 1H, H1 naphthyl), 7.52–7.47 (m, 2H, H naphthyl), 7.39 (dd, ³J = 8.4 Hz and ³J = 1.6 Hz, 1H, H3 naphthyl), 4.54 (s, 2H, naphthyl–CH₂–N), 4.43 (t, ³J = 5.2 Hz, 1H, OH), 3.38 (q, ³J = 5.9 Hz, 2H, CH₂–O), 3.26-3.20 (m, 2H, CH₂–N), 1.63 (quintet, ³J = 6.7 Hz, 2H, C–CH₂–C), 1.52–1.27 (m, 9H, CH₃ tBu). R_f: 0.72 (CH₂Cl₂/MeOH 9:1). General procedure for the preparation of extended N-Boc protected amino-aldehydes (170a to 170f). To a solution of oxalyl chloride (1.5 eq.) in dry CH2Cl2 (0.3 ^M) at -78 °C was added DMSO (2 eq.) in CH₂Cl₂. After 15 min, N-Boc protected amino-alcohol (162a-f) (1 eq.) in CH₂Cl₂ was added. After 30 min, Et₃N was added (5 eq.) and the mixture was allowed to warm up to rt. The organic phase was washed with a freshly prepared citric acid solution (5 % w/w), then an aq. sat. NaHCO₃ solution and brine, before being dried over Na₂SO₄, filtered and evaporated. The corresponding residue was pure enough to be used without further purification. tert-butyl benzyl(3-oxopropyl)carbamate (170a). yield: 1003 mg, 3.809 mmol, 92 %. C₁₅H₂₁NO₃ (263.34 g/mol).¹H-NMR (400 MHz; DMSO-d6): d 9.63 (t, ³J = 1.7 Hz, 1 7.30 (m, 2H, m-H), 7.28–7.24 (m, 1H, p-H), 7.24–7.21 (m, 2H, o-H), 4.38 (s, 2H, N-C

38 (m, 2H, CH₂-N), 2.60 (td, ³J = 6.6 Hz and ³J = 1.7 Hz, 2H, CH₂-CHO), 1.41–1.35 (m, 9H, CH₃ tBu). R_f: 0.75 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-oxopropyl)(3-phenoxybenzyl)carbamate (170b). yield: 322 mg, 0.906 mmol, 93 %. C₂₁H₂₅NO₄ (355.43 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.61 (t, ³J = 1.6 Hz, 1H, CHO), 7.41– 7.34 (m, 3H, m-H, m''-H), 7.15 (tt, ³J = 7.4 Hz and ³J = 1.2 Hz, 1H, p''-H), 7.03–6.99 (m, 3H, o-H, o''-H), 6.96–6.88 (m, 1H, p-H), 6.85–6.81 (m, 1H, o'-H), 4.34 (bs, 2H, N-CH2-Ph), 3.40–3.38 (m, 2H, CH₂-N), 2.58 (td, ³J = 6.6 Hz and ³J = 1.6 Hz, 2H, CH₂-CHO), 1.37–1.27 (m, 9H, CH₃ tBu). R_f: 0.8 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-(benzyloxy)benzyl)(3-oxopropyl)carbamate (170c). yield: 686 mg, 1.857 mmol, 85 %. C₂₂H₂₇NO₄ (369.46 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.62 (t, ³J = 1.7 Hz, 1H, CHO), 7.45–7.42 (m, 2H, o''-H), 7.41–7.37 (m, 2H, m''-H), 7.34–7.30 (m, 1H, p''-H), 7.26 (t, ³J = 8.0 Hz, 1H, m-H), 6.91 (dd, ³J = 8.4 Hz and ³J = 2.4 Hz, 1H, o-H), 6.88–6.84 (m, 1H, o'-H), 6.81 (d, ³J = 7.6 Hz, 1H, p-H), 5.09 (s, 2H, Ph-CH₂-O), 4.34 (s, 2H, N-CH₂-Ph), 3.41–3.37 (m, 2H, CH₂-N), 2.58 (td, ³J = 6.6 Hz and ³J = 1.7 Hz, 2H, CH₂-CHO), 1.41–1.35 (m, 9H, CH₃ tBu). R_f: 0.82 (CH₂Cl₂/MeOH 9:1). tert-butyl (3-oxopropyl)(4-phenoxyphenethyl)carbamate (170d). yield: 591 mg, 1.60 mmol, 83 %. C₂₂H₂₇NO₄ (369.46 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.65 (s, 1H, CHO), 7.39–7.35 (m, 2H, m''-H), 7.22–7.20 (m, 2H, o-H), 7.14–7.08 (m, 1H, , p''-H), 6.97–6.93 (m, 4H, m-H, o''-H), 3.42–3.38 (m, 2H, CH₂-N), 3.34 (t, J = 7.4 Hz, 2H, N-CH₂), 2.74 (t, J = 7.4 Hz, 2H, CH₂-Ph), 2.61 (td, J = 6.8, 2.0 Hz, 2H, CH₂-CHO), 1.39–1.30 (m, 9H, CH₃ tBu). R_f: 0.69 (CH₂Cl₂/MeOH 9:1). tert-butyl (4-(benzyloxy)benzyl)(3-oxopropyl)carbamate (170e). yield: 1.045 g, 2.283 mmol, 88 %. C₂₂H₂₇NO₄ (369.46 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.62 (t, ³J = 1.9 Hz, 1H, CHO), 7.45–7.42 (m, 2H, o''-H), 7.41–7.36 (m, 2H, m''-H), 7.34–7.30 (m, 1H, p''-H), 7.16 (d, ³J = 8.6 Hz, 2H, o-H), 6.99 (d, ³J = 8.6 Hz, 2H, m-H), 5.08 (s, 2H, Ph-CH₂-O), 4.29 (s, 2H, N-CH₂-Ph), 3.45–3.29 (m, 2H, CH₂-N), 2.58 (td, ³J = 6.8 Hz and ³J = 1.9 Hz, 2H, CH₂-CHO), 1.39 (s, 9H, CH₃ tBu). R_f: 0.8 (CH₂Cl₂/MeOH 9:1). tert-butyl (naphthalen-2-ylmethyl)(3-oxopropyl)carbamate (170f). yield: 656 mg, 2.09 mmol, 62 %. C₁₉H₂₃NO₃ (313.40 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.64 (t, ³J = 1.8 Hz, 1H, CHO), 7.95–7.84 (m, 3H, H naphthyl), 7.72 (s, 1H, H1 naphthyl), 7.53–7.47 (m, 2H, H naphthyl), 7.38 (dd, ³J = 8.4 Hz and ³J = 1.2 Hz, 1H, H3 naphthyl), 4.55 (s, 2H, N-CH2-Ph), 3.50–3.44 (m, 2H, CH2-N), 2.63 (td, ³J = 6.6 Hz and ³J = 1.6 Hz, 2H, CH₂-CHO), 1.44–1.36 (m, 9H, CH₃ tBu). R_f: 0.67 (CH₂Cl₂/MeOH 9:1). Synthesis of Fivemethyl-Lock (5-ML) prodrug (200): 2-(trimethylsilyl)ethyl (3-hydroxypropyl)(3-phenoxybenzyl)carbamate (163). To an ice-cooled solution of 161b (440 mg, 1.69 mmol, 1 eq.), in dry DCM (17 mL) was added Et3N (715 µL, 5.08 mmol, 3 eq.), followed by Teoc-OSu (887 mg, 3.39 mmol, 2 eq.). The mixture was stirred at rt for 24 h, followed by 3 h at 60 °C. After completion, according to TLC, H₂O was added to quench the reaction and the organic phase was separated. The aqueous phase was then extracted 2 more times with DCM. Combined organic phases were dried over Na₂SO₄, dried, filtered and evaporated to afford the crude product that was subjected to flash column chromatography (DCM/MeOH 99.7:0.3–98.5:1.5). 163 was obtained as a yellow oil (668 mg, 1.66 mmol, 98 %). C22H31NO4Si (401.58 g/mol).¹H-NMR (400 MHz; DMSO-d6): d 7.40–7.33 (m, 3H, m-H'', m-H), 7.16–7.12 (m, 1H, p-H''), 7.01–6.98 (m, 3H, o-H'', o-H), 6.91–6.89 (m, 1H, p-H), 6.87– 6.80 (m, 1H, o-H'), 4.43–4.42 (m, 1H, OH), 4.40 (s, 2H, Ph-CH₂-N), 4.10–4.04 (m, 2H, O-CH₂), 3.35 (q, ³J = 5.8 Hz, 2H, H1''), 3.19 (t, ³J = 7.0 Hz, 2H, H3''), 1.58 (quintet, ³J = 7.0 Hz, 2H, H2''), 0.95– 0.92 (m, 1H, CH_{2 A}-TMS), 0.86–0.83 (m, 1H, CH_{2 B}-TMS), 0.0 (m, 9H, Si(CH₃)₃).¹³C NMR (101 MHz, DMSO-d₆) d 139.9, 137.8, 137.5, 128.3, 128.2, 127.8, 127.7, 127.6, 127.6, 127.5, 127.4, 97.5, 90.7, 84.9, 81.5, 80.1, 75.7, 72.3, 71.7, 71.1, 69.0; R_f: 0.77 (CH₂Cl₂/MeOH 9:1). Alcohol to aldehyde oxidation procedure was the same as for the “General procedure for the preparation of extended N-Boc protected amino-aldehydes (170a to 170f)”. 2-(trimethylsilyl)ethyl (3-oxopropyl)(3-phenoxybenzyl)carbamate (164). yield: 518 mg, 1.30 mmol, 80 %. C₂₂H₂₉NO₄Si (399.56 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 9.61 (t, ³J = 1.6 Hz, 1H, CHO), 7.41–7.34 (m, 3H, m-H'', m-H), 7.16–7.12 (m, 1H, p-H''), 7.02–6.98 (m, 3H, o- H'', o-H), 6.92–6.90 (m, 1H, p-H), 6.86–6.85 (m, 1H, o-H'), 4.41 (s, 2H, Ph-CH₂-N), 4.09–4.03 (m, 2H, O-CH₂), 3.43 (t, ³J = 6.6 Hz, 2H, H1''), 2.62–2.60 (m, 2H, H2''), 0.94–0.92 (m, 1H, CH_{2 A}-TMS), 0.85–0.81 (m, 1H, CH_{2 B}-TMS), 0.00 (m, 9H, Si(CH₃)₃). R_f: 0.82 (CH₂Cl₂/MeOH 9:1). tert-butyl (S)-11-(((3aR,4R,6R,6aS)-6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)-14-((tert- butoxycarbonyl)amino)-2,2-dimethyl-6-oxo-7-(3-phenoxybenzyl)-5-oxa-7,11-diaza-2- silapentadecan-15-oate (197). After having stirred a solution of the intermediate 70 (130 mg, 0.191 mmol, 1.1 eq.), aldehyde 164 (70 mg, 0.174 mmol, 1 eq.) and AcOH (11 µL, 0.191 mmol, 1 eq.) in dry DCE (1.4 mL) for 6 h at rt, NaBH(OAc)₃ (97 mg, 0.451 mmol, 2.6 eq.) were added portionwise and the mixture was stirred for 16 h. After completion, the reaction mixture was quenched by the addition of 5% NaHCO₃ solution and the aqueous phase was extracted with DCM (3 x). The combined organic layers were dried over Na₂SO₄, filtered and evaporated and the corresponding crude was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.6:0.4–96:4) to afford the tertiary amine 197. (78 mg, 0.074 mmol, 42 %). C₅₆H₈₃N₇O₁₁Si (1058.40 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 8.60 (s, 1H, H2), 7.71 (d, ³J = 3.8 Hz, 1H, H8), 7.38–7.33 (m, 2H, m-H''), 7.31–7.24 (m, 1H, m-H), 7.17–7.08 (m, 2H, p-H'', NH- carbamate), 6.97–6.95 (m, 3H, o-H'', o-H), 6.87–6.80 (m, 2H, p-H, o-H'), 6.43 (d, ³J = 3.8 Hz, 1H, H7), 5.10–5.05 (m, 1H, H1'), 4.89-4.83 (m, 1H, H2'), 4.38–4.35 (m, 3H, H3', CH₂), 4.09–4.00 (m, 2H, CH2-O), 3.89–3.85 (m, 1H, Ha), 3.19–3.16 (m, 2H, H1''), 2.43–2.35 (m, 4H, H5', Hg), 2.32 (m, 2H, H3''), 2.24 (s, 2H, H4', H6'_A), 1.99–1.93 (m, 1H, H6'_B), 1.76–1.72 (m, 1H, Hb_A), 1.60–1.55 (m, 3H, Hb_B, H2''), 1.47–1.41 (m, 12H, CH₃, CH₃ tBu), 1.36 (s, 9H, CH₃ tBu), 1.32 (s, 9H, CH₃ tBu), 1.20–1.16 (m, 3H, CH₃), 0.92–0.87 (m, 1H, CH_{2 A}-TMS), 0.85–0.80 (m, 1H, CH_{2 B}-TMS), -0.03 (s, 9H, Si(CH₃)₃); HRMS (ESI): calcd. for C₅₆H₈₄N₇O₁₁Si ^M+H ^⁺: 1058.5993, found: 1058.5988; R_f: 0.89 (CH₂Cl₂/MeOH 92:8). tert-butyl (S)-4-((((3aR,4R,6R,6aS)-6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)(3-((3- phenoxybenzyl)amino)propyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (198). To a stirred solution of the intermediate 197 (75 mg, 0.07 mmol, 1 eq.) in dry THF (1.4 mL) was added 563 µL of a 1 ^M solution of TBAF in THF (0.562 mmol, 8 eq.). After stirring for 2 h, the mixture was extracted with DCM/H₂O (3 times), the combined organic layers were dried over Na₂SO₄, filtered and the volatiles were evaporated to afford the crude that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.7:0.3–9:1) to afford 198 as a white foam (47 mg, 0.051 mmol, 73 %). C50H71N7O9 (914.16 g/mol). ¹H-NMR (400 MHz; DMSO-d6): d 8.61 (s, 1H, H2), 7.73 (d, J³J = 3.6 Hz, 1H, H8), 7.42–7.34 (m, 2H, m-H''), 7.34–7.26 (m, 1H, m-H), 7.17–7.08 (m, 3H, NH-carbamate, o-H, p-H''), 7.01–6.97 (m, 3H, o-H', o-H''), 6.88–6.86 (m, 1H, p-H), 6.43 (d, ³J = 3.6 Hz, 1H, H7), 5.12–5.06 (m, 1H, H1'), 4.91–4.86 (m, 1H, H2'), 4.42–4.39 (m, 1H, H3'), 3.94– 3.85 (m, 1H, Ha), 3.83–3.67 (m, 2H, CH₂), 2.62–2.57 (m, 1H, H5'_A), 2.56–2.36 (m, 7H, H5'_B, Hg, H1'', H3''), 2.32–2.22 (m, 2H, H4', H6'_A), 1.97–1.91 (m, 1H, H6'_B), 1.82–1.70 (m, 1H, Hb_A), 1.67–1.51 (m, 3H, Hb_B, H2''), 1.46 (s, 3H, CH₃), 1.44 (s, 9H, CH₃ tBu), 1.36 (s, 9H, CH₃ tBu), 1.31 (s, 9H, CH₃ tBu), 1.20 (s, 3H, CH3); Rf: 0.50 (CH2Cl2/MeOH 9:1). tert-butyl (S)-4-((((3aR,4R,6R,6aS)-6-(4-((tert-butoxycarbonyl)(methyl)amino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)(3-(3-methyl- N-(3-phenoxybenzyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1- yl)butanamido)propyl)amino)-2-((tert-butoxycarbonyl)amino)butanoate (199).

To a stirred solution of 198 (47 mg, 0.051 mmol, 1 eq.) and 2,2-dimethyl-3-(2,4,5-trimethyl-3,6- dioxocyclohexa-1,4-dien-1-yl)propanoic acid (13 mg, 0.051 mmol, 1 eq.) in dry DCM (1.5 mL) were added successively EDCI (11 mg, 0.056 mmol, 1.1 eq.), DMAP (1 mg, 0.005 mmol, 0.1 eq.) and Et3N (8 µL, 0.056 mmol, 1.1 eq.). After stirring for 36 h, the mixture was extracted with DCM/H₂O (3 times), the combined organic layers were dried over Na₂SO₄, filtered and the volatiles were evaporated to afford the crude that was subjected to silica gel column chromatography eluting with CH₂Cl₂/MeOH (99.5:0.5–97:3) to afford 199 as a colorless oil (32 mg, 0.028 mmol, 55 %). C₆₄H₈₇N₇O₁₂ (1146.44 g/mol).¹H-NMR (400 MHz; DMSO-d₆): d 8.63–8.58 (rotamer, 1H, H2), 7.75– 7.64 (rotamer, 1H, H8), 7.37–7.33 (rotamer, 2H, m-H''), 7.26–7.08 (rotamer, 3H, NH-carbamate, m- H, p-H''), 6.99–6.94 (rotamer, 2H, o-H''), 6.87–6.74 (rotamer, 3H, o-H, p-H, o-H'), 6.46–6.38 (rotamer, 1H, H7), 5.15–5.04 (rotamer, 1H, H1'), 4.91–4.79 (rotamer, 1H, H2'), 4.56–4.40 (rotamer, 2H, CH2), 4.39–4.34 (rotamer, 1H, H3'), 3.91–3.84 (rotamer, 1H, Ha), 3.02–2.90 (rotamer, 1H), 2.43– 2.39 (rotamer, 4H), 2.32–2.21 (rotamer, 2H, H4', H6'_A), 2.05–1.87 (rotamer, 4H, CH₃, H6'_B), 1.83– 1.80 (rotamer, 4H, CH₃), 1.80–1.69 (rotamer, 3H, CH₃), 1.64–1.59 (rotamer, 2H), 1.46–1.44 (rotamer, 3H, CH₃), 1.44–1.41 (rotamer, 9H, CH₃ tBu), 1.39–1.34 (rotamer, 9H, CH₃ tBu), 1.34–1.29 (rotamer, 9H, CH₃ tBu), 1.20–1.15 (rotamer, 3H, CH₃); HRMS (ESI): calcd. for C₆₄H₈₈N₇O₁₂ ^M+H ^⁺: 1146.6485, found: 1146.6470; R_f: 0.68 (CH₂Cl₂/MeOH 95:5). (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin- 7-yl)cyclopentyl)methyl)(3-(3-methyl-N-(3-phenoxybenzyl)-3-(2,4,5-trimethyl-3,6- dioxocyclohexa-1,4-dien-1-yl)butanamido)propyl)amino)butanoic acid (200).

199 was dissolved (0.02 M) in a freshly prepared TFA/H₂O (4:1) solution and stirred at rt for 6 h. The reaction was concentrated under reduced pressure and the obtained residue was used without further purification (21 mg, 0.022 mmol, 100 %). C₄₇H₅₉N₇O₈ (850.03 g/mol). ¹H-NMR (400 MHz; DMSO-d₆): d 9.69–9.27 (rotamer, 1H), 8.79–8.37 (rotamer, 2H), 8.34 (s, 1H), 7.58 (bs, 1H), 7.44–7.29 (rotamer, 3H), 7.23–7.09 (rotamer, 1H), 7.04–6.77 (rotamer, 5H), 4.96–4.91 (rotamer, 1H), 4.66–4.33 (rotamer, 2H), 4.20–4.09 (rotamer, 1H), 4.05–3.99 (rotamer, 1H), 3.92–3.76 (rotamer, 1H), 3.30–2.95 (rotamer, 11H), 2.36–2.26 (rotamer, 3H), 2.09–1.90 (rotamer, 5H), 1.85– 1.80 (rotamer, 4H), 1.71 (rotamer, 2H), 1.36–1.27 (rotamer, 3H), 1.27–1.15 (rotamer, 3H); HRMS (ESI): calcd. for C₄₇H₅₈N₈O₇ ^M–H ^^–: 848.4352, found: 848.4352. 2. Testing of the compounds for KMT9-inhibition and KMT9-binding Methylation assay to test KMT9-inhibition by compounds of the present invention Methylation assays were performed to test inhibition of the KMT9 methyltransferase activity by compounds. To test these potential inhibitors, 1 µL of the compounds, dissolved in DMSO at different concentrations, were added to a 0.5 ml tube (Brand Gmbh&Co KG). Afterwards, 4 µL of assay buffer (50 mM BTP, 1 mM MgCl2, 1 mM DTT, 0.01 % TX-100, pH 8.5) were added together with 10 µL of 2X solution of KMT9 diluted in assay buffer (final concentration 0.025-0.6 µM). The solutions were mixed and incubated for 20 min at room temperature, shaking at 300 rpm. Afterwards, 5 µL of 4X Protein-SAM mix was added (final concentrations: 5 µM ETF1 or histone H4, SAM: 1-2.5 µM (including 30% of radioactively labelled [³H]SAM)) to a final assay volume of 20 µL. The reaction mixtures were mixed and incubated in an Eppendorf thermomixer comfort for 2 h at 30°C, shaking at 300 rpm. The reaction was quenched using 5 µL of 50 % trichloroacetic acid (TCA) in water, mixed and incubated for 5 min at room temperature without shaking.22 µL of the solution was transferred to a filter binding plate (MultiScreenHTS FB Filter Plate, 1.0/0.65 µm, opaque, non-sterile, Merck KGaA Darmstadt), vacuum filtered using MultiScreen®HTS Vacuum Manifold (Merck KGaA Darmstadt) and washed with 4x 50 µL TCA 10% followed by 2x 50 µL ethanol 100%. After air-drying overnight, the filters were transferred to individual scintillation vials; 3 mL of Ultima Gold (PerkinElmer) was added and shook for 1 h. The scintillation signal was measured for 3x1 min using Tri-Carb 2910 TR (PerkinElmer) scintillation counter in [³H] CPM mode. The obtained IC₅₀-values of the tested compounds are shown in the table below as follows: IC50-value > 10 µM is denoted with a “+”, IC50-value from 10 µM to 100 nM is denoted with “++”,

and IC₅₀-value < 100 nM is denoted with “+++”. Microscale thermophoresis (MST) to test KMT9-binding by compounds of the present invention To determine the binding affinity of a compound to KMT9, microscale thermophoresis (MST) analysis was performed with a NanoTemper Monolith NT.115 instrument (NanoTemper Technologies GmbH). KMT9 was labelled with a RED-Tris-NTA labelling kit (NanoTemper Technologies GmbH) based on the manufacturer’s instructions. Buffer including 25 mM HEPES (pH 7.5), 100mM NaCl, 1mM DTT and 0.05% Tween was used for the reaction buffer. Varying concentrations of compounds were titrated against His-tag labelled KMT9 proteins (20 nM). Samples were loaded into standard Capillaries (NanoTemper Technologies GmbH) and MST measurements were performed using 40 % MST power and 100 % LED power. For each set of binding experiments, MST measurement was carried out with Binding Affinity module in MO. Control program under Nano-RED Excitation. Datasets were processed with the MO. Affinity Analysis software (NanoTemper Technologies GmbH). The obtained binding affinities of the tested compounds are shown in the table below as follows: binding affinity > 10 µM is denoted with a “+”, binding affinity from 10 µM to 100 nM is denoted with “++”, and binding affinity < 100 nM is denoted with “+++”. Thermal Shift Assay to test the increase in thermal stability of KMT9 upon inhibitor binding For inhibitor testing, 1 µL of the compounds, dissolved in DMSO at different concentrations, were added to a 96 well hard-shell PCR plate (Bio-Rad). Afterwards 4 µL of assay buffer (50 mM BTP, 1 mM MgCl₂, 1 mM DTT, pH 8.5) were added, followed by 10 µL of 2X KMT9 (final concentration 2 µM) in assay buffer. After addition of 5 µL 4X SYPRO-Orange (Sigma) (final concentration 5x), the plate was spun for 1 min at 700 rpm, then shaken at 600 rpm for 15 minutes. After another spinning at 700 rpm for 1 min, measurement was performed using a CFX96 Touch Real-Time PCR Detection System (Bio-Rad). The plate was equilibrated at 20°C for 4 minutes before heating gradually by 1°C every 15 seconds until 95°C. After every step, the fluorescence was measured in FRET mode. The thermal shift at 500 µM is detected in K (Kelvin). For Example 9o, the thermal shift at 250 µM is detected in K (Kelvin). The obtained thermal shifts obtained by adding the tested compounds are shown in the table below as follows: shift £ 5 K is denoted with a “+”, shift > 5 and £ 15 K is denoted with “++”, and shift > 15 K is denoted with “+++”. Table 1: Activity of compounds towards KMT9; n.a. denotes “not available” since these data were not tested

Compound A has the following structure, which is known from Dowden et al.; Org. Biomol. Chem., 2011, 9, 7814 (see compound 19 therein):

Compound B has the following structure, which is known from Mori et al.; Bioorg. Med. Chem., 2010, 18(23), 8158 (see compound 1a therein):

Effects of the addition of KMT9-inhibitors to cells on the proliferation of the cells Compounds 75a to 75c, 110, 112, 120, 140, and 200 are assumed to correspond to prodrugs and are therefore examples of compounds that can directly be used in cells since they are membrane-permeable. Upon entering the cell, the ester-moiety (here for compounds 75a to 75c, 110, 112, 120, and 140 a methyl- or ethyl-ester) or the amide-moiety (here for compound 200 a quinone derivative bound via an amide) is cleaved by cellular esterases, amidases and/or other suitable enzymes, resulting in the acid-moiety and the amino-moiety, respectively, found in compounds of the present invention that are active in vitro (see Table 1 above, where all active compounds have a H in the R¹ position and the RH-position). Compound 75b was tested in a proliferation assay in cell culture as described in the following. Thus, compound 75b (alternatively referred to as “KMI95423411”) was added to a final concentration of 30 µM (in the controls, DMSO was added) to cells of the following cell lines: LNCaP, SW-480, A549, MDA-MB-468 and HepG2, and the cells were cultured in the presence of inhibitor or DMSO. At the time points indicated in Figure 1, the cells were seeded in E-plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below. As can be derived from Figure 1, compound 75b blocks proliferation of LNCaP prostate tumour cells, SW-480 colorectal cancer cells, MDA-MB-468 breast cancer cells, and A549 lung tumour cells. KMI95423411 does not affect proliferation of the KMT9 non-responsive HepG2 cells. Compound 120 was tested in a proliferation assay in cell culture as described in the following. Thus, compound 120 (alternatively referred to as “KMI95423512”) was added to final concentrations as indicated in Fig. 5 (10, 15, 20 and/or 30 µM, in the controls, DMSO was added) to cells of the following cell lines: HepG2 and HEK293 with KMT9a KO (as controls); HT-1376, 5637, CAL-29, TCCSUP and T24 (all bladder cancer cells); SW480, Caco2, RKO (all colon cancer cells); LAPC4, PC-3M, C42B, DU145 and 22Rv1 (all prostate cancer cells); BT-20, MDA-MB-231 (both breast cancer cells), as welll as GLC2 and PC-9 (all lung cancer cells). The cells were cultured in the presence of inhibitor or DMSO. At the time points indicated in Fig.5, the cells were seeded in E-plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below. As can be derived from Figure 5, compound 120 blocks proliferation of bladder cancer cells, colon cancer cells, prostate cancer cells, breast cancer cells and lung cancer cells. Compound 120 does not affect proliferation of the KMT9 non-responsive HepG2 cells and the HEK293 cells, where KMT9a was knocked-down (positive control). Further, the cellular target engagement of Compound 120 for KMT9 in Caco2, PC-3M and RKO cells was tested using a cellular thermal shift assay (CETSA) assay. The results are shown in Fig.5f and it can be derived therefrom that Compound 120 binds to KMT9 in Caco2, PC-3M and RKO cells, while it does not bind to KMT5a in Caco2 cells (control). Accordingly, there is target engagement of Compound 120 for KMT9 inside the tested cells, i.e. Compound 120 is membrane-permeable (likely as prodrug) and active inside the cells (likely after cleavage of the ester-moiety by a cellular esterase). Compound 140 was also tested in a proliferation assay in cell culture. Thus, compound 140 (alternatively referred to as “KMI95423712”) was added to final concentrations as indicated in Fig. 6 (10, 15, 20, 30 and 50 µM, in the controls, DMSO was added) to cells of the following cell lines: HepG2 (as control), HT-1376 and CAL-29 (bladder cancer cells). The cells were cultured in the presence of inhibitor or DMSO. At the time points indicated in Fig. 6, the cells were seeded in E- plates and the cell proliferation was determined using the xCelligence RTCA system (Roche) as described below. As can be derived from Figure 6, compound 140 blocks proliferation of bladder cancer cells. Compound 140 does not affect proliferation of the KMT9 non-responsive HepG2 cells. Cell proliferation was determined using the X-Celligence RTCA system (Roche). For real-time recording of LNCaP, SW-480, A549, MDA-MB-468, HT-1376, 5637, CAL-29, TCCSUP, T24, Caco2, RKO, LAPC4, PC-3M, C42B, DU145, 22Rv1, BT-20, MDA-MB-231, GLC2, PC-9, HEK293 and HepG2 cell proliferation, cells were seeded in 16 well E-plates (Roche). Cell indices were automatically recorded every 15 minutes. Relative velocities represent the change of the cell index over time. All cell lines used herein were cultured according to standard methods. LNCaP, 5637, LAPC4, PC-3M, C42B, GLC2 and PC-9 cells were cultured in RPMI 1640. SW480, A549, MDA-MB-468, HT-1376, CAL-29, TCCSUP, SW480, 22Rv1, MDA-MB-231, HEK293 and HepG2 cells were cultured in DMEM. Caco2, DU145, BT-20 and RKO cells were cultured in EMEM. T24 cells were cultured in McCoy’s 5A. All media were supplemented with 10% fetal calf serum, penicillin/streptomycin, and glutamine. PC-3M, C42B, DU145, and 22Rv1 were cultured under low glucose (1 g/l) conditions. Method for cellular Thermal Shift Assay (CETSA) according to Jafari et al (Nature protocols, 2010, doi:10.1038/nprot.2014.138): For CETSA, cells were cultivated at 37 °C and 5 % CO2 according to published procedures and incubated with Compound 120 at a final concentration of 15 µM or DMSO for 2 hours Then, cells were washed with PBS, trypsinised, and resuspended at (3.6x 107 cells/mL) in PBS with Complete (w/o EDTA, Roche) protease inhibitor. Cells were then frozen in liquid nitrogen and thawed at 25 °C three times, before being divided in 16 aliquots. Each aliquot was heated to a defined temperature between 40 °C and 70 °C in a PCR cycler (16 well gradient, 55 °C ± 15). After incubation for 3 minutes, the aliquots were frozen again in liquid nitrogen and thawed at 25 °C. The lysates were then centrifuged at 14000rpm, 4 °C for 20 minutes. The supernatant was then spiked and mixed with 5x loading buffer and heated to 70 °C for 5 minutes. Proteins in the samples were separated on an SDS-PAGE gel and analyzed per Western blot 3. Specificity of compounds according to the present invention towards KMT9 Compound 72b was tested against a plurality of methyltransferases as described in the following. Thus, compound 72b was tested against the methyltransferases as indicated in Table 2 below, wherein the compound was tested in a 10-dose IC50 mode with 3-fold serial dilution, in singlet, starting at 10 mM. Control compounds, namely SAH (S-(5'-Adenosyl)-L-homocysteine), Chaetocin, LLY 507, or Ryuvidine (as also indicated in Table 2 below) were tested in 10-dose IC50 mode with 3-fold serial dilution starting at 100 or 200 mM. Reactions were carried out at 1 mM SAM. Curve fits were performed where the enzyme activities at the highest concentration of compounds were less than 65%. Empty cells indicate no inhibition or compound activity that could not be fit to an IC50 curve. Compound 72b is referred to as KMI9542321 in Table 2.

These data clearl show that com ound 72b is s ecific for KMT9-inhibition

. It is presently assumed that key determinants for the specificity towards methyltransferases of the seven-beta strand family and in particular towards KMT9 (see Table 2) can be attributed to the following moieties of the inhibitors, when aligning the different moieties of the general structure of the inhibitors as shown in formula (I) with the substrate S-Adenosyl-L-methionin: in the (i) adenosine moiety, there are interactions between KMT9 and the inhibitors at (a) D103 of KMT9 and the N6 amine; (b) L104 of KMT9 and the N1; (c) I78 of KMT9 and the N3; and (d) D77 of KMT9 and the two hydroxyl-groups; in the (ii) methionine moiety, there are interactions between KMT9 and the inhibitors at (a) E51, S54, G53 of KMT9 and the amine and (b) T29, N122 of KMT9 and the carboxyl; and in the (iii) anchor moiety [corresponding to the R2-substitutent of formula (I)], where a nitrogen corresponds to an anchor point interacting with D28 and P123 of KMT9. When it comes to the structure of KMT9, reference is made to Metzger at al., Nat. Struct. Mol. Biol., 2019 May, 26(5): 361, in particular Fig.2 and Table 1 therein. 4. Effects of KMT9-knockdown on the proliferation of cancer cell lines The data by Metzger at al., Nat. Struct. Mol. Biol., 2019 May, 26(5): 361 nicely show that KMT9 controls growth of prostate cancer cell. Thus, in particular by carrying out experiments in PC-3M xenograft tumors, Metzger et al. showed that KMT9 knockdown has a pronounced effect on the tumor, namely in that the tumor volume and the tumor weight are significantly reduced upon KMT9 knockdown (see in particular Figure 6 of the afore-mentioned publication). This is completely consistent with the effect of a compound of the present invention on the proliferation of LNCaP prostate tumour cells as shown in Figure 1, i.e. by inhibiting KMT9. KMT9 alpha knockdown was furthermore carried out in various cancer cells lines, namely cell lines of breast cancer, ovarian carcinoma, colon cancer, glioblastoma, lung cancer and neuroblastoma and it was observed for all tested cell lines that the knockdown of KMT9alpha results in a proliferation block of these cancer cells lines (see Fig.2 and 3, also for details of the tested cell lines). Accordingly, KMT9 inhibition also results in a proliferation block of these cancer cell lines, which has been confirmed herein explicitly for colorectal cancer, breast cancer cells, and lung tumour cells (see in particular Figure 1). When it comes to lung cancer, the data by Baumert et al., Cancer Cell Int (2020) 20:52 (https://doi.org/10.1186/s12935-020-1141-2) nicely show the implication of KMT9 in lung cancer. KMT9 alpha knockdown was also carried out in cancer cells lines of bladder cancer cells (TCCSUP, HT-1376, JON, 5637, CAL-29 and T24), and the proliferation as well as the migration (for some of the cell lines) was tested. As indicated in Fig.4, the proliferation and the migration were blocked. Accordingly, KMT9 inhibition results in a proliferation and migration block of bladder cancer cell lines. All cell lines used in this example were cultured according to standard methods, usually in DMEM. All media were supplemented with 10% fetal calf serum, penicillin/streptomycin, and glutamine. Cell proliferation and migration was determined using the X-Celligence RTCA system (Roche). For real-time recording of cell proliferation, 20000 cells/well were seeded in 16 well E- plates (Roche). For real-time recording of cell migration, 40000 cells/well were seeded into the transwell of CIM-plates containing 0.5% FCS in the upper chamber and 10% FCS in the lower chamber. Cells were transfected with the indicated siRNAs 24 h before seeding in E-plates or CIM-plates. Cell indices were automatically recorded every 15 minutes. Relative velocities represent the change of the cell index over time. The sequences of the siRNAs (Stealth RNAi™ siRNAs; Life Technologies) used in the experiments are as following: siCtrl: 5’- GAAAGUCCUAGAUCCACACGCAAAU-3’ [SEQ ID NO: 3]; siKMT9 ^#1 (also referred to as “RNAi N6AMT1” or “RNAi N6AMT1#1” or siKMT9a#1): 5’-ACGCUGUAACAAAGUUCACAUUCAA-3’ [SEQ ID NO: 4]; siKMT9a#2: 5’-CACGCUGUAACAAAGUUCACAUUCA-3’ [SEQ ID NO: 5]. As the Stealth RNAis are comprised of a duplex of single-stranded RNA, the respective reverse complement sequences are also given for the sake of completeness: for the siCtrl.: 5’- AUUUGCGUGUGGACUUAGGACUUUC-3’ [SEQ ID NO: 6], for siKMT9a#1: 5’- UUGAAUGUGAACUUUGUUACAGCGU-3’ [SEQ ID NO: 7] and for siKMT9a#2: 5’- UGAAUGUGAACUUUGUUACAGCGUG-3’ [SEQ ID NO: 8]. References 1. Moore TW, Zhu S, Randolph R, Shoji M, Snyder JP. Liver S9 Fraction-Derived Metabolites of Curcumin Analogue UBS109. ACS Med Chem Lett.2014;5(4):288-292. doi:10.1021/ml4002453 2. Hsu S-W, Cheng H-Y, Huang A-C, Ho T-L, Hou D-R. Total Synthesis of Quebrachamine through Macrolactamization. European J Org Chem.2014;2014(15):3109-3115. doi:10.1002/ejoc.201400064 3. Bracher F, Papke T. Total syntheses and antimicrobial activities of pyridine alkaloids from Rubiaceae. Monatshefte für Chemie / Chem Mon. 1995;126(6):805-809. doi:10.1007/BF00807174 4. Yang L, Morriello G, Patchett AA, et al.1-[2(R)-(2-Amino-2-methylpropionylamino)-3-(1H- indol-3-yl)propionyl]-3- benzylpiperidine-3(S)-carboxylic Acid Ethyl Ester (L-163,540): A Potent, Orally Bioavailable, and Short-Duration Growth Hormone Secretagogue. J Med Chem.1998;41(14):2439-2441. doi:10.1021/jm9800191 5. Pfaffenbach M, Roller A, Gaich T. Synthesis of Indolophanes by Photochemical Macrocyclization. Chem – A Eur J.2016;22(25):8444-8447. doi:10.1002/chem.201600835 6. Huang J, Orac CM, McKay S, McKay DB, Bergmeier SC. The synthesis of 5-substituted ring E analogs of methyllycaconitine via the Suzuki–Miyaura cross-coupling reaction. Bioorg Med Chem.2008;16(7):3816-3824. doi:https://doi.org/10.1016/j.bmc.2008.01.050 7. Bernhardt S, Shen Z-L, Knochel P. Preparation of Functionalized Organoindium Reagents by Means of Magnesium Insertion into Organic Halides in the Presence of InCl3 at Room Temperature. Chem – A Eur J. 2013;19(3):828-833. doi:10.1002/chem.201203795 8. Emmett GC, Cain GA, Estrella MJ, et al. Efficient Preparation of (3S)-3-(4- Fluorobenzyl)piperidinium Mandelate. Synthesis (Stuttg). 2005;2005(01):92-96. doi:10.1055/s-2004-834903 9. Wang J-B, Li Y-L, Deng J. Metal-Free Activation of DMF by Dioxygen: A Cascade Multiple- Bond-Formation Reaction to Synthesize 3-Acylindoles from 2-Alkenylanilines. Adv Synth Catal.2017;359(19):3460-3467. doi:10.1002/adsc.201700584 10. Sugiura M, Hirano K, Kobayashi S. a-Aminoallylation of Aldehydes with Ammonia: Stereoselective Synthesis of Homoallylic Primary Amines. J Am Chem Soc. 2004;126(23):7182-7183. doi:10.1021/ja049689o 11. Nishikawa Y, Kimura S, Kato Y, Yamazaki N, Hara O. Pd(II)-Catalyzed Allylic C–H Amination for the Preparation of 1,2- and 1,3-Cyclic Ureas. Org Lett. 2015;17(4):888-891. doi:10.1021/ol5037453 12. Ojima I, Tzamarioudaki M, Eguchi M. New and Efficient Route to Pipecolic Acid Derivatives by Means of Rh-Catalyzed Intramolecular Cyclohydrocarbonylation. J Org Chem. 1995;60(22):7078-7079. doi:10.1021/jo00127a002 13. Lu Y, Yuan H, Zhou S, Luo T. Total Syntheses of (- )-Hibiscone C and Lysergine: A Cyclization/Fragmentation Strategy. Org Lett. 2017;19(3):620-623. doi:10.1021/acs.orglett.6b03778 14. Magano J, Waldo M, Greene D, Nord E. The Synthesis of (S)-5-Fluoro-1-(2-fluorophenyl)- 3-(piperidin-3-ylmethoxy)-1H-indazole, a Norepinephrine/Serotonin Reuptake Inhibitor for the Treatment of Fibromyalgia. Org Process Res Dev.2008;12(5):877-883. doi:10.1021/op800113s 15. Li P, Yamamoto H. Amino acid salt catalyzed intramolecular Robinson annulation. Chem Commun.2009;(36):5412-5414. doi:10.1039/B912325C 16. Youn SW, Kim YH. Pd(II)/Ag(I)-Promoted One-Pot Synthesis of Cyclic Ureas from (Hetero)Aromatic Amines and Isocyanates. Org Lett.2016;18(23):6140-6143. doi:10.1021/acs.orglett.6b03151 17. Liu B, Su D, Wei Z, et al. Condensation of Vilsmeier Salts, Derived from Tetraalkylureas, with a-Hydroxy Amide Derivatives: One-pot Approach to Synthesize 2-Dialkylamino-2- oxazolin-4-ones. Chem Lett.2017;46(2):249-252. doi:10.1246/cl.161006 18. Ikeuchi H, Meyer ME, Ding Y, Hiratake J, Richards NGJ. A critical electrostatic interaction mediates inhibitor recognition by human asparagine synthetase. Bioorg Med Chem. 2009;17(18):6641-6650. doi:https://doi.org/10.1016/j.bmc.2009.07.071 19. Armarego, W. L. F.; Chai, C. Purification of Laboratory Chemicals, 5 ed.; Butterworth- Heinemann: Burlington, 2012

Claims

Claims 1. A compound of formula (I)

formula (I) or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C1-C4-alkyl; R² is (C₃-C₅-alkyl)-NH-( C₁-C₃-alkyl), (C₃-C₅-alkyl)-NHR^A, (C₂-C₅-alkyl)-NR^AR^H, (C₁-C₃-alkyl)- CR^BR^CNH₂, (C₂-C₄-alkyl)-NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)- CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is (C₁-C₄-alkyl)-phenyl, (C₁-C₄-alkyl)-naphthyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^H is (C=O)-(C1-C3-alkyl)-C(C1-C3-alkyl)2R^V; R^M is H or halogen; R^V is H, C₁-C₂₀ hydrocarbyl, C₁-C₂₀ oxaalkyl, C₁-C₂₀ thiaalkyl, C₁-C₂₀ azaalkyl, a benzoquinone, a hydrobenzoquinone, or a phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^W is H, halogen, C(=O)-(C1-C4-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl, with the proviso that when R² is (i) (C3-C5-alkyl)-NH-( C1-C3-alkyl) or (ii) (C3-C5-alkyl)-NHR^A and R^A is unsubstituted (C₁-C₄-alkyl)-phenyl, X¹ is CH₂ and/or X² is CH.

2. The compound according to claim 1, wherein R³ is selected from the group consisting of H, methyl, and phenyl.

3. The compound according to claim 1 or 2, wherein R² is (C₃-C₄-alkyl)-NHR^A; and wherein R^A is (C₁-C₃-alkyl)-phenyl or (C₁-C₃-alkyl)-naphthyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, F, Cl, Br, or phenyloxy, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents selected from H, F, Cl, or Br.

4. The compound according to claim 1 or 2, wherein R² is (C₃-alkyl)-NH-(C₁-C₃-alkyl) or (C₃-alkyl)-NHR^A; and wherein R^A is (C₁-C₄-alkyl)-phenyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyloxy, or benzyloxy, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; and R^Y is H, halogen, CN, or NO₂.

5. The compound according to claim 1 or 2, wherein R² is (C₁-alkyl)-CHR^FR^G; and wherein R^F and R^G together with the carbon atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one N-atom, wherein said N-atom is non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^Z is H or (C₁-C₂-alkyl)-phenyl.

6. The compound according to claim 1 or 2, wherein R² is (C₁-alkyl)-CHR^FR^G; and wherein R^F and R^G together with the carbon atom to which they are bonded form a 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are non-oxidized, and wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cyclohexyl.

7. The compound according to claim 1 or 2, wherein R¹ is methyl or ethyl; and/or R² is (C₂-C₅-alkyl)-NR^AR^H; and wherein R^H is (C=O)-(C₁-C₂-alkyl)-C(C₁-C₂-alkyl)₂R^V; and R^V is a benzoquinone, wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z.

8. The compound according to any one of claims 1 to 7, wherein X² is N or CH.

9. The compound according to any one of claims 1 to 8, wherein X¹ is CH₂ and X² is CH.

10. The compound according to any one of claims 1 to 7, wherein R³ is methyl, X¹ is CH₂, and X² is CH.

11. The compound according to claim 1, wherein the compound according to formula (I) is selected from the group consisting of (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(piperidin-3-yl)amino)butanoic acid; (2S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(piperidin-3-ylmethyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((5-ethylpiperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-(cyclohexylmethyl)piperidin-3- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)((5-benzylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)- 2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)((5-phenethylpiperidin-3-yl)methyl)amino)butanoic acid; (2S)-2-amino-4- ((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(6- ethylpiperidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(2-(piperidin-3-yl)ethyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(pyrrolidin-3-yl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-3- phenylpropyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-4-((3-((1-acetylazetidin-3-yl)amino)propyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)-2-aminobutanoic acid; (2S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(2-(pyrrolidin-2-yl)ethyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- morpholinopropyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-3,4-dihydroxy-5-(6- (phenylamino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl)(3- (methylamino)propyl)amino)butanoic acid; (2S,2'S)-4,4'-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)azanediyl)bis(2-aminobutanoic acid); (S)-2-amino- 4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((R)-3- aminobutyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-4,4,4-trifluorobutyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-((3-amino-3-methylbutyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-(((S)-3-amino-4- methylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (2S)-2-amino-4-((3-amino-5-methylhexyl)(((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (2S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-aminohexyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5- phenylpentyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)amino)butanoic acid; (S)-2-amino-4-((3-amino-5-(phenylamino)pentyl)(((2R,3S,4R,5R)- 5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2- amino-4-(((S)-3-amino-4-(methylamino)butyl)(((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxytetrahydrofuran-2-yl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1s,3S)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(((1r,3R)-3- aminocyclobutyl)methyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-(methylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(4-(methylamino)butyl)amino)butanoic acid; methyl (S)-2-amino-4-((((2R,3S,4R,5R)-5- (6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3- (phenethylamino)propyl)amino)butanoate; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3- (phenethylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H- purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoic acid; methyl (S)-2-amino-4-((((1R,2R,3S,4R)-2,3- dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((3- phenoxyphenethyl)amino)propyl)amino)butanoate; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)((S)-3,4-diamino-4- oxobutyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid; (S)-ethyl 2-amino-4-((3- ((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate; (S)-2- amino-4-((3-((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4- (4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoic acid; (S)- methyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3-fluorobenzyl)amino)propyl)(((1R,2R,3S,4R)-2,3- dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)methyl)amino)butanoate; (S)-ethyl 2-amino-4-((3-((4-(4-chlorophenoxy)-3- fluorophenethyl)amino)propyl)(((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentyl)methyl)amino)butanoate; ethyl (S)-2-amino-4-((3-((2-(6,7- dichloronaphthalen-2-yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4- yl)methyl)amino)butanoate; (S)-2-amino-4-((3-((2-(6,7-dichloronaphthalen-2- yl)ethyl)amino)propyl)(((3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-(methylamino)-7H-pyrrolo[2,3- d]pyrimidin-7-yl)tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)methyl)amino)butanoic acid; (S)-2- amino-4-((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl)(3-(benzylamino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- phenoxybenzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6-amino- 9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((3- (benzyloxy)benzyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((2R,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(3-((naphthalen-2- ylmethyl)amino)propyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-(3-methyl-N-(3- phenoxybenzyl)-3-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dien-1- yl)butanamido)propyl)amino)butanoic acid; (S)-2-amino-4-((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4- (methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentyl)methyl)(3-((4- phenoxyphenethyl)amino)propyl)amino)butanoic acid; and methyl (S)-2-amino-4- ((((1R,2R,3S,4R)-2,3-dihydroxy-4-(4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentyl)methyl)(3-((4-phenoxyphenethyl)amino)propyl)amino)butanoate.

12. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 11 and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

13. A compound according to any one of claims 1 to 11 for use in medicine.

14. A compound according to any one of claims 1 to 11, for use in the treatment of a cancer, preferably for use in the treatment of cancer selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, osteosarcoma, liposarcoma, leukemia, colorectal cancer, rectal adenocarcinoma, mesothelioma, endometrium adenocarcinoma, erythroleukemia, medulloblastoma, astrocytoma, Ewing sarcoma, myelodysplastic syndrome (MDS), diffuse large B-cell lymphoma, leukemia, myelogenic leukemia, medulloblastoma, myeloid leukemia, acute monocytic leukemia, gallbladder carcinoma, cecum adenocarcinoma, gastric adenocarcinoma, stomach adenocarcinoma, renal cell carcinoma, bladder carcinoma, melanoma, cervical squamous cell carcinoma, pancreatic carcinoma, chondrosarcoma, duodenal adenocarcinoma, rhabdomyosarcoma, hepatocellular carcinoma and uterine adenocarcinoma, more preferably wherein said cancer is selected from the group consisting of prostate cancer, breast cancer, ovarian cancer, colon cancer, glioblastoma, lung cancer, neuroblastoma, colorectal cancer, and bladder carcinoma.

15. A compound of formula (I)

formula (I) or a salt, stereoisomer, or tautomer thereof, wherein X¹ is O or CH₂; X² is N or CR^M; R¹ is H or C₁-C₄-alkyl; R² is H, (C₂-C₅-alkyl)-NHR^A, (C₁-C₃-alkyl)-CR^BR^CNH₂, (C₂-C₅-alkyl)-NR^AR^H, (C₂-C₄-alkyl)-NR^DR^E, (C₁-C₃-alkyl)-cyclobutane-NHR^B, CHR^FR^G, or (C₁-C₃-alkyl)-CHR^FR^G; and R³ is H, C₁-C₄-alkyl, C₁-C₄-haloalkyl, or phenyl; and wherein R^A is H, C₁-C₃-alkyl, (C₁-C₄-alkyl)-phenyl, (C₁-C₄-alkyl)-naphthyl, cyclobutane, or azetidine, wherein each substitutable carbon or heteroatom in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^W; R^B is H or C₁-C₄-alkyl; R^C is C₁-C₄-alkyl, phenyl, C₂-C₄-phenyl, benzyl, fluorinated C₁-C₄-alkyl, (C₁-C₃-alkyl)-NH-(C₁-C₃- alkyl), (C₁-C₃-alkyl)-NH-phenyl, or C(=O)R^X; R^D and R^E together with the nitrogen atom to which they are bonded form a 5- or 6-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more further, same or different heteroatoms selected from O, N, or S, wherein said N- and/or S atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon or heteroatom in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^B; and R^F and R^G together with the carbon atom to which they are bonded form a 4- to 7-membered saturated heterocycle, wherein said heterocyclic ring comprises one or more N-atoms, wherein said N-atoms are independently oxidized or non-oxidized, and wherein each substitutable carbon in the aforementioned group is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^H is (C=O)-(C₁-C₃-alkyl)-C(C₁-C₃-alkyl)₂R^V; R^M is H or halogen; R^V is H, C₁-C₂₀ hydrocarbyl, C₁-C₂₀ oxaalkyl, C₁-C₂₀ thiaalkyl, C₁-C₂₀ azaalkyl, a benzoquinone, a hydrobenzoquinone, or a phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Z; R^W is H, halogen, C(=O)-(C₁-C₄-alkyl), phenyl, heteroaryl, phenyloxy, benzyloxy, C(=O)-phenyl, S-phenyl, S(=O)-phenyl, S(=O)₂-phenyl, or NR^B-phenyl, wherein each substitutable carbon in the aforementioned groups is independently unsubstituted or substituted with one or more, same or different substituents R^Y; R^X is H, C₁-C₂-alkyl, phenyl, benzyl, OR^B, or NHR^B; R^Y is H, halogen, CN, or NO₂; and R^Z is H, C₁-C₃-alkyl, (C₁-C₃-alkyl)-phenyl, or (C₁-C₂-alkyl)-cycloalkyl; for use in the treatment of castration-resistant prostate cancer.