6-(HET)aryl-7-deazapurine ribonucleoside bisphosphonates as CD73 inhibitors for clinical use

Abstract

The invention relates to compounds of general formula I, wherein n is 0 or 1; X, Y, Z and W are independently C, O, N or S; R1 is the same or different from each other and independently selected from H; –NR2; NR2–(C1–C3)alkyl–, wherein R are the same or different from each other and selected from H and (C1–C3)alkyl; –OH; –CN; phenyl;; halogen; –COOH; (C1– C5)alkyl; (C1–C5)alkyloxycarbonyl; (C1–C5)alkoxy; (C2–C3)alkynyl; benzyloxy group; and / or one or two pairs of two neighbouring substituents R1 together with the atoms to which they are bound form a five- membered or a six-membered aromatic, heteroaromatic, cycloalkyl or heterocycloalkyl ring, or a bicyclic heteroaromatic ring; and R2 is selected from the group comprising hydrogen, halogen, –NR2, wherein R are the same or different from each other and selected from H and (C1–C3)alkyl; (C1–C5)alkyl, (C1–C5)alkoxy, (C1– C5)alkylamino. The invention further relates to the use of said compounds as medicaments, preferably in the treatment of diseases related to pathological cell proliferation, immune system disregulation, and CD73 overexpression.

Description

[0001] 6-(Het)aryl-7-Deazapurine Ribonucleoside Bisphosphonates as CD73 Inhibitors for Clinical Use

[0002] Field of the Invention

[0003] The invention provides novel inhibitors of CD73, their preparation, pharmaceutical compositions containing these inhibitors and their use in the treatment of cancer and other diseases connected with CD73 overexpression or mediated by adenosine.

[0004] Background of the Invention

[0005] Cancer is the second leading cause of death globally and the immune system plays a critical role in the identification and elimination of cancer cells. One mechanism by which tumors evade the immune system is through increased production of small molecule signaling compounds like adenosine within the tumor microenvironment (TME). Adenosine has been shown to accumulate in tumors and exert profound immunosuppressive effects on a variety of tumor-infiltrating leukocytes via the A2A / A2Badenosine receptors. In addition to mediating immune escape, adenosine stimulates angiogenesis, metastasis and proliferation of cancer cells. A major source of adenosine the in extracellular environment is the hydrolysis of ATP by CD39 to AMP, which is then hydrolyzed by CD73 to adenosine (Zhang, B. Cancer Res. 2010; 70. 6407-6411).

[0006] CD73 (ecto-5´-nucleotidase) is Zn2+-binding glycosylphosphatidylinositol-anchored membrane protein. Its expression on tumor cells has been reported in several types of cancer, including bladder cancer, leukemia, melanoma, glioblastoma, ovarian cancer, thyroid cancer and breast cancer (Stagg, J. et al. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 1547–1552).

[0007] Although CD73 has been known and validated as a promising target in oncology for years (Nocentini, A.; Capasso, C.; Supuran, T. C. Expert Opin. Ther. Pat. 2021, 31, 867-876), there is no approved inhibitor on the market yet. Several ongoing clinical trials are investigating the treatment of various tumors by anti-CD73 monoclonal antibodies alone or in combination with other anticancer drugs. However, antibodies typically show only partial inhibition of CD73, and they may not penetrate well into solid tumors. Small molecules on the other hand can easily diffuse across physiologic barriers leading to greater exposure within the TME. Moreover, they can be optimized to have shorter half-lives and flexibility for intermittent dosing (Lawson, K. V. et al. J. Med. Chem. 2020, 63, 11448-11468). Despite this, only five small molecules (EXS-21546, Quemliclustat formerly known as AB680, ATG-037, ORIC-533 and BPI-472372) are currently in clinical trials, highlighting the unmet medical need for new small molecule CD73 inhibitors for cancer treatment. Cell surface enzymes CD39 and CD73 are new emerging targets for immunotherapy. Both are involved in the metabolism of extracellular ATP. CD39 hydrolyzes ATP to AMP; and subsequently, CD73 metabolizes AMP to adenosine and phosphate. In the tumor microenvironment, large amounts of ATP are released into theextracellular environment due to hypoxia and cellular stress. Extracellular ATP acts as an activator of immune cells. To evade immune control, tumor cells express increased levels of CD39 and CD73 to convert ATP to adenosine, which binds to specific receptors on immune cells leading to immunosuppression (Allard, B.; Allard, D.; Buisseret, L.; Stagg, J. Nat. Rev. Clin. Oncol. 2020, 17, 611-629). Higher expression levels of CD39 and CD73 in cancer patients correlate with worse prognosis. Thus, there is a constant need for novel CD73 inhibitors. Majority of the known purine-based CD73 inhibitors are based on α,β-methylene adenosine diphosphate (AMPCP) scaffold, where the 6-amino group is often further modified like in commercially available potent CD73 inhibitor PSB12379 (Scheme 1) (Ge, G.-h et al. Eur. J. Med. Chem. 2024, 264, 116028).

[0008]

[0009] Scheme 1. Structures of purine-based CD73 inhibitors

[0010] Summary of the Invention

[0011] The above-described need for novel CD73 inhibitors is addressed by the present invention, which relates to 7-deazapurine ribonucleoside bisphosphonates substituted at position 6 with an aryl or heteroaryl moiety as small-molecular CD73 inhibitors. Their 7-deazapurine scaffold bears heteroaryl groups attached directly to C-6 via C-C bond, leading to a different binding mode and higher binding affinity to the target enzyme.

[0012] In one aspect, the object of the present invention are 6-substituted 7-deazapurine ribonucleoside 5 -0-bisphosphonates of general formula I:

[0013]

[0014] wherein

[0015] n is 0 or 1;

[0016] X, Y, Z and W are independently C, 0, N or S; with the proviso that at most two of X, Y, Z and W are other than C, and with the proviso that R1is only present when the valency allows that;

[0017] R1is the same or different from each other and independently selected from H; –NR2; NR2–(C1–C3)alkyl–, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; halogen; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group;

[0018] and / or

[0019] one or two pairs of two neighbouring substituents R1together with the atoms to which they are bound form a five-membered or a six-membered aromatic, heteroaromatic, cycloalkyl or heterocycloalkyl ring, or a ninemembered or a ten-membered bicyclic heteroaromatic ring;

[0020] wherein said five-membered or the six-membered aromatic, heteroaromatic, cycloalkyl or heterocycloalkyl ring, or said nine-membered or the ten-membered bicyclic heteroaromatic ring may optionally be substituted with one or more substituents independently selected from the group consisting of -NR2; NR2-(C1-C3)alkyl-, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl- C5)alkoxy; (C2-C3)alkynyl; benzyloxy group;

[0021] and

[0022] R2is selected from the group comprising hydrogen, halogen, -NR2, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; (Cl-C5)alkyl, (Cl-C5)alkoxy, (Cl-C5)alkylamino; and pharmaceutically acceptable salt thereof.

[0023] In a preferred embodiment, R2is selected from the group consisting of H, halogen, -NH2, (Cl-C3)alkyl, (Cl-C3)alkoxy, and (Cl-C3)alkylamino. More preferably, R2is selected from the group consisting of H, Cl, F, Br, I, -NH2, -CH3, -CH2CH3, CH3-O-, CH3CH2-O-, CH3-NH-, CH3CH2-NH-.

[0024] Most preferably, R2is selected from hydrogen, chloro, fluoro, iodo, methyl, amino, methoxy, -methylamino. In some embodiments, R2is not hydrogen.

[0025] In some embodiments, two of X, Y, Z and W are other than C.

[0026] In some embodiments, one of X, Y, Z and W is other than C.

[0027] In some embodiments, all of X, Y, Z and W are C.

[0028] In some embodiments, when n is 0, then at least one of X, Y, Z and W is other than C.

[0029] The substituent of the structural formula (II) at position 6 of the 7-deazapurine ribonucleoside 5 -0-bisphosphonate,n R

[0030]

[0031] (II),

[0032] may in some embodiments be a bicyclic aromatic, heteroaromatic or partially saturated bicyclic ring of formula (i), (ii) or (iii),

[0033]

[0034] wherein

[0035] X is 0, S orNH,

[0036] ring A is 6-membered aryl ring or 6-membered heteroaryl ring, containing at least one heteroatom selected from 0, N, S, preferably the heteroatom is N;

[0037] ring B is 6-membered aryl ring or 6-membered heteroaryl ring containing at least one heteroatom selected from 0, N, S, preferably the heteroatom is N, attached via carbon atom to the deazapurine moiety of the general formula (I);

[0038] ring C is 6-membered aryl ring, 6-membered heteroaryl ring containing at least one heteroatom selected from 0, N, S, preferably the heteroatom is N; 6-membered cycloalkyl ring or 6-membered heterocyclo alkyl ring containing at least one heteroatom selected from 0, N, S, preferably the heteroatom is N,

[0039] ring D is 5 -membered heteroaryl or 5 -membered heterocycloalkyl ring, containing at least one heteroatom selected from 0, N, S.

[0040] The bicyclic ring of formula (i), (ii) or (iii) may optionally be substituted with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0041] In some embodiments, the substituent of the structural formula (II) may be a tricyclic aromatic or heteroaromatic ring, e.g. dibenzofuranyl, carbazolyl, acridinyl, phenanthrenyl or anthracenyl; which may optionally be substituted with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (C1–C5)alkoxycarbonyl, (C1–C5)alkoxy, (C2–C3)alkynyl; and benzyloxy.Preferably, the substituent of general formula (II) at position 6 of the 7-deazapurine ribonucleoside 5 -0-bisphosphonate is selected from naphthyl, naphthalenyl, benzofuranyl, tetrahydronaphthyl, ethynylbenzofuranyl, chromanyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl, fluoronaphthalenyl, chloronaphthalenyl, bromonaphthalenyl, 4-bromo-l-fluoronaphthalen-2-yl, (methoxycarbonyl)naphthalenyl, 2,3 -dihydrobenzofuranyl, dimethyl-2, 3 -dihydrobenzofuranyl, benzyloxynaphthalenyl, hydroxynaphthalenyl, aminonaphthyl, cyanonaphthyl, methoxynaphthalenyl.

[0042] In some embodiments, two of X, Y, Z and W are other than C, and n is 0. In this embodiment, the heteroaryl substituent of general formula (II) is a 5-membered heteroaryl containing two heteroatoms (same or different from each other) independently selected from 0, N, and S (e.g. pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl), wherein R1is as defined above.

[0043] In some embodiments, two of X, Y, Z and W are other than C, and n is 1. In this embodiment, the heteroaryl substituent of general formula (II) is a 6-membered heteroaryl containing two heteroatoms (same or different from each other) independently selected from 0, N, and S (e.g. pyrazinyl, pyrimidinyl, and pyridazinyl), wherein R1is as defined above.

[0044] In some embodiments, one of X, Y, Z and W is other than C and n is 0. In this embodiment, the heteroaryl substituent of general formula (II)is a 5-membered heteroaryl containing one heteroatom selected from 0, N, S, wherein R1is as defined above.

[0045] Preferably, said 5 -membered heteroaryl is selected from furanyl, thiophenyl, azolyl, and may optionally be substituted with -NHz or NHz-(Cl-C3)alkyl-, such as NH2CH2-.

[0046] In some embodiments, one of X, Y, Z and W is other than C and n is 1. In this embodiment, the substituent of general formula (II) is a 6-membered heteroaryl containing one heteroatom selected from 0, N, S, preferably the heteroatom is N, more preferably, the 6-membered heteroaryl is pyridinyl; wherein R1is as defined above. Preferably, said 6-membered heteroaryl is pyridinyl or pyridinyl substituted with (Cl-C5)alkoxy; benzyloxy; F; Cl; Br; -OH; -NH2; NH2-(C1-C3)alkyl-; -CN; (Cl-C5)alkyloxycarbonyl.

[0047] In some embodiments, all of X, Y, Z and W are C, and n is 1, therefore the substituent of general formula (II) is phenyl, wherein R1is as defined above.

[0048] Preferably the substituent of general formula (II) is phenyl or phenyl substituted with one or more of the following substituents: -CN; aminomethyl group (-CH2-NH2); phenyl; F; Cl; Br; and / or -COOCH3;In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a six-membered aromatic ring, therefore the substituent of general formula (II) is e.g. naphtalen-2-yl, napht-l-yl, benzofuran-2-yl, quinolin-4-yl, quinolin-3-yl, isoqinolinyl, quinazolinyl, indol-2-yl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0049] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a five-membered heteroaromatic ring, therefore the substituent of general formula (II) is e.g. benzofuran-7-yl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0050] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a six-membered heteroaromatic ring, therefore the substituent of general formula (II) is e.g. quinolin-6-yl, isoquinolin-8-yl, isoquinolin-6-yl, quinazolin-7-yl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (C1–C5)alkoxycarbonyl, (C1–C5)alkoxy, (C2–C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0051] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a six-membered cycloalkyl ring, therefore the substituent of general formula (II) is e.g. tetrahydronaphtyl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NHz, CN, methyloxycarbonyl (CH3-O-C(=O)-), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0052] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a five-membered heterocycloalkyl ring, therefore the substituent of generalformula (II) is e.g. dihydrobenzofuran-5-yl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0053] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a six-membered heterocycloalkyl ring, therefore the substituent of general formula (II) is e.g. chromanyl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NHz, CN, methyloxycarbonyl (CHs-O-C(=O)-), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0054] In some embodiments, two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a nine- or ten-membered bicyclic heteroaromatic ring, therefore the substituent of general formula (II) is e.g. dibenzofuran-4-yl, carbazolyl or acridinyl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0055] In some embodiments, two pairs of two neighbouring substituents R1together with neighboring two atoms of the aromatic cycle to which they are bound form a six-membered aromatic or hetero aromatic ring, therefore the substituent of general formula (II) is e.g. phenanthrenyl or anthracenyl, and may optionally be substituted as defined above, preferably with one or more substituents selected from the group comprising halogen, hydroxy, amino, cyano, (Cl-C5)alkoxycarbonyl, (Cl-C5)alkoxy, (C2-C3)alkynyl; and benzyloxy; preferably, the substituents are selected from ethynyl, F, Cl, Br, OH, NH2, CN, methyloxycarbonyl (CH3–O–C(=O)–), ethyloxycarbonyl, methyl, ethyl, methoxy, ethoxy, benzyloxy.

[0056] In one embodiment, the substituent of general formula (II) is selected from phenyl, naphthyl, naphthalenyl, furanyl, benzofuranyl, thiophenyl, pyridinyl, 1 / 7-indolyl, dibenzofuranyl, biphenyl, phenanthrenyl, quinolinyl, isoquinolinyl, quinazolinyl, tetrahydronaphthyl, tetrahydronaphthalenyl, dihydrobenzofuranyl, and chromanyl;which may further be substituted with one or more substituents selected from the group comprising -NH2, -CN, -CH2NH2, -F, -Br, -Cl, CH3O-C(=O)-, benzyloxy, -OH, CH3O-, ethynyl, and CH3-;

[0057] preferably, the substituent of general formula (II) is selected from phenyl; -aminomethylphenyl; furan-2-yl; furan-3-yl; benzofuran-2-yl; 1-indol-2-yl; thiophen-2-yl; thiophen-3-yl; -cyanophenyl; pyridin-4-yl; naphth-1-yl; naphthalen-2-yl; 6-fluoronaphthalen-2-yl; 4-bromo-l-fluoronaphthalen-2-yl; 6-chloronaphthalen-2-yl; 4-fluoronaphth-l-yl; 6-(methoxycarbonyl) naphthalen-2-yl; 6-(benzyloxy)naphthalen-2-yl; 6-hydroxynaphthalen-2-yl; 4-aminonaphth-l-yl; 4-cyanonaphth-l-yl; 6-methoxynaphthalen-2-yl; dibenzofuran-4-yl; biphen-4-yl; 4-ethynylbenzofuran-2-yl; phenanthren-9-yl; quinolin-4-yl; quinolin-6-yl; quinolin-3-yl; isoquinolin-6-yl; isoquinolin-8-yl; quinazolin-7-yl; 5,6,7,8-tetrahydronaphth-l-yl; 5,6,7,8-tetrahydronaphthalen-2-yl; chroman-8-yl; 2,3-dihydrobenzofuran-5-yl; 2,2-dimethyl-2,3-dihydrobenzofuran-5 -yl.

[0058] In one preferred embodiment, the substituent of general formula (II) is selected from naphtyl, tetrahydronaphtyl, quinolinyl, isoquinolinyl, benzofuranyl, furanyl, (aminomethyl)phenyl, indolyl, fluoronaphthalenyl, 4-bromo-l-fluoronaphthalen-2-yl, chloronaphthalenyl, fluoronaphthyl, (methoxycarbonyl)naphthalen-2-yl, dimethyl-2,3-dihydrobenzofuran-5-yl, (benzyloxy )naphthalen-2-yl, hydroxynaphthalen-2-yl, aminonaphth- 1-yl, cyanonaphth- 1-yl, methoxynaphthalen-2-yl, and naphthalen-2-yl; and the substituent R2is selected from the group comprising H, CH3, NH2, Cl, F, and I.

[0059] In a more preferred embodiment, the substituent of general formula (II) is selected from naphtyl, tetrahydronaphtyl, benzofuranyl, furanyl, (aminomethyl)phenyl, indolyl, fluoronaphthalenyl, 4-bromo-l-fluoronaphthalen-2-yl, dimethyl-2,3-dihydrobenzofuran-5-yl, and hydroxynaphthalen-2-yl; and the substituent R2is selected from the group comprising H, CH3, NH2, Cl, F, and I.

[0060] In one embodiment, the substituent of general formula (II) is selected from naphtyl, tetrahydronaphtyl, benzofuranyl, (aminomethyl)phenyl, indolyl, fluoronaphthalenyl, 4-bromo-l-fluoronaphthalen-2-yl, dim ethyl -2,3-dihydrobenzofuran-5-yl, and hydroxynaphthalen-2-yl; and the substituent R2is selected from the group comprising H, CH3, NH2, Cl, F, and I.

[0061] In one embodiment, the substituent of general formula (II) is selected from naphtyl, tetrahydronaphtyl, furanyl, indolyl, fluoronaphthalenyl, dimethyl-2,3-dihydrobenzofuran-5-yl, and hydroxynaphthalen-2-yl; and the substituent R2is selected from the group comprising H, CH3, NH2, Cl, F, and I.

[0062] As described herein and unless otherwise indicated, the individual substituents have the following meanings:“alkyl” is a linear or branched saturated hydrocarbon chain, based on an alkane missing one hydrogen, containing the number of carbons indicated at the place of use of the term. Alkyls may include, but are not limited to, methyl, ethyl, propyl, isopropyl.

[0063] “cycloalkyl” is a saturated cyclic hydrocarbon residue, based on a cycloalkane missing one hydrogen, wherein all carbon atoms of the cycloalkyl are part of the cycle. The cycloalkyl comprises one cycle.

[0064] “aryl” is an aromatic cyclic hydrocarbon comprising one, two or three aromatic rings, and containing the total number of carbons indicated at the place of use of the term. In particular, the aryl may be phenyl, naphthyl, naphtalenyl, biphenyl, phenanthrenyl, anthracenyl.

[0065] “heterocycloalkyl” is a saturated cyclic hydrocarbon residue comprising at least one heteroatom selected from 0, S, and N, wherein all carbon atoms and heteroatoms of the heterocycle are part of the cycle. Preferably, the heterocycloalkyl comprises one or two heteroatoms.

[0066] “heteroaryl” is an aromatic cyclic hydrocarbon group containing at least one heteroatom selected from 0, S, and N, preferably one, two or three heteroatoms, and at least one aromatic ring; the number of carbons and the number and type of heteroatom being indicated at the place of use of the term. Heteroaryl may also contain more than one aromatic ring, then these rings may be condensed or non-fused; examples of heteroaryl are furanyl, thiophenyl, pyridinyl, benzofuranyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinazolinyl, indolyl. “halogen” means F, Cl, Br or I.

[0067] “amino” denotes -NHz;

[0068] “alkylamino” is a group formed by the substitution of one or two hydrogen atoms of an amino group with alkyl; examples of alkylamino are dimethylamino or ethylamino.

[0069] “alkoxy” refers to a group of -(9-alkyl (-OR1), where R' corresponds to the definition of alkyl; an example of an alkoxy group is methoxy (CH3O-) or ethoxy (CH3CH2O-).

[0070] “benzyloxy” denotes phcnyl-CHz-O-.

[0071] “cyano” denotes -CN.

[0072] “alkyloxycarbonyl” is an alkoxy group as defined above attached to a carbonyl group (-C(=O)OR’).

[0073] „alkynyl“ is a linear or branched unsaturated hydrocarbon chain containing at least one carbon-carbon triple bond, based on an alkyne missing one hydrogen. Alkynyls may include, but are not limited to, ethynyl (HC^C-) or propynyl (HOC-CH?- or CH3-OC-).

[0074] “partially saturated bicycloaryl” is an aromatic cyclic hydrocarbon comprising one aromatic ring condensed with one cycloalkyl ring. Partially saturated bicycloaryls are e.g. tetrahydronaphthalenyl, tetrahydronaphthyl, dihydrobenzofuranyl, chromanyl.

[0075] “naphthyl”, “naphthalenyl” denote a hydrocarbon residue of naphthalene formed by removing one hydrogen. The term "pharmaceutical composition" refers to the formulation of a compound and medium, generally accepted in the art, for the delivery of a biologically active compound to a mammal, e.g., a human. Such amedium includes all pharmaceutically acceptable carriers, diluents or excipients.

[0076] The term "pharmaceutically acceptable carrier, diluent or filler" as used herein includes, without limitation, any excipient, carrier, glidant, sweetener, preservative, dye, flavor enhancer, surfactant, dispersing agent, suspending agent, isotonic agent, solvent, or emulsifier that has been approved for use in humans or domestic animals.

[0077] As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the claimed compounds of general formula I according to this invention, and which are within reasonable medical judgment suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like, and have an acceptable benefit / risk ratio. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto (e.g., phenol or hydroxyamic acid). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, -toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like; particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts can be found, e.g., in Remington's Pharmaceutical Sciences, 20th ed., Mack Publishing Company, Easton, Pa., (1985), which is herein incorporated by reference.In a preferred embodiment, the present invention provides the following 6-substituted or 2,6-disubstituted 7-deazapurine ribonucleoside 5'-O-bisphosphonates of formula I:

[0078] [(5-{[4-(Naphthalen-2-yl)-7H-pyrrolo[2,3-<7|pyrimidin-7-yl]-?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5a)

[0079] |(5-{|4-(Bcnzofuran-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5b)

[0080] [(5-{[4-(Furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5 c)

[0081] | (5- { 14-(Naph th - 1 -y l)-7 / / -py rrolo [ 2.3-t / |py rim idin-7

[0082]

[0083] -yl ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5d)

[0084] [(5-{[4-(5,6,7,8-Tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5e)

[0085] [(5-{[4-(p-Cyanophenyl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]-?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5f)

[0086] |(5-{|4-( -Aminomcthylphcnyl)-7

[0087]

[0088] / / -pyrrolo|2.3-<7|pyrimidin-7-yl ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5g)

[0089] [(5-{[4-Phenyl-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5h)

[0090] | (5 - { 14-( B iphcn -4-yl )-7H-pyrrolo [ 2.3 -t / |py rim idi n-7-y l | - / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5i)

[0091] |(5-{|4-(5-Ethynylbcnzofuran-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5j)

[0092] [(5 - { [4-(Thiophen-3 -y 1 )-7Z7-py rrolo [2,3 - 1 / 1 py r i m i d i n - 7-y l | - / > - D -ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5k)

[0093] [(5 - { 14-(Th iophcn-2-y I )-7 / / -py rrolo [2,3 - 1 / 1 py r i m i d i n - 7-y l | - / > - D -ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (51)

[0094] [(5-{[4-(Furan-3-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5m)

[0095] |(5-{|4-(Dibcnzofuran-4-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5n)

[0096] |(5-{|4-(Phcnanthrcn-9-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5o)

[0097] [(5-{[4-(Chroman-8-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5p)[(5-{[4-(Benzofuran-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-β-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5q)

[0098] [(5-{[4-(2,3-Dihydrobenzofuran-5-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofiiranosyl}oxy)phosphonomethyl]phosphonic acid (5r)

[0099] | (5- { 14-( Pyridin -4-y l)-7 / / -py rrolo [ 2.3-t / |py rim idin-7-yl

[0100]

[0101] ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5s)

[0102] [(5-{[4-(Quinolin-4-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5t)

[0103] [(5 - { [4-(Isoquinolin-8 -y I )-7 / / -py rrolo [2,3 -<7|py rim idi n-7-y 11 - / >- D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5u)

[0104] [(5-{[4-(Quinolin-6-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5v)

[0105] [(5-{[4-(Quinolin-3-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5w)

[0106] [(5-{[4-(Quinazolin-7-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5x)

[0107] [(5-{[4-(Isoquinolin-6-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5y)

[0108] [(5-{[2-Methyl-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10a)

[0109] [(5-{[2-Methyl-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10b)

[0110] [(5-{[2-Methyl-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10c)

[0111] [(5-{[2-Methyl-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10d)

[0112] |(5-{|2-Mctliyl-4-(5.6.7.8-tctraliydronaplit-l-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl

[0113]

[0114] ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10e)

[0115] [(5-{[2-Amino-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15a)

[0116] [(5-{[2-Amino-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15b)

[0117] [(5-{[2-Amino-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15c)[(5-{[2-Amino-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15d)

[0118] [(5-{[2-Amino-4-(5,6,7,8-tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15e)

[0119] [(5-{[2-Chloro-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18a)

[0120] [(5-{[2-Chloro-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18b)

[0121] [(5-{[2-Chloro-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18c)

[0122] [(5-{[2-Chloro-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18d)

[0123] [(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrirnidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18e)

[0124] [(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18f)

[0125] [(5-{[4-(4-(Aminomethyl)phenyl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18g)

[0126] [(5-{[2-Chloro-4-(177-indol-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]-?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18h)

[0127] [(5-{[2-Chloro-4-(6-fluoronaphthalen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-β-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18i)

[0128] [(5-{[2-Chloro-4-(4-bromo-l -fluoronaphth al en-2-yl)-7H-pyrrolo[2, 3 -t / |py rim idin-7-y l |- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18j)

[0129] [(5-{[2-Chloro-4-(6-chloronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18k)

[0130] [(5-{[2-Chloro-4-(4-fluoronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (181)

[0131] [(5-{[2-Chloro-4-(6-(methoxycarbonyl)naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18m)

[0132] [(5-{[2-Chloro-4-(2,2-dimethyl-2, 3 -dihydrobenzofur an-5-yl)-7H-pyrrolo[2, 3 -t / |pyrim idin-7-y l |- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18n)

[0133] [(5-{[4-(6-(Benzyloxy)naphthalen-2-yl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18o)[(5 - { 12-Chloro-4-(6-hydroxy naph thalcn-2-y I )-7 / / -py rrolo [2,3 -<7|py ri m idin -7 -yl] - / >- D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18p)

[0134] [(5-{[4-(4-Aminonaphth-l-yl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18q)

[0135] [(5-{[2-Chloro-4-(4-cyanonaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18r)

[0136] [(5-{ [2-Chloro-4-(6-m ethoxynaphthal en -2 -yl)-7H-pyrrolo[2, 3 -t / |py rim idin-7-y l |- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18s)

[0137] [(5-{[2-Fluoro-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21a)

[0138] [(5-{[2-Fluoro-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21b)

[0139] [(5-{[2-Fluoro-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21c)

[0140] [(5-{[2-Fluoro-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21d)

[0141] [(5-{[2-Fluoro-4-(5,6,7,8-tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21e)

[0142] [(5-{[2-Methoxy-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (23a)

[0143] [(5-{[2-A-Methylamino-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (25a)

[0144] [(5-{[2-Iodo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (28f).

[0145] In a more preferred embodiment, the 6-substituted or 2,6-disubstituted 7-deazapurine ribonucleoside 5 -0-bisphosphonates of formula I are selected from the group comprising compounds 5a, 5b, 5c, 5d, 5e, 5g, 5h, 5j, 5k, 51, 5n, 5o, 5p, 5q, 5r, 5t, 5u, 5v, 5w, 5x, 5y, 10a, 10b, 10c, lOd, lOe, 15a, 15b, 15c, 15d, 15e, 18a, 18b, 18c, 18d, 18e, 18f, 18g, 18h, 18i, 18j, 18k, 181, 18m, 18n, 18o, 18p, 18q, 18r, 18s, 21a, 21b, 21c, 21d, 21e, 23a, 25a, and 28f, as defined above. More preferably, the 6-substituted or 2,6-disubstituted 7-deazapurine ribonucleoside 5 -O-bisphosphonates of formula I are selected from the group comprising compounds 5a, lOd, 18a, 18b, 18c, 18d, 18e, 18f, 18g, 18h, 18j, 181, 18n, 18p, 21e, and 28f.Additionally, the object of the present invention are 6-(het)aryl-7-deazapurine ribonucleoside 5 -0-bisphosphonates of general formula I for use as medicaments.

[0146] Compounds of the general formula (I) are particularly suitable for inhibition of pathological cell proliferation of tumor / non-tumor / cancer origin and for treatment of tumor / non-tumor / cancer disease associated with cell hyperproliferation. They may be used in conditions, where increased adenosine production is detrimental and where a decrease in adenosine levels leads to activation of the immune system. They may be used in the treatment of diseases involving pathological cell proliferation and CD73 overexpression, such as diseases selected from the group comprising various cancers (e.g. bladder cancer, leukemia, glioblastoma, breast cancer including TNBC, prostate cancer, colorectal cancer, ovarian cancer, lung cancer, pancreatic cancer, papillary thyroid cancer, gastric cancer, and melanoma), autoimmune diseases, inflammation, pain management, cardiovascular diseases, transplantation and neurological disorders.

[0147] Compounds of general formula I can be formulated into pharmaceutical preparations with pharmaceutically acceptable excipients. The preparations may be in liquid form or solid form, or in other forms such as aerosol. Liquid forms include solutions, suspensions, dispersions, emulsions formulated, for example, for injection or oral administration, gels, ointments. Solid forms include, for example, capsules, tablets, coated tablets, powders, suppositories, and other forms, known in the art. Another object of the present invention is thus a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula I and one or more pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients include solvents, solubility controlling agents, pH controlling agents, carriers, fillers, binders, glidants, disintegrants, preservatives, sorbents, viscosity controlling agents, agents affecting sensory properties such as taste, odour or colour of the product.

[0148] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of the compound or drug that is effective in treating a disease or disorder in a human or mammal. In the case of cancer treatment the "effective amount" refers to the amount that inhibits or reduces proliferation of cancer cells, reduces the primary tumor / cancer size, inhibits (that is, to a certain extent slow down and preferably stop) cancer cell infiltration into peripheral organs, inhibits (that is, to a certain extent slow down and preferably stop) the formation of tumor metastases, inhibits, to a certain extent, tumor growth and / or relieves at least to some extent one or more symptoms associated with tumor or cancer. Whereas the drug can prevent growth and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic.

[0149] The invention also provides the pharmaceutical composition mentioned above for use in inhibition of pathological cell proliferation of tumor / non-tumor / cancer origin and / or for treatment of tumor / nontumor / cancer disease associated with cell hyperproliferation. Said pharmaceutical composition may be used for the treatment of diseases listed above.

[0150] Detailed Description of the Invention

[0151] Standard abbreviations and acronyms: MS mass spectrometry

[0152] Bz benzoyl Na₂CO₃ sodium carbonate

[0153] CH₂I₂ diiodomethane NaOMe sodium methoxide

[0154] Cui copper(I) iodide NMR nuclear magnetic resonance d doublet Pd(OAc)₂ palladium(II) acetate

[0155] dd doublet of doublets Ph phenyl

[0156] ddd doublet of doublets of doublets PPhs triphenylphosphine

[0157] DMF N,N-dimethylformamide q quartet

[0158] DMSO dimethylsulfoxide s singlet

[0159] dt doublet of triplets SiO₂ silica gel

[0160] ESI electrospray ionization t triplet

[0161] EtOH ethanol TBAF tetra-n-butylamoniumfluorid HPFC high-performance flash TBN tert -butyl nitrite chromatography td triplet doublet

[0162] HPLC high-performance liquid TEA triethylamine

[0163] chromatography TFA trifluoroacetic acid

[0164] HR high resolution THF tetrahydrofuran

[0165] I2 iodine TLC thin layer chromatography m multiplet TMP or PO(OMe)₃ trimethyl phosphate Me methyl TMSC1 trimethylsilyl chloride

[0166] MeCN acetonitrile TPPTS triphenylphosphine-3,3′,3″ MeNH₂ methylamine trisulfonic acid trisodium salt

[0167] MeOH methanol

[0168] Compounds numbering

[0169] Following numbering of compounds is used:A X M A

[0170] n; s J b d o u tu | C6 xo j x) 6 >1 f! M 6 J

[0171] a p o q e A-eg

[0172]

[0173] L\R

[0174] o 0ONN^CH3HO6^ OH° M HO OH

[0175] 10a-e

[0176] ■ ■ 50 a b e d e R

[0177] <crS o o0N-^N NH2xP^^o^f 7HO<£T o ° M HO OH

[0178] 15a-e - § 2 20 20

[0179]

[0180] a b e d eII

[0181]

[0182] ZI

[0183]

[0184]

[0185] f

[0186] Synthesis of compounds

[0187] All the target bisphosphonates were synthesized from corresponding 2-substituted nucleosides by Suzuki coupling and bisphosphonation. In most cases, the modular approach was used and the aryl substituent was introduced in the last step to 6-chlorobisphosphonate. However, for synthesis of 2-chloro analogues, the Suzuki coupoling had to be performed before the final bisphosphonation (Schemes 1-8). The key intermediates 2, 7, 12, 16, 19 were obtained after full or partial deprotection of known nucleosides by either TBAF (Malnuit, V. et al. Eur. J. Org. Chem. 2019, 2019, 5409-5423) or 75 % TFA TBAF (Malnuit, V. et al. ChemMedChem 2015, 10, 1079-1093) and used either for bisphosphonation or Suzuki cross coupling reaction. Bisphosphonation was done in TMP with 2-5 equiv. of methylene bis(phosphonic dichloride) at 0 °C (Lawson, K. V. et al. J. Med. Chem. 2020, 63, 11448-11468). Palladium catalyzed Suzuki cross coupling reactions were performed with water soluble ligand TPPTS and corresponding boronic acids (Malnuit, V. et al. ChemMedChem, 2015, 10, 1079-1093). The key 2-halo intermediates 16, 19 and 27 were synthesized from amino derivatives 11 or 26 via diazotation. Reaction with TBN and TMSC1 in DCM gave chloro derivative 16 (Scheme 4) (Francom, P. and Robins, M. J. J. Org. Chem. 2003, 68, 666-669), TBN and 70 % HF Py furnished fluoro 19 (Scheme 5) (Malnuit, V. et al. ChemMedChem, 2015, 10, 1079-1093; Eldrup, A. B. J. Med. Chem. 2004, 47, 5284-5297) and reaction with isopentylnitrite, Cui, L in CH2I2 led to iodo derivative 27 (Scheme 7) (Wang, B. et al., 2018, WO 2018 / 183635 Al). Compounds 22 and 24 were synthesized by nucleophilic substitution from the same key intermediate 17a (Seela, F and Xu, K. Helv. Chim. Acta 2008, 91, 1083-1105; Zhao, Y. et al., 2019, CN109810110A) followed by bisphosphonation to obtain final bisphosphonates 23 and 25 (Scheme 8).Scheme 1. Reaction conditions: a: TBAF 1 M solution in THF, 22 °C, 30 min; b: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h; c: R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O / MeCN, 80–100 °C, 1h.

[0188]

[0189] 7 9b-d 10b-dScheme 2. Reaction conditions: a: 75 % TFA, 22 °C, 1 h; b: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H20, 22 °C, 1 h; c: R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O / MeCN, 80- 100 °C, 1 h.

[0190] Scheme 3. Reaction conditions: a: 75 % TFA, 22 °C, 1 h; b: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 b; 2) H2O, 22 °C, 1 h; c: R-B(0H)2, Na2CO3, Pd(OAc)2, TPPTS, H20 / MeCN, 80- 100 °C, 1 h.

[0191]

[0192] Scheme 4. Reaction conditions: a: 1) TBN, TMSC1, DCM, 22 °C, 1 h; 2) 75 % TFA, 22 °C, 1 h; b: R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H20 / MeCN, 80-100 °C, 10 min-1 h; c: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h.

[0193]

[0194] 20a-e 21a-e

[0195] Scheme 5. Reaction conditions: a: 1) 75 % TFA, 22 °C, 1 h; 2) TBN, 70 % HF Py, -30 °C, 30 min; b: R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O / MeCN, 80-100 °C, 1 h; c: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h.

[0196]

[0197] 17a 22 23

[0198] Scheme 6. Reaction conditions: a: 0.5 MNaOMe, 60 °C, 16 h; b: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h.

[0199]

[0200] Scheme 7. Reaction conditions: a: MeNH2(33 % in EtOH), TEA, 80 °C, 16 h; b: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h.

[0201]

[0202] Scheme 8. Reaction conditions: a R-B(OH)2, Na2CO3, Pd(OAc)2, TPPTS, H2O / MeCN, 100 °C, 1 h; b: 1) Isopentylnitrite, CuI, I2, CH2I2, THF, 80 °C, 45 min; 2) 75 % TFA, 22 °C, 1 h; c: 1) methylene bis(phosphonic dichloride), PO(OMe)3, 0 °C, 3 h; 2) H2O, 22 °C, 1 h.

[0203] Examples

[0204] General Experimental Part

[0205] Reactions were monitored by thin layer chromatography (TLC) on TLC Silica gel 60F254 (Merck) and detected by UV (254 nm) and by TLC-MS analysis using an Advion Expression Compact mass spectrometer with electrospray ionization (ESI). NMR spectra were measured on a Bruker Avance 500 MHz spectrometer (500.0 MHz for ’H. 125.7 MHz for13C) or a Bruker Avance 600 MHz spectrometer (600.1 MHz for1H and 150.9 MHz for13C) in DMSO-<76, CDC13 (referenced to the residual solvent signal). Chemical shifts are given in ppm (8-scale) and coupling constants (J) in Hz. Complete assignment of all NMR signals was performed using a combination of H, H-COSY, H, H-ROESY, H, C-HSQC, and H, C-HMBC experiments. Low resolution mass spectra were measured on LCQ Fleet (Thermo Fisher Scientific) using electrospray ionization (ESI). High resolution mass spectra were measured on LTQ Orbitrap XL (Thermo Fisher Scientific). High performance flash chromatography (HPFC) was performed with an ISCO Combiflash Rf system on RediSep Rf Gold Silica Gel Disposable columns. The purity of all final compounds (>95%) was determined by analytical HPLC and by clean NMR spectra.

[0206] Table 1: List of Compounds in Examples

[0207] Example Compound Structure Systematic name

[0208]

[0209] JO

[0210] C* [(5-{ [4-(Naphthalen-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5a

[0211] ribofuranosyl}oxy)phosphonomethyl]pho CO1

[0212] sphonic acid

[0213] ° 2 z^z°'IN'

[0214] HO(£T6H° M

[0215] HO OH

[0216] [(5 - { [4-(Benzofuran-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5b

[0217] < T J ribofuranosyl}oxy)phosphonomethyl]pho g? z— ZO'J sphonic acid

[0218] HO OH

[0219] O^C [(5 -{ [4-(Furan-2-yl)-7H-pyrrolo [2,3- <7| py ri m idin -7 -yl]

[0220] 5c

[0221] O 9 _ _zo C. J X VJNribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0222] HOObT OH M

[0223] HO OH CO [(5-{ [4-(Naphth-l -yl)-7H-pyrrolo[2,3- <7| py ri m idin -7 -yl] - / ?-D- 5d OTJ ribofuranosyl}oxy)phosphonomethyl]pho ° S z^zoz!Nsphonic acid

[0224] HO6FCOH M

[0225] HO OH

[0226]

[0227] 00 [(5-{[(4-(5,6,7,8-Tetrahydronaphth-l-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl] - / ?-D- 5e CUJ ribofuranosyl}oxy)phosphonomethyl]pho 9 gN

[0228] sphonic acidHO<£7OH° M

[0229] HO OH CN

[0230] [(5 - { [4-(p-Cyanophenyl)-7H-pyrrolo [2,3 - 0

[0231] <7| py ri m idin -7 -yl]

[0232] 5f

[0233] / O| N ribofuranosyl}oxy)phosphonomethyl]pho o 9 sphonic acidHOXOH° M

[0234] HO OH

[0235] H2N

[0236] [(5-{[4-(p-Aminomethylphenyl)-7Z7- 0

[0237] pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5g

[0238] ribofuranosyl}oxy)phosphonomethyl]pho Cr J sphonic acid

[0239] ° g

[0240] zP\ / 1 o \ 7

[0241] HOoX oH M

[0242] HO OH

[0243] 0 [(5 - { [4-Phenyl-7H-pyrrolo [2,3 - <7| py ri m idin -7 -yl]

[0244] 5h

[0245] ribofuranosyl}oxy)phosphonomethyl]pho sphonic acidHO6X6H° M

[0246] HO OH

[0247]

[0248] 0

[0249] [(5 - { [4 -( [ 1, 1 ’-Biphenyl] -4-yl)-7Z7- 0 pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5i

[0250] ribofuranosyl}oxy)phosphonomethyl]pho fn sphonic acid

[0251] fl fl__ Xi

[0252] H

[0253] H0

[0254] o,p^^0^O

[0255] OH OH;

[0256] HO OH

[0257] /

[0258] [(5-{[4-(5-Ethynylbenzofuran-2-yl)-7Z7- oX pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5j

[0259] ribofuranosyl}oxy)phosphonomethyl]pho O J sphonic acid

[0260] fl ° ^XiN>

[0261] HOX6H° M

[0262] HO OH

[0263] o [(5 - { [4-(Thiophen-3 -y 1 )-7Z7-py rrolo [2,3 - <7| py ri m idin -7 -yl]

[0264] 5k XT i

[0265] ribofuranosyl}oxy)phosphonomethyl]pho fl " y^Xl

[0266] X -oX 7 sphonic acid

[0267] H° oX OH M

[0268] HO OH

[0269] sX

[0270] [(5 - { 14-(Th iophcn-2-yl )-7 / / -py rrolo [2,3 - <7| py ri m idin -7 -yl] - / ?-D- 51 CTJ ribofuranosyl}oxy)phosphonomethyl]pho z °P\ / ? 1 o \ 7N'

[0271] HOsphonic acid XH M HO OH

[0272]

[0273] Q [(5 -{ [4-(Furan-3 -y 1 )-7Z7-py rrolo [2,3 - t / |pyrimidin-7-yl|- / >-D- 5m Co ribofuranosyl}oxy)phosphonomethyl]pho 0 °N

[0274] I sphonic acid

[0275] o IHoso^M 6^ O'HO^ M /

[0276] 070=s- 07 0=' HO OH

[0277] <T

[0278] <x07= 0- 07= 0- [(5 - { [4-(Dibenzo \b, <7]furan-4-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5n < CfS S o

[0279] ribofuranosyl}oxy)phosphonomethyl]pho 00 \ \ / 7 I _? " ^ / OjN

[0280] sphonic acid

[0281] H° OH^ OH M O ■o HK ^ / X ' (z V— — HO OH

[0282] z\ o

[0283] [(5 - { [4-(Phenanthren-9-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5o

[0284] ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0285] [(5-{[(4-(Chroman-8-yl)-7H-pyrrolo[2,3- <7|pyrimidin-7-yl|- / >-D- 5p

[0286] ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0287]

[0288] 0 \' O O> [(5 - { [4-(Benzofuran-7-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5q Or j ribofuranosyl}oxy)phosphonomethyl]pho 2 g

[0289] xP\z i"o \ 7Nsphonic acidHO(£T OH° M

[0290] HO OH

[0291] O— \

[0292] [(5 - { [4-(2,3 -Dihydrobenzo furan-5 -yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 5r

[0293] Or ribofuranosyl}oxy)phosphonomethyl]pho J

[0294] ° g x^ sphonic acid

[0295] , P\ / 1 o \ 7

[0296] HO8 / OH M

[0297] HO OH

[0298] , N.

[0299] Q [(5-{[4-(Pyridin-4-yl)-7H-pyrrolo[2,3- <7|pyrimidin-7-yl|- / >-D- 5s

[0300] Or J ribofuranosyl}oxy)phosphonomethyl]pho ° g x-O?Nsphonic acid

[0301] HOi o \ 7

[0302] OH^ OH M

[0303] HO OH

[0304] oo [(5 - { [4-(Quinolin-4-yl)-7H-pyrrolo [2,3 - <7|pyrimidin-7-yl|- / >-D- 5t

[0305] Or? ribofuranosyl}oxy)phosphonomethyl]pho „ ° P^X g i o \ 7Nsphonic acid

[0306] H° OH^ OH HO M OH

[0307] [(5 - { [4-(Isoquinolin-8 -yl)-7H-pyrrolo [2,3 - <7|pyrimidin-7-yl|- / >-D- 5u

[0308] CO ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0309] HO.p^^o^X /

[0310] 6 / 6H° M

[0311] HO OH

[0312]

[0313] JO [(5 - { [4-(Quinolin-6-yl)-7H-pyrrolo [2,3 - t / |pyrimidin-7-yl|- / >-D- 5v <rS ribofuranosyl}oxy)phosphonomethyl]pho sphonic acidHO(£T 6H H

[0314] HO OH

[0315] o.

[0316] [(5 - { [4-(Quinolin-3 -y 1 )-7Z7-py rrolo [2,3 - v

[0317] <7|pyrimidin-7-yl|- / >-D- 5w

[0318] ribofuranosyl}oxy)phosphonomethyl]pho OTJ

[0319] sphonic acid

[0320] ° BN

[0321] HOiHOH / ■;

[0322] HO OH

[0323] , N.

[0324] A 1. N H

[0325] |T T [(5-{[4-(Quinazolin-7-yl)-7H-pyrrolo[2,3- <7|pyrimidin-7-yl|- / >-D- 5x

[0326] ribofuranosyl}oxy)phosphonomethyl]pho On

[0327] sphonic acid

[0328] ° §

[0329] i O \ / N

[0330] HOOH^ OH M

[0331] HO OH

[0332] . M

[0333] ex

[0334] XJ [(5-{[4-(Isoquinolin-6-yl)-7H-pyrrolo[2,3- <7|pyrimidin-7-yl|- / >-D- 5y

[0335] ribofuranosyl}oxy)phosphonomethyl]pho On

[0336] sphonic acid

[0337] ° 2N

[0338] HO^-^OQ n_j

[0339] HOOH OH

[0340] HO OH

[0341]

[0342] CJ [(5 -{ [2-Methyl-4-(naphthalen-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 10a

[0343] ribofuranosyl}oxy)phosphonomethyl]pho Co

[0344] ° II N CH3sphonic acid

[0345] H° O M

[0346] HO OH

[0347] [(5-{ [2 -Methyl -4-(benzo fur an-2-yl)-7Z7- °C

[0348] pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 10b

[0349] ribofuranosyl}oxy)phosphonomethyl]pho Cn

[0350] n "NCH3sphonic acid

[0351] H°O M

[0352] HO OH

[0353] °C [(5-{[4-(Furan-2-yl)-2-methyl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 10c < X i

[0354] O II N CH3ribofuranosyl}oxy)phosphonomethyl]pho.p\z-F?" OZ\^ / sphonic acid

[0355] HO<£T OH M

[0356] HO OH

[0357] CO [(5 - { [2-Methyl-4-(naphth- 1 -yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- lOd

[0358] co ribofuranosyl}oxy)phosphonomethyl]pho ° °N<^H3

[0359] sphonic acid

[0360] HO60 M

[0361] HO OH

[0362]

[0363] QO [(5-{ [2-Methyl-4-(5, 6,7,8- tetrahydronaphth- 1 -y 1 )-7Z7-py rrolo [2,3 - lOe <7|pyrimidin-7-yl|- / >-D- 0 u coN<^H3ribofuranosyl}oxy)phosphonomethyl]pho P'-^z Co^^ X 7

[0364] HOO M sphonic acid

[0365] HO OH

[0366] JO QI [(5-{[2-Amino-4-(naphthalen-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 15a

[0367] ribofuranosyl}oxy)phosphonomethyl]pho 0 n Co N NH2sphonic acid xP^z^^J X 7

[0368] HOoO M

[0369] HO OH

[0370] °C [(5 - { [2-Amino-4-(benzofuran-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 15b

[0371] ribofuranosyl}oxy)phosphonomethyl]pho ° ° Z^Z° C-J oN^NH2 sphonic acid

[0372] HO-P6^O / ^O^ MX 7

[0373] HO OH

[0374] °x^ [(5-{[2-Amino-4-(furan-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 15c

[0375] 0 n Co N NH2ribofuranosyl}oxy)phosphonomethyl]phoH° „P6\Oz'F?"o / ^

[0376] HO M\ 7 sphonic acid

[0377] OH

[0378]

[0379] QO [(5 - { [2-Amino-4-(naphth- 1 -yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 15d

[0380] co ribofuranosyl}oxy)phosphonomethyl]pho 0 uN^NH2

[0381] zP^ / ^O^^ X / sphonic acid

[0382] HOO M

[0383] HO OH

[0384] [(5-{[2-Amino-4-(5, 6,7,8- 00

[0385] tetrahydronaphth- 1 -y 1 )-7Z7-py rrolo [2,3 - 15e <7| py ri m idin -7 -yl]

[0386] Co

[0387] 0 u / - zOq N NH2ribofuranosyl}oxy)phosphonomethyl]phoH° OH OH sphonic acid

[0388] HO OH

[0389] JO

[0390] [(5-{[2-Chloro-4-(naphthalen-2-yl))-7Z7- O'

[0391] pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18a

[0392] ^T i ribofuranosyl}oxy)phosphonomethyl]pho o 9 Z^ / OsjN<31 sphonic acid.zP\z'F?''OZ^ \ /

[0393] HOO M

[0394] HO OH

[0395] [(5 - { [2-Chloro-4-(benzofuran-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18b

[0396] < Cf l ribofuranosyl}oxy)phosphonomethyl]pho 0 9 / ^ / O^I bCci sphonic acid

[0397] HOOH^ OH M

[0398] HO OH

[0399]

[0400] O^ C

[0401] [(5-{[2-Chloro-4-(furan-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18c fn

[0402] ft ft n i N-^ci ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0403] HOOH OH H

[0404] HO OH

[0405] 00 [(5-{[2-Chloro-4-(naphth-l-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18d

[0406] co ribofuranosyl}oxy)phosphonomethyl]pho ft °

[0407] sphonic acid

[0408] HHOo'^ OH O '" H° H \_ /

[0409] HO OH

[0410] [(5-{[2-Chloro-4-(5, 6,7,8- 00

[0411] tetrahydronaphth- 1 -y 1 )-7Z7-py rrolo [2,3 - 18e <7|pyrimidin-7-yl|- / >-D- co

[0412] ft °N Clribofuranosyl}oxy)phosphonomethyl]phoHOO M sphonic acid

[0413] HO OH

[0414] [(5-{ [2-Chloro-4-(5, 6,7,8- O' tetrahydronaphthalen-2-yl)-7Z7- 18f pyrrolo|2.3-t / |pyrimidin-7-yl|- / >-D- N

[0415] ribofuranosyl}oxy)phosphonomethyl]pho ft °N<31

[0416] ^P\zF?" O / ^ \ 7 sphonic acid

[0417] H° OH^ OH M

[0418] HO OH

[0419]

[0420] H2N

[0421] [(5-{[4-(4-(Aminomethyl)phenyl)-2- chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl]- 0 / 3-D- 18g ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0422] ft 9 N Cl

[0423] H° OH^ OH M

[0424] HO OH

[0425] HN [(5-{[2-Chloro-4-(177-indol-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18h

[0426] ^Y l ribofuranosyl}oxy)phosphonomethyl]pho ft ft / ^ / Oq1 Nsphonic acid ZP^Z'^'XJ X /

[0427] HOOH^ OH M

[0428] HO OH

[0429] F

[0430] [(5-{[2-Chloro-4-(6-fluoronaphthalen-2- Qj

[0431] yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D- 18i

[0432] ribofuranosyl}oxy)phosphonomethyl]pho Co sphonic acid

[0433] ft ft / Ox.!KN^d

[0434] H° OH M

[0435] HO OH

[0436] [(5 - { [2-Chloro-4-(4-bromo- 1 - TX fluoronaphthalen-2-yl)-7H-pyrrolo [2,3 - 18j <7|pyrimidin-7-yl|- / >-D- Ci ribofuranosyl}oxy)phosphonomethyl]pho ft ft / O. I NT ^CI

[0437] sphonic acid

[0438] HOO^T OH M

[0439] HO OH

[0440]

[0441] Cl

[0442] QI [(5-{[2-Chloro-4-(6-chloronaphthalen-2- yl)-7H-pyrrolo|2.3-t / |pyrimidin-7-yl|- / >-D- 18k

[0443] ribofuranosyl}oxy)phosphonomethyl]pho < YS

[0444] FT FT ^AINsphonic acid

[0445] ti

[0446] HO OH

[0447] F

[0448] [(5-{[2-Chloro-4-(4-fluoronaphth-l-yl)- 00

[0449] 7H-pyrrolo|2.3-t / |pyrimidin-7-yl|- / >-D- 181

[0450] ribofuranosyl}oxy)phosphonomethyl]pho cn

[0451] ft ft ^0 ^01 sphonic acid

[0452] HOiO M

[0453] HO OH

[0454] JO [(5-{[2-Chloro-4-(6- fj (methoxycarbonyl)naphthalen-2-yl)-7Z7- 18m pyrrolo[2,3-d]pyrimidin-7-yl]

[0455] ribofuranosyl}oxy)phosphonomethyl]pho ^Y i

[0456] ft ft / 0\TNCl sphonic acid

[0457] HOOH OHsAAz

[0458] HO OH

[0459] °” \

[0460] [(5 - { [2-Chloro-4-(2,2-dimethyl-2,3 - (Y

[0461] dihydrobenzofur an-5 -y 1 )-7 / / -py rrolo [2,3 - 18n t / |py rim idin-7-y l Co ribofuranosyl}oxy)phosphonomethyl]pho ft ft ^ A| NACI

[0462] sphonic acid

[0463] HOxP 6^FT^-o^V /

[0464] OH M HO OH

[0465]

[0466] [(5-{[4-(6-(Benzyloxy)naphthalen-2-yl)- 2-chloro-7H-pyrrolo[2,3-d]pyrimidin-7- JO

[0467] 18o yl]-^-D- ribofuranosyl}oxy)phosphonomethyl]pho Co sphonic acid

[0468] ft ft O^ N Cl

[0469] HO6^6H°

[0470] HO M OH OH

[0471] [(5-{[2-Chloro-4-(6-hydroxynaphthalen- (Qj 2-yl)-7H-pyrrolo|23-<7|pyrimidin-7-yl|- / >- 18p D- Co ribofuranosyl}oxy)phosphonomethyl]pho ft ft o. IXN^xCI sphonic acid O O /

[0472] H° ObT OH

[0473] HO M OH NH2

[0474] [(5-{[4-(4-Aminonaphth-l-yl)-2-chloro- Oo

[0475] 7H-pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 18q

[0476] Co ribofuranosyl}oxy)phosphonomethyl]pho ft ii sphonic acid, P\ / f?''O / ^>\ 7

[0477] HOOH^ OH

[0478] HO M OH

[0479]

[0480] CN

[0481] 00 [(5-{ [2-Chloro-4-(4-cyanonaphth-l -yl)- 7H-pyrrolo|23-t / |pyrimidin-7-yl|- / >-D- 18r

[0482] ribofuranosyl}oxy)phosphonomethyl]pho I

[0483] ox0 ° coN<31 sphonic acid

[0484] 075 0=-HOOH<x^O075= 0-H

[0485] HO M OH

[0486] [(5-{[2-Chloro-4-(6-methoxynaphthalen- 2-yl)-7H-pyrrolo|23-<7|pyrimidin-7-yl|- / >- 18s QQ-y / D- \ / 0 — ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0487] JO

[0488] [(5-{[2-Fluoro-4-(naphthalen-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 21a

[0489] ribofuranosyl}oxy)phosphonomethyl]pho 0 n ^ / O c^jo N F sphonic acid

[0490] HOO M

[0491] HO OH

[0492] °C [(5-{[4-(Benzofuran-2-yl)-2-fluoro)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 21b

[0493] ribofuranosyl}oxy)phosphonomethyl]pho Ci?

[0494] ° B z^-0'! sphonic acid

[0495] H° xP 6FT / 0 7N"

[0496] \

[0497] O 1H \FM HO OH

[0498]

[0499] [(5-{[2-Fluoro-4-(furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 21c CO ribofuranosyl}oxy)phosphonomethyl]pho ° SN"F

[0500] sphonic acid

[0501] HOOH OH

[0502] HO OH

[0503] 00 [(5-{[2-Fluoro-4-(naphth-l-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 21d N

[0504] ribofuranosyl}oxy)phosphonomethyl]pho H §N'F

[0505] HoC''"'''' '" O^ X / sphonic acid

[0506] H° OH OH

[0507] HO OH

[0508] [(5-{[2-Fluoro-4-(5, 6,7,8- 00

[0509] tetrahydronaphth- 1 -y 1 )-7Z7-py rrolo [2,3 - 21e <7|pyrimidin-7-yl|- / >-D- co

[0510] ribofuranosyl}oxy)phosphonomethyl]pho / ° a

[0511] PX / 'l'O \ / N"F

[0512] HOO M sphonic acid

[0513] HO OH

[0514] n

[0515] [(5 -{ [2-Methoxy-4-(naphthalen-2-yl)-7Z7- pyrrolo[2,3-d]pyrimidin-7-yl]- / >-D- 23a

[0516] ribofuranosyl}oxy)phosphonomethyl]pho co

[0517] o 9 oji N OMe sphonic acid

[0518] HOO^T OH M

[0519] HO OH

[0520]

[0521] (V [(5-{[2-(Methylamino)-4-(naphthalen-2- yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl |- / >-D- 104 25a

[0522] ribofuranosyl}oxy)phosphonomethyl]pho co

[0523] sphonic acid

[0524] ° S / -vCN

[0525] HOOH^OH M

[0526] HO OH

[0527] [(5-{ [2-Iodo-4-(5, 6,7,8- tetrahydronaphthalen-2-yl)-7Z7- 107 28f pyrrolo [2,3 -<7|pyrimidin-7-yl|- / >-D- co ribofuranosyl}oxy)phosphonomethyl]pho sphonic acid

[0528] HOOH^OH M

[0529] HO OH

[0530]

[0531] General Procedure A: Deprotection of silyl groups

[0532] Protected nucleoside was treated with TBAF (1.6 or 3.2 equiv.) at rt for 30 min. The mixture was then diluted with EtOAc, evaporated, and purified by HPFC.

[0533] General Procedure B: Deprotection of PG

[0534] Protected nucleoside was treated with 75 % TFA at rt for Ih. The mixture was then co-evaporated 3 times with MeOH, evaporated, and purified by HPFC.

[0535] General Procedure C: Synthesis of bisphosphonates

[0536] Nucleoside was dissolved in trimethylphosphate and cooled to 0 °C. A cold solution of methylene bis(phosphonic dichloride) (2-5 equiv.) in trimethylphosphate was added dropwise and the mixture was stirred at 0 °C for 3 h. The mixture was treated with water and lyophilized. The crude mixture was purified by RP-HPFC (C-18, H2O / MeOH 0 100 %) or HPLC purification (C-18, H2O + 0.05% TFA / MeCN 0

[0537] 80 %) and lyophilized from H2O / / -BuOH.

[0538] General Procedure D: Suzuki cross-coupling reaction

[0539] H2O / MeCN (2:1 or 1:1) was added trough a septum to an argon purged vial containing protected or unprotected nucleoside intermediate (1 equiv.), corresponding boronic acid (1.1-2 equiv.), Na2CO3(1.5equiv.), TPPTS (0.06 equiv.) and Pd(OAc)2(0.025 equiv.). The mixture was heated at 80-100 °C from 10 min to overnight. Solvent was evaporated and the crude mixture was purified by HPFC (SiO2, DCM / MeOH 1:0 —> 9:1) and lyophilized from H2O / i-BuOH.

[0540] General Procedure E: Suzuki cross-coupling reaction

[0541] H2O / MeCN (2:1 or 1:1) was added trough a septum to an argon purged vial containing protected or unprotected nucleoside intermediate (1 equiv.), corresponding boronic acid (1.1-2 equiv.), Na2CO3(3 equiv.), TPPTS (0.12 equiv.) and Pd(OAc)2(0.05 equiv.). The mixture was heated at 80-100 °C from 10 min to overnight. Solvent was evaporated and the crude mixture was purified by HPFC (SiO2, DCM / MeOH 1:0 —> 9:1) and lyophilized from H2O / i-BuOH.

[0542] Example 1

[0543] 4-Chloro-7-(2,3-(?-isopropylidene- / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (2) Compound 1 (1.04 g, 2.36 mmol) was treated with 3.8 mL TBAF according to the general procedure A. HPFC (SiO2, cHex / EtOAc 5.7:1 —> 1:1) gave compound 2 (653.6 mg, 85 %) as a white oily solid. *HNMR (500 MHz, CDCls): 1.37 and 1.64 (2xs, 2x3H, (CH3)2C); 3.81 (dd, 1H, Jgem= 12.6 Hz, J5 a,4= 2.1 Hz, H-5'a); 3.96 (dd, 1H, Jgan= 12.6 Hz, J5 w= 1.9 Hz, H-5 'b); 4.49 (q, 1H, J4^a= J4',n= J4,3= 1.9 Hz, H-4 ); 5.11 (dd, 1H, J3-,2= 6.1 Hz, J3,4= 1.8 Hz, H-3'); 5.23 (dd, 1H, J2-,3= 6.1 Hz, J2,i = 4.8 Hz, H-2'); 5.87 (d, 1H,,z = 4.8 Hz, H-l '); 6.63 (d, 1H, J5fi= 3.7 Hz, H-5); 7.33 (d, 1H, J6,5= 3.7 Hz, H-6); 8.63 (s, 1H, H-2); HR-ESI-MS -.found. 326.0905 ([M + H]+, calcd for C14H17O4N3CE: 326.0902); HR-ESI-MS: found.

[0544] 348.0724 ([M +Na]+, calcd for Ci4Hi6O4N3ClNa+: 348.0722).

[0545] Example 2

[0546] [(5-{[4-Chloro-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (3)

[0547] General procedure C starting from nucleoside 2 (643 mg, 1.97 mmol) gave bisphosphonate 3 (476.1 mg, 54 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.07 -4.15 (m, 3H, H-5 ',4'); 4.20 (dd, 1H, J3,2 = 5.1 Hz, J5 4 = 2.9 Hz, H-3'); 4.46 (dd, 1H, J2; / ' = 6.2 Hz, J2;r = 5.2 Hz, H-2'); 6.24 (d, 1H, Jr,2= 6.2 Hz, H-l'); 6.74 (d, 1H, Jj 6= 3.8 Hz, H-5); 8.00 (d, 1H, J6J= 3.8 Hz, H-6); 8.68 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.76 and 19.83 (2xd, 2x IP, JPP= 6.7 Hz, PCHzP). HR-ESI-MS -.found. 441.9973 ([M - H]“, calcd for CizHisOgNsCIPz’: 441.9978).Example 3

[0548] 4-(p-Cyanophenyl)-7-(2,3-0-isopropylidene-5-0- / er / -butyldimethylsilyl-jff-D-ribofuranosyl)-7H-pyrrolo[2,3-< / ]pyrimidine (4f)

[0549] General procedure E starting from nucleoside 1 (463.6 mg, 1.05 mmol) gave nucleoside 4f (513.3 mg, 96 %) as a yellow foam. ‘H NMR (500 MHz, CDC13): 0.08 and 0.09 (2xs, 2x3H, (CH3)2Si); 0.90 (s, 9H, (CH3)3C); 1.40 and 1.67 (2xs, 2x3H, (CH3)2C); 3.82 (dd, 1H, Jgem= 11.3 H

[0550]

[0551] z, = 3.6 Hz, H-5'a); 3.92 (dd, 1H, Jgem= 11.3 Hz, Jb,4' = 3.4 Hz, H-5'b); 4.38 (bq, 1H, J4,5 a = J4,5 'b = J4',3' = 3.2 Hz, H-4 ); 4.98 (dd, 1H, J3,2= 6.2 Hz,

[0552]

[0553] 4= 2.9 Hz, H-3'); 5.09 (dd, 1H, J2,5 = 6.2 Hz, J2,1 = 3.1 Hz, H-2'); 6.51 (d, 1H,,2= 3.1 Hz, H-l ); 6.80 (d, 1H,.7= 3.8 Hz, H-5); 7.69 (d, 1H, J6,5= 3.8 Hz, H-5); 7.85 (m, 2H, H-w-Ph); 8.22 (m, 2H, H-o-Ph); 9.02 (s, 1H, H-2); HR-ESI-MS: found: 507.2421 ([M + H]+, calcd for C27H35O4N4Si+: 507.2422); HR-ESI-MS: found: 529.2240 ([M +Na]+, calcd for C27H34O4N4NaSi+: 529.2242).

[0554] Example 4

[0555] 4-(5-((Trimethylsilyl)ethynyl)benzofuran-2-yl)-7-(2,3-0-isopropylidene-5-0-tert-butyldimethylsilyl- / LD-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (4j)

[0556] 1) Suzuki cross coupling: General procedure E starting from nucleoside 1 (520.8 mg, 1.18 mmol) gave nucleoside 4-(5-Bromobenzofuran-2-yl)-7-(2,3-O-isopropylidene-5-O-tert- butyldimethylsilyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (450.8 mg, 63 %) as ayellow oil. *HNMR (500 MHz, DMSO-d6): -0.014 and -0.010 (2xs, 2x3H, (CH3)2Si); 0.83 (s, 9H, (CH3)3C); 1.34 and 1.57 (2xs, 2x3H, (CH3)2C); 3.72 (dd, 1H, Jgem= 11.2 Hz, Ja,4' = 5.3 Hz, H-5'a); 3.78 (dd, 1H, Jgem= 11.2 Hz, Jb,4' = 4.8 Hz, H-5'b); 4.21 (td, 1H,4 7a = J4',s'b = 5.0 H

[0557]

[0558] z, = 3.2 Hz, H-4'); 4.97 (dd, 1H, J3,2= 6.3 H

[0559]

[0560] z, = 3.2 Hz, H-3'); 5.31 (dd, 1H, J2,5 = 6.3 Hz, J2,7 = 2.9 Hz, H-2'); 6.42 (d, 1H,,2= 2.9 Hz, H-l '); 7.28 (d, 1H, J5,6= 3.8 Hz, H-5); 7.61 (dd, 1H, J6,7= 8.8 Hz, J6,4= 2.1 Hz, H-6-benzofuiyl); 7.81 (bd, 1H, J76= 8.8 Hz, H-7-benzofuryl); 7.89 (d, 1H, J3,7= 0.9 Hz, H-3-benzofuiyl); 8.96 (d, 1H, J6,5= 3.8 Hz, H-6); 8.02(d, 1H, J46= 2.1 Hz, H-4-benzofuryl); 8.91 (s, 1H, H-2); HR-ESI-MS: found. 600.1518 ([M + H]+, calcd for C28H35O5N3BrSi+: 600.1524).

[0561] 2) Sonogashira cross coupling reaction: The obtained 4-(5 -Bromobenzofuran -2 -yl)-7-(2, 3-O-isopropylidene-5-O-tert-butyldimethylsilyl-P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (335.5 mg, 0.56 mmol), Pd(PPh3)2Cl2(19.6 mg, 5 mol%), Cui (5.3 mg, 5 mol%) were dissolved in DMF (8 mL) under argon and treated by the addition of 1 mL trimethylsilylacetylene and 1 mL DIPEA. Reaction mixture was heated up to 130 °C and let to stir overnight. After the completion of the reaction, solvent was removed in vacuo. HPFC (SiO2, cHex / EtOAc 1:0 — 9:1) gave crude 4j (251.5 mg, 73 %) as a brownish oil. The characterization was done after deprotection of silyl groups. HR-ESI-MS: found. 618.2809 ([M + H]+, calcd for C33H44O5N3Si+: 618.2814)..Example 5

[0562] [(5-{[4-(Naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5a)

[0563] General procedure E starting from bisphosphonate 3 (55.2 mg, 0.12 mmol) gave bisphosphonate 5a (62.8 mg, 95 %) as a white powder. ’H NMR (600.1 MHz, D2O): 2.15 (t, 2H, JCH2.p = 19.7 Hz, PCH2P); 4.16 (ddd, 1H, Jgem= 11.5 Hz, J5■a. P = 5.0 Hz, J5

[0564] = 3.8 Hz, H-5 'a); 4.22 (ddd, 1H, Jgem= 11.5 Hz, J5’b,P= 5.9 Hz, Aw = 3.7 Hz, H-5'b); 4.28 (bq, 1H, ',5' = J4,3' =.1 Hz, H-4 ); 4.60 (dd, 1H, J32 = 5.2 Hz, A;r = 3.9 Hz, H-3'); 4.75 (t, 1H, J2,3 = J2',r = 5.6 Hz, H-2'); 6.37 (d, 1H,,2= 5.9 Hz, H-l ); 6.92 (d, 1H, J56= 3.8 Hz, H-5); 7.51 (ddd, 1H, J78= 8.0 Hz, J76= 6.8 Hz, J75= 1.3 Hz, H-7-naphthyl); 7.55 (ddd, 1H, J6:5= 8.0 Hz, J6,7= 6.8 Hz, s = 1.3 Hz, H-6-naphthyl); 7.83 (d, 1H, J5,6= 8.0 Hz, H-5 -naphthyl); 7.85 (bd, 1H, J6.5 = 3.7 Hz, H-6); 7.86 (d, 1H, J87= 8.0 Hz, H-8-naphthyl); 7.88 (bs, 2H, H-3,4-naphthyl); 8.22 (s, 1H, H-2-naphthyl); 8.60 (s, 1H, H-2);31PNMR (202.4 MHz, D2O): 13.52 and 21.42 (2xd, 2xlP, JPP= 8.8

[0565]

[0566] Hz, PCH2P). HR-ESI-MS: found: 534.0832 ([M - H]“, calcd for C22H22O9N3P2- 534.0837); HR-ESI-MS: found: 556.0652 ([M - 2H + Na]“, calcd for C22H2iO9N3NaP2’: 556.0656).

[0567] Example 6

[0568] [(5-{[4-(Benzofuran-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5b)

[0569] General procedure C starting from nucleoside 4b (240 mg, 0.59 mmol) gave bisphosphonate 5b (51 mg, 17 %) as a white powder. ’H NMR (500.0 MHz, DMSO-A): 2.29 (t, 2H, A,p = 20.0, CH2P); 4.09-4.18 (bm, 3H, H-4', 5'); 4.23 (dd, 1H, J3^ = 5.1, Jy.v = 3.3, H-3'); 4.50 (dd, 1H, Jp.v = 6.2, J2^ = 5.1, H-2'); 6.33 (d, 1H, Jp,2' = 6.2, H-l'); 7.29 (d, 1H, A, 6 = 3.8, H-5); 7.37 (ddd, 1H, A, 4 = 7.8, A, 6 = 7.2, A, 7 = 1.1, H-5- benzofuryl); 7.48 (ddd, 1H, A, 7 = 8.3, A, 5 = 7.2,.r = 1 3, H-6-benzof yl);. 7.81-7.84 (m, 2H, H-4,7- benzofuryl); 7.94 (d, 1H, A, 7 = 0,8, H-3-benzofuryl);. 8.05 (d, lH, A,5 = 3.8, H-6); 8.90 (s, lH, H-2).31P{1H} NMR (202.4 MHz, DMSO-A): 15.81, 19.82. HR-ESI-MS: found 526.07716 ([M + H]+, calcd for C20H22O10N3P2+: 526.07749).

[0570] Example 7

[0571] [(5-{[4-(Furan-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5c)

[0572] General procedure E starting from bisphosphonate 3 (51.6 mg, 0.12 mmol) gave bisphosphonate 5c (30.8 mg, 56 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2, P = 19.9 Hz, PCH2P); 4.06 - 4.17 (m, 3H, H-4', 5'); 4.21 (m, 1H, H-3'); 4.47 (t, 1H, A,; = A.s = 5.6 Hz, H-2'); 6.29 (d, 1H, A,2= 6.2 Hz, H-l '); 6.79 (dd, 1H, J43= 3.5 Hz, J45=1.7 Hz, H-4-fuiyl); 7.07 (d, 1H,.7= 3.7 Hz, H-5); 7.48 (dd, 1H, J3,4= 3.5 Hz, J3,5= 0.7 Hz, H-3-furyl); 7.94 (d, 1H, J6,5= 3.7 Hz, H-6); 8.07 (d, 1H, J5,4= 1.7 Hz, J5,3= 0.7 Hz, H-5-furyl); 8.78 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.83 and 19.68 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found. 474.0467 ([M - H]“, calcd for C16H18O10N3P2⁻ 474.0462); HR-ESI-MS: found: 496.0285 ([M - 2H +Na]“, calcd for C16H17O10N3NaP2⁻: 496.0281).

[0573] Example 8

[0574] [(5-{[4-(Naphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5d)

[0575] General procedure E starting from bisphosphonate 3 (68.4 mg, 0.15 mmol) gave bisphosphonate 5d (55.6 mg, 67 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2,p = 20.5 Hz, PCH2P); 4.09 - 4.18 (m, 3H, H-4',5'); 4.23 (dd, 1H, J3,2= 5.1 Hz, J3,4= 2.5 Hz, H-3'); 4.52 (bt, 1H, J2,i = J2,3= 5.7 Hz, H-2'); 6.37 (d, 1H,,2= 6.3 Hz, H-l'); 7.46 (d, 1H, J5,6= 3.8 Hz, H-5); 7.52 (ddd, 1H, s = 8.5 Hz, J7.6 = 6.8 Hz, J7:5= 1.4 Hz, H-7-naphthyl); 7.60 (ddd, 1H, J6.s = 8.2 Hz, J6.7= 6.8 Hz, J6.s = 1.3 Hz, H-6-naphthyl); 7.70 (dd, 1H, J3,4= 8.21 Hz, J3,2= 7.1 Hz, H-3 -naphthyl); 7.79 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 7.94 (d, 1H, J6,5= 3.8 Hz, H-6); 8.03 (bd, 1H, J87= 8.5 Hz, H-8 -naphthyl); 8.07 (bd, 1H, J45= 8.3 Hz, H-4-naphthyl); 8.14 (bd, 1H, J43= 8.3 Hz, H-4 -naphthyl); 9.03 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.71 and 19.83 (2xd, 2x IP, JPP= 6.8 Hz, PCH2P). HR-ESI-MS: found: 534.0835 ([M - H]“, calcd for C22H22O9N3P2- 534.0837).

[0576] Example 9

[0577] [(5-{[(4-(5,6,7,8-Tetrahydronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5e)

[0578] General procedure E starting from bisphosphonate 3 (88.3 mg, 0.20 mmol) gave bisphosphonate 5e (35.5 mg, 33 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.64 (m, 2H, H-3-CioHn); 1.75 (H-2-CioHn); 2.25 (t, 2H, JCH2P = 20.5 Hz, PCH2P); 2.63 (H-4-CioHn); 2.84 (H-l-CioHn); 4.07 - 4.16 (m, 3H, H-4',5'); 4.21 (dd, 1H, J3y = 5.2 Hz, = 2.7 Hz, H-3'); 4.50 (dd, 1H, J2-,7• = 6.3 H

[0579]

[0580] z, = 5.2 Hz, H-2'); 6.32 (d, 1H,,2= 6.3 Hz, H-l '); 6.47 (d, 1H, J5,6= 3.8 Hz, H-5); 7.21 - 7.29 (m, 3H, H-6,7,8-CioHn); 7.91 (d, 1H, J6,5= 3.8 Hz, H-6); 8.91 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 15.72 and 19.79 (2xd, 2x IP, JPP= 8.1 Hz, PCH2P). HR-ESI-MS: found: 538.1147 ([M-H]', calcd for C22H26O9N3P2’: 538.1150).Example 10

[0581] [(5-{[4-(p-Cyanophenyl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5f)

[0582] 1) Deprotection: Compound 4f (513.3 mg, 1.01 mmol) was treated with 1.6 mL TBAF according to the general procedure A. HPFC (SiO2, cHex / EtOAc 4:1 —> 1:1) gave 4-(p-cyanophenyl)-7-(2,3-O- isopropylidene-P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (303.1 mg, 76 %) as white foam. HR-ESI- MS: found: 393.1555 ([M + H]+, calcd for C21H21O4N4+: 393.1557); *HNMR (500 MHz, DMSO-d6): 1.34 and 1.57 (2xs, 2x3H, (CH3)2C); 3.56 (dt, 1H, Jgem= 11.7 Hz, J5 a,4=J5a, OH = 5.1 Hz, H-5'a); 3.59 (dt, 1H, Jgem= 11.7 Hz, J5'b,4' = J5'bX)H = 5.2 Hz, H-5'b); 4.20 (td, 1H, fsb= J4^b= 4.8 Hz, J4^ = 2.9 Hz, H-4'); 4.97 (dd, 1H, J3 2= 6.3

[0583]

[0584] Hz, = 2.9 Hz, H-3'); 5.13 (t, 1H, Jous = 5.4 Hz, OH-5'); 5.25 (dd, 1H, J2 3= 6.3 Hz, = 3.4 Hz, H-2'); 6.43 (d, 1H,

[0585]

[0586] 2= 3.4 Hz, H-l ); 7.08 (d, 1H, J5,6= 3.8 Hz, H-5); 8.05 (d, 1H, J6,s = 3.8 Hz, H-6); 8.06 (m, 2H, H-w-Ph); 8.35 (m, 2H, H-o-Ph); 8.98 (s, 1H, H-2); HR-ESI-MS: found 415.1376 ([M +Na]+, calcd for C21H20O4N4Na+: 415.1377).

[0587] 2) Bisphosphonation:

[0588] General procedure C starting from 4-(p-cyanophenyl)-7-(2,3-O-isopropylidene-P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (299.1 mg, 0.76 mmol) gave bisphosphonate 5f (210.9 mg, 54 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2,P= 20.3 Hz, PCH2P); 4.06 - 4.16 (m, 3H, H- 5 ',4'); 4.22 (m, 1H, H-3'); 4.50 (bt, 1H, J2,3= J2,i = 5.6 Hz, H-2'); 6.34 (

[0589]

[0590] d, 1H,2= 6.1 Hz, H-l'); 7.05 (d, 1H, Js,6 = 3.7 Hz, H-5); 8.05 (d, 1H, J6,s = 3.7 Hz, H-6); 8.06 (m, 2H, H-w-Ph); 8.35 (m, 2H, H-o-Ph); 8.97 (s, 1H, H2);31P NMR (202.4 MHz, DMSO-d6): 15.75 and 19.83 (2xs, 2xlP, PCH2P). HR-ESI-MS: found: 509.0631 ([M - H]“, calcd for CI9HI9O9N4P2“: 509.0633).

[0591] Example 11

[0592] [(5-{[4-(p-Aminomethylphenyl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5g)

[0593] General procedure E starting from bisphosphonate 3 (54.1 mg, 0.12 mmol) gave bisphosphonate 5g (51.7 mg, 82 %) as a pinkish white powder. ’H NMR (500 MHz, D2O): 2.17 (t, 2H, JCH2,p = 19.6 Hz, PCH2P); 4.14 - 4.27 (m, 4H, H-5', CH2NH2); 4.39 (q, 1H, J4,5= J4',3' = 3.7 Hz. H-4'); 4.50 (

[0594]

[0595] dd, 1H, = 5.3 Hz, J3',4' = 3.8 Hz, H-3'); 4.61 (

[0596]

[0597] t, 1H, J2,7= = 5.7 Hz, H-2'); 6.33 (d, 1H, J7 2= 5.9 Hz, H-l'); 6.76 (d, 1H, J5,6= 3.7 Hz, H-5); 7.41 (m, 2H, H-w-Ph); 7.67 (m, 2H, H-o-Ph); 7.79 (d, 1H, J6,5= 3.8 Hz, H-6); 8.60 (s, 1H, H-2);31P NMR (202.4 MHz, D2O): 13.87 and 20.98 (2xbs, IP, PCH2P). HR-ESI-MS: found: 513.0941 ([M - H]“, calcd for Ci9H23O9N4P2-: 513.0946); HR-ESI-MS:foun d: 535.0759 ([M - 2H + Na]“, calcd for Ci9H22O9N4NaP2-: 535.0765).Example 12

[0598] [(5-{[4-Phenyl-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5h)

[0599] General procedure E starting from bisphosphonate 3 (51.5 mg, 0.12 mmol) gave bisphosphonate 5h (34.1 mg, 61 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2.p = 20.2 Hz, PCH2P); 4.07 - 4.17 (m, 3H, H-4',5'); 4.22 (dd, 1H, J,2- = 5.3 Hz, fay = 2.9 Hz, H-3'); 4.49 (bdd, 1H, J2-,7- = 6.2 Hz, = 5.2 Hz, H-2'); 6.33 (d, 1H, J7,2= 6.2 Hz, H-l ); 7.01 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 - 7.63 (m, 3H, H- / n. / ?-Ph): 7.97 (d, 1H, fa,5= 3.8 Hz, H-6); 8.17 (m, 2H, H-o-Ph); 8.91 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 15.82 and 19.71 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found: 484.0674 ([M - H]“, calcd for CI8H2O09N3P2’: 484.0669); HR-ESI-MS: found: 506.0490 ([M - 2H + Na]“, calcd for CisHisOgNsNaPE: 506.0489).

[0600] Example 13

[0601] [(5-{[4-([l,r-Biphenyl]-4-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5i)

[0602] General procedure E starting from bisphosphonate 3 (53.6 mg, 0.12 mmol) gave bisphosphonate 5i (24.4 mg, 36 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2,P= 20.3 Hz, PCH2P); 4.07 - 4.19 (m, 3H, H-4',5'); 4.23 (m, 1H, H-3'); 4.50 (t, 1H, J2,i =

[0603]

[0604] = 5.7 Hz, H-2'); 6.35 (d, 1H, J7.2= 6.2 Hz, H-l ); 7.08 (d, 1H, J5,6= 3.8 Hz, H-5); 7.43 (m, 1H, H-4'-biphe); 7.52 (m, 2H, H-3'-biphe); 7.79 (m, 2H, H-2'-biphe); 7.91 (m, 2H, H-3-biphe); 8.00 (d, 1H, fa,5= 3.8 Hz, H-6); 8.29 (m, 2H, H-2-biphe); 8.93 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 15.80 and 19.76 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found 560.0988 ([M - H]“, calcd for C24H24O9N3P2’: 560.0982); HR-ESI-MS: found: 582.0807 ([M - 2H + Na]“, calcd for C24H23O9N3NaP2“: 582.0802).

[0605] Example 14

[0606] [(5-{[4-(5-Ethynylbenzofuran-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5j)

[0607] 1) Deprotection: Impure compound 4j (82.1 mg, 0.13 mmol) was treated with 0.4 mL TBAF according to the general procedure A. The crude was purified by RP-HPFC (C-18, H2O / MeOH 0 — 100 %) and used directly for the next step.

[0608] 2) Bisphosphonation: General procedure C starting from nucleoside 4-(5-ethynylbenzofuran-2-yl)-7-(2,3- O-isopropylidene-P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (240 mg, 0.59 mmol) gave bisphosphonate 5j (22 mg, 37 %) as a yellow powder. ’H NMR (500 MHz, DMSO-de): 2.28 (t, 2H, JCH2, P= 20.4 Hz, PCH2P); 4.09 - 4.16 (m, 2H, H-5'); 4.15 (m, 1H, H-4 ); 4.18 (s, 1H, C =CH): 4.23 (dd, 1H, J,2- = 5.1 Hz, J3’,4' = 3.0 Hz, H-3'); 4.50 (bt, 1H, J2,i ■ = Jr.3’ = 5.6 Hz, H-2'); 6.33 (d, 1H, J7,2= 6.1 Hz, H-l ); 7.28 (d, 1H, J56= 3.7 Hz, H-5); 7.56 (dd, 1H, J67= 8.5 Hz, J6,4=1.7 Hz, H-6-benzofuryl); 7.85 (d, 1H, J76= 8.6 Hz, H-7-benzofuryl); 7.92 (d, 1H, J3,7= 0.7 Hz, H-3 -benzofuryl); 7.96 (dd, 1H, J4.6= 1.7 Hz, =0.7 Hz, H-4 -benzofuryl); 8.06 (d, 1H, J6,s = 3.8 Hz, H-6); 8.90 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 15.81 and 19.75 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found: 548.0627 ([M - H]“, calcd for C22H2OOION3P2“: 548.0629).

[0609] Example 15

[0610] [(5-{[4-(Thiophen-3-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5k)

[0611] General procedure E starting from bisphosphonate 3 (52.2 mg, 0.12 mmol) gave bisphosphonate 5k (39.9 mg, 69 %) as a white powder. ’H NMR (600.1 MHz, DMSO-d6): 2.26 (t, 2H, JCH2.p = 20.3 Hz, PCH2P); 4.06 - 4.17 (m, 3H, H-5',4'); 4.22 (dd, 1H,,2= 5.2 Hz,

[0612]

[0613] = 3.1 Hz, H-3 '); 4.48 (bt, 1H, J2= J2,i = 5.7 Hz, H-2'); 6.31 (d, 1H,,2= 6.2 Hz, H-l ); 7.14 (d, 1H, J5,6= 3.8 Hz, H-5); 7.76 (dd, 1H, J5,4= 5.0 Hz, J32= 2.9 Hz, H-5-thienyl); 7.95 (d, 1H, J6,5= 3.8 Hz, H-6); 7.96 (dd, 1H, J45= 5.0 Hz, J42= 1.3 Hz, H-4-thienyl); 8.55 (dd, 1H, J2:5= 2.9 Hz, J24= 1.3 Hz, H-2-thienyl); 8.83 (s, 1H, H-2); HR-ESI-MS: found: 490.0240 ([M - H]“, calcd for CieHisOgN^S’: 490.0245); HR-ESI-MS: found: 512.0058 ([M - 2H + Na]“, calcd for C16H17O9N3NaP2S⁻: 512.0064).

[0614] Example 16

[0615] [(5-{[4-(Thiophen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (51)

[0616] General procedure E starting from bisphosphonate 3 (52.2 mg, 0.12 mmol) gave bisphosphonate 51 (33.2 mg, 57 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCHp = 20.1 Hz, PCH2P); 4.05 - 4.17 (m, 3H, H-4', 5'); 4.21 (m, 1H, H-3'); 4.47 (t, 1H, J2,7= J2,3= 5.6 Hz, H-2'); 6.30 (d, 1H, J7,2= 6.2 Hz, H-l'); 7.17 (d, 1H, J5,6= 3.8 Hz, H-5); 7.31 (dd, 1H, J45= 5.0 Hz, J43= 3.8 Hz, H-4-thienyl); 7.86 (dd, 1H, J5:4= 5.0 Hz, J5,3= 1.0 Hz, H-5-thienyl); 7.96 (d, 1H, J6,s = 3.8 Hz, H-6); 8.17 (dd, 1H, J3,4= 3.8 Hz, J3:5= 1.0 Hz, H-3-thienyl); 8.76 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 18.15 and 21.91 (2xbs, 2xlP, PCH2P). HR-ESI-MS -.found. 490.0238 ([M - H]“, calcd for CIHI8O9N3P2S“: 490.0234).Example 17

[0617] [(5-{[4-(Furan-3-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5m)

[0618] General procedure E starting from bisphosphonate 3 (68.9 mg, 0.16 mmol) gave bisphosphonate 5m (38.9 mg, 53 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.06 - 4.17 (m, 3H, H-4',5 '); 4.21 (dd, 1H,,2= 5.1 Hz, J3-,4- = 3.0 Hz, H-3 '); 4.47 (dd, 1H, J2,i = 6.2 Hz,,3 = 5.1 Hz, H-2'); 6.29 (d, 1H,. / / ,2= 6.2 Hz, H-l '); 7.10 (d, 1H, J5,6= 3.9 Hz, H-5); 7.27 (dd, 1H, J 4,5 = 1.9 Hz, J 42 = 0.6 Hz, H-4-furyl); 7.90 (t, 1H, J5,4= J5.2 = 1.7 Hz, H-5-furyl); 7.92 (d, 1H, J6,5= 3.9 Hz, H-6); 8.74 (bs, 1H, H-2-furyl); 8.80 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.80 and 19.67 (2xd, 2xlP, JP, P = 7.1 Hz, PCH2P). HR-ESI-MS: found-. 474.0470 ([M - H]“, calcd for Ci6Hi8OioN3P2’: 474.0473).

[0619] Example 18

[0620] [(5-{[4-(Dibenzo[ / >,< / ]furan-4-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5n)

[0621] General procedure E starting from bisphosphonate 3 (59.3 mg, 0.13 mmol) gave bisphosphonate 5n (63.5 mg, 82 %) as a white powder. ’H NMR (500 MHz, D2O): 2.18 (t, 2H, JCH2. P = 19.7 Hz, PCH2P); 4.17 (ddd, 1H, Jgem= 11.4 Hz, J5 a,P= 5.0 Hz,

[0622]

[0623] = 4.0 Hz, H-5'a); 4.22 (ddd, 1H, Jgem= 11.4 Hz, Jb,P= 5.8 Hz, Js-b.4- = 3.8 Hz, H-5'b); 4.41 (bq, 1H, J4-.5- = J4'.3- = 3.8 Hz, H-4 ); 4.58 (dd, 1H, J3-,2- = 5.3 Hz, J3-,4- = 3.9 Hz, H-3'); 4.75 (t, 1H, J2-,3= J2,i = 5.7 Hz, H-2'); 6.38 (d, 1H, Ji -,2= 5.9 Hz, H-l'); 6.53 (d, 1H, J5,6 = 3.7 Hz, H-5); 7.29 (t, 1H, J2,i = J2,3= 7.8 Hz, H-2-dibenzofuryl); 7.42 (td, 1H, J87= Js,9 = 7.3 Hz, J8,6= 1.2 Hz, H-8-dibenzofuryl); 7.51 (bddd, 1H, J8= 8.2 Hz, J78= 7.0 Hz, J 9 = 1.2 Hz, H-7-dibenzofuryl); 7.56 (d, 1H, J6:7= 8.2 Hz, H-6-dibenzofuryl); 7.63 (bd, 1H, J6,5= 3.7 Hz, H-6); 7.65 (bd, 1H, J32= 7.8 Hz, H-3-dibenzofuryl); 7.91 (d, 1H, J12 = 7.7 Hz, H-l-dibenzofuryl); 7.96 (d, 1H, J = 7.6 Hz, H-9-dibenzofuryl); 8.41 (s, 1H, H-2);31P NMR (202.4 MHz, D2O): 14.27 and 20.52 (bd, IP, JP,P= 8.7 Hz, PCH2P). HR-ESI-MS: found-. 574.0782 ([M - H]“, calcd for C24H22O10N3P2⁻ 574.0786); HR-ESI-MS -.faun d. 596.0597 ([M - 2H +Na]“, calcd for C24H21O10N3NaP2⁻: 596.0605).

[0624] Example 19

[0625] [(5-{[4-(Phenanthren-9-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5o)

[0626] General procedure E starting from bisphosphonate 3 (61.5 mg, 0.14 mmol) gave bisphosphonate 5o (73.9 mg, 91 %) as a white powder. *HNMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2, P = 20.4 Hz, PCH2P); 4.10 - 4.19 (m, 3H, H-4',5'); 4.24 (

[0627]

[0628] dd, 1H,2= 5.1 Hz, J3-4- = 2.5 Hz, H-3'); 4.54 (bt, 1H, J2-.i ■ = J2-,3- = 5.7Hz, H-2'); 6.39 (d, 1H, J7,2= 6.3 Hz, H-l ); 6.52 (d, 1H, J5fi= 3.8 Hz, H-5); 7.62 (ddd, 1H, A.s = 8.3 Hz, J, 6 = 6.9 HZ, J7,5 = 1.2 Hz, H-7-phenantrenyl); 7.73 (ddd, 1H, J2I= 7.9 Hz, J2,3= 7.1 Hz, A.4 = 1.1 Hz, H-2-phenantrenyl); 7.77 (ddd, 1H, Je,s = 8.4 Hz, Je = 7.0 Hz, Je.s = 1.4 Hz, H-6-phenantrenyl); 7.81 (ddd, 1H, J3,4 = 8.4 Hz, J3,2= 7.0 Hz, J3: I= 1.4 Hz, H-3-phenantrenyl); 7.96 (bd, 1H, J6,s = 3.9 Hz, H-6); 8.03 (dd, 1H, J8:7= 8.3 Hz, J8:6= 1.3 Hz, H-8-phenantrenyl); 8.12 (dd, 1H, JI:2= 8.0 Hz, JI:3= 1.4 Hz, H-l-phenantrenyl); 8.14 (s, 1H, H-10-phenantrenyl); 8.95 (bd, 1H, A, 5 = 8.5 Hz, H-4-phenantrenyl); 8.99 (bd, 1H, J5:6= 8.5 Hz, H-5-phenantrenyl); 9.06 (s, 1H, H-2);31PNMR (202.4 MHz, DMSO-d6): 15.69 and 19.84 (2xbs, 2xlP, PCH2P). HR-ESI-MS -.found. 584.0991 ([M - H]“, calcd for C26H24O9N3P2⁻: 584.0993).

[0629] Example 20

[0630] [(5-{[(4-(Chroman-8-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5p)

[0631] General procedure E starting from bisphosphonate 3 (91.1 mg, 0.21 mmol) gave bisphosphonate 5p (34.2 mg, 31 %) as a white powder. ’H NMR (500 MHz, DMSO-de): 1.94 - 2.03 (m, 2H, H-3-chromanyl); 2.26 (t, 2H, d, JCH2. P = 20.5 Hz, PCH2P); 2.87 (t, 2H, J43= 6.4 Hz, H-4-chromanyl); 4.09 - 4.14 (m, 3H, H-4', 5'); 4.16 (m, 2H, H-2-chromanyl); 4.22 (dd, 1H, J3-,2- = 5.1 Hz, A = 2.5 Hz, H-3'); 4.49 (dd, 1H, Ax = 6.4 Hz, J2,3= 5.1 Hz, H-3'); 6.31 (d, 1H, A7= 6.4 Hz, H-l ); 6.62 (d, 1H, s = 3.8 Hz, H-5); 7.01 (t, 1H, J6,5 =J6,7= 7.5 Hz, H-7-chromanyl); 7.28 (dd, 1H, J5,6= 7.5 Hz, J5,7= 1.7 Hz, H-5-chromanyl); 7.37 (dd, 1H, J76 = 7.6 Hz, J7,5= 1.7 Hz, H-7-naphthyl); 7.93 (d, 1H, J6,5= 3.8 Hz, H-6); 8.96 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 19.77 and 15.74 (2xd, 2xlP, JPP= 7.7 Hz, PCH2P). HR-ESI-MS: found.

[0632] 540.0942 ([M - H]“, calcd for C2IH24OION3P2’: 540.0942).

[0633] Example 21

[0634] [(5-{[4-(Benzofuran-7-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5q)

[0635] General procedure E starting from bisphosphonate 3 (63.3 mg, 0.14 mmol) gave bisphosphonate 5q (16.2 mg, 22 %) as a pale-yellow powder. *HNMR (500 MHz, DMSO-d6): 2.24 (bt, 2H, JCH P = 16.5 Hz, PCH2P); 4.07 - 4.19 (m, 3H, H-4',5'); 4.23 (m, 1H, H-3'); 4.51 (t, 1H, J2-,i = J2-,3- = 5.5 Hz, H-2'); 6.36 (d, 1H, Jp,2-= 6.2 Hz, H-l'); 6.68 (d, 1H, J5,6= 3.6 Hz, H-5); 7.12 (d, 1H, J2,4= 2.2 Hz, H-2-benzofuryl); 7.47 (t, 1H, J5.6 = Js.4= 7.6 Hz, H-5 -benzofuryl); 7.83 (dd, 1H, J6:5= 7.6 Hz, J6:4= 1.2 Hz, H-6-benzofuryl); 7.87 (dd, 1H, J45= 7.7 Hz, J46= 1.2 Hz, H-4-benzofuryl); 7.94 (bd, 1H, J6,5= 3.5 Hz, H-6); 8.10 (d, 1H, J2,4= 2.2 Hz, H-2-benzofuryl); 8.96 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.91 and 19.52 (2xs, 2xlP, PCH2P). HR-ESI-MS -.found: 524.0625 ([M - H]“, calcd for C2OH2OOION3P2“: 524.0629).22 [(5-{[4-(2,3-Dihydrobenzofuran-5-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5r) General procedure E starting from bisphosphonate 3 (73.1 mg, 0.17 mmol) gave bisphosphonate 5r (32 mg, 37 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2, P = 20.4 Hz, PCH2P); 3.31 (t, 2H, J3:2= 8.8 Hz, H-3-C8H7O); 4.07 - 4.17 (m, 3H, H-4',5'); 4.21 (dd, 1H,2= 5.2 Hz, = 3.0 Hz, H-3'); 4.48 (dd, 1H, J2,7= 6.2 Hz,J= 5.2 Hz, H-2'); 4.65 (t, 2H, J2,3= 8.8 Hz, H-2-C8H7O); 6.31 (d, 1H, J7,2= 6.2 Hz, H-l'); 6.97 (d, 1H, J76= 8.4 Hz, H-7-C8H7O); 7.03 (d, 1H, J5,6= 3.8 Hz, H-5); 7.94 (d, 1H, J6,5= 3.9 Hz, H-6); 7.97 (dd, 1H, J6,7= 8.4 Hz, J6,4= 1.9 Hz, H-6-C8H7O); 8.08 (bd, 1H, J46= 1.9 Hz, H-4-C8H7O); 8.85 (s, 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.73 and 19.73 (2xs, 2×1P, PCH₂P). HR-ESI-MS: found: 526.0782 ([M - H]“, calcd for C2OH22OION3P2“: 526.0786).

[0636] 23 [(5-{[4-(Pyridin-4-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5s) General procedure E starting from bisphosphonate 3 (72.1 mg, 0.16 mmol) gave bisphosphonate 5s (12.1 mg, 15 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, d, JCH2,P= 20.5 Hz, PCH2P); 4.08 - 4.18 (m, 3H, H-4',5'); 4.23 (dd, 1H, J3-,2- = 5.1 Hz, = 2.9 Hz, H-3 '); 4.50 (dd, 1H,,7= 6.2 Hz, = 5.1 Hz, H-2'); 6.35 (d, 1H, J2-.r = 6.2 Hz, H-l '); 7.12 (d, 1H, J5,6= 3.9 Hz, H-5); 8.08 (d, 1H, J6,5 = 3.9 Hz, H-6); 8.21 (m, 2H, H-3,5-py); 8.86 (m, 2H, H-2,6-py); 9.00 (s 1H, H-2);31P NMR (202.4 MHz, DMSO-d6): 15.78 and 19.77 (2xd, 2xlP, JPP= 7.7 Hz, PCH2P). HR-ESI-MS: found: 485.0628 ([M - H]“, calcd for C17H19O9N4P2⁻: 485.0633).

[0637] 24 [(5-{[4-(Quinolin-4-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5t) General procedure E starting from bisphosphonate 3 (69.7 mg, 0.16 mmol) gave bisphosphonate 5t (28.4 mg, 34 %) as a yellow powder. *HNMR (500 MHz, D2O): 2.31 - 2.50 (m, 2H, PCH2P); 4.26 (ddd, 1H, J_gem = 11.7 Hz, J5■a. P = 5.5 Hz, = 3.2 Hz, H-5 'a); 4.30 (ddd, 1H, Jgem= 11.7 Hz, J5-b,P= 5.4 Hz, J5-b,4- = 2.7 Hz, H-5'b); 4.46 (m, 1H, H-4 ); 4.57 (

[0638]

[0639] dd, 1H,2= 5.0 Hz, J3 pP= 3.2 Hz, H-3'); 4.77 (

[0640]

[0641] bt, 1H, J2 7= = 5.6 Hz, H-2'); 6.49 (bs, 1H, H-5); 6.52 (d, 1H,,2= 6.3 Hz, H-l '); 7.84 (dd, 1H, J6,5= 8.6 Hz, J6.7= 6.9 Hz, H-6-quinolinyl); 8.02 (bs, 1H, H-6); 8.10 - 8.15 (m, 2H, H-5,7-quinolinyl); 8.22 (d, 1H, J3,2= 5.0 Hz, H-3-quinolinyl); 8.33 (d, 1H, J8,7= 8.7 Hz, H-8-quinolinyl); 9.01 (s, 1H, H-2); 9.27 (bs, 1H, H-2-quinolinyl);31P NMR (202.4 MHz, D2O): 16.35 and 19.36 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found:

[0642] 535.0784 ([M - H]“, calcd for C21H21O9N4P2⁻ 535.0789).

[0643] Example 25

[0644] [(5-{[4-(Isoquinolin-8-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5u)

[0645] General procedure E starting from bisphosphonate 3 (81.4 mg, 0.18 mmol) gave bisphosphonate 5u (37.5 mg, 38 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.13 (t, 2H, JCH2,P= 19.7 Hz, PCH2P); 4.16 (ddd, 1H, Jgem= 11.5 Hz, J5 aj> = 5.0 Hz, = 3.6 Hz, H-5 'a); 4.23 (ddd, 1H, Jgem= 11.5 Hz, J5^P= 5.9

[0646]

[0647] Hz, J5= 3.5 Hz, H-5'b); 4.41 (bqd, 1H, J4',5'a= J4',5'b= J4',3'= 3.5 Hz, J4 J>= 1.0 Hz, H-4 ); 4.62 (dd, 1H, Jr,2= 5.3 Hz, Jj, 4 = 3.5 Hz, H-3'); 4.81 (dd, 1H, J2,i = 6.2 Hz, J2,3= 5.3 Hz, H-2'); 6.51 (d, 1H, J1',2'= 6.2 Hz, H-l '); 6.58 (d, 1H, J5,6= 3.8 Hz, H-5); 7.89 (d, 1H, J6,5= 3.9 Hz, H-6); 7.90 - 7.94 (m, 2H, H-6, 7- iso quinolinyl); 7.94 (bd, 1H, J43= 5.8 Hz, H-4-isoquinolinyl); 8.12 (m, 1H, H-5-isoquinolinyl); 8.44 (d, 1H, J3,4= 5.8 Hz, H-3-isoquinolinyl); 8.87 (s, 1H, H-2); 9.21 (s, 1H, H-l-isoquinolinyl);31P NMR (202.4 MHz, DMSO-d6): 21.68 and 13.21 (2xbd, 2xlP, JPP= 8.9 Hz, PCH2P). HR-ESI-MS -.found: 535.0784 ([M - H]“, calcd for C2IH2IO9N4P2’: 535.0789).

[0648] Example 26

[0649] [(5-{[4-(Quinolin-6-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5v)

[0650] General procedure E starting from bisphosphonate 3 (88.5 mg, 0.20 mmol) gave bisphosphonate 5v (25.9 mg, 24 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2P= 20.4 Hz, PCH2P); 4.10 -4.19 (m, 3H, H-5 ',4'); 4.24 (dd, 1H, J3,2= 5.1 Hz, J3,4= 2.9 Hz, H-3'); 4.52 (t, 1H, J2-,7= J2,3= 5.7 Hz, H-2'); 6.37 (d, 1H, J7,2= 6.2 Hz, H-l '); 7.24 (d, 1H, J5,6= 3.8 Hz, H-5); 7.68 (dd, 1H, J3= 8.2 Hz, J3,2= 4.2 Hz, H-3-quinolinyl); 8.05 (d, 1H, J6,5= 3.8 Hz, H-6); 8.23 (d, 1H, J&,7= 8.8 Hz, H-8-quinolinyl); 8.60 (dd, 1H, J7:&= 8.8 Hz, J75= 2.0 Hz, H-7-quinolinyl); 8.71 (d, 1H, J43= 8.2 Hz, H-4-quinolinyl); 8.87 (d, 1H, J5,7= 2.0 Hz, H-5-quinolinyl); 8.98 (s, 1H, H-2); 9.03 (bs, 1H, H-2-quinolinyl);31PNMR (202.4 MHz, DMSO-d6): 15.81 and 19.70 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found: 535.0784 ([M - H]“, calcd for C2IH2IO9N4P2“: 535.0789).

[0651] Example 27

[0652] [(5-{[4-(Quinolin-3-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5w)General procedure E starting from bisphosphonate 3 (88.8 mg, 0.20 mmol) gave bisphosphonate 5w (41.3 mg, 38 %) as ayellow powder. 'HNMR (500 MHz, DMSO-d6): 2.28 (t, 2H, JCH2,P= 20.5 Hz, PCH2P); 4.10 - 4.20 (m, 3H, H-5',4'); 4.21 (dd, 1H, J3 2 = 5.1 Hz, J3 4 = 3.0 Hz, H-3'); 4.52 (dd, 1H, J2’p = 6.2 Hz,,3 = 5.1 Hz, H-2'); 6.37 (d, 1H, Ji = 6.2 Hz, H-l '); 7.28 (d, 1H, J5,6= 3.8 Hz, H-5); 7.75 (ddd, 1H, Je,5 = 8.2 Hz, Je,7 = 6.9 Hz, Je,s = 1.2 Hz, H-6-quinolinyl); 7.91 (ddd, 1H, J7is = 8.4 Hz, J e = 6.9 Hz, J75 = 1.5 Hz, H-7-quinolinyl); 8.07 (d, 1H, J6,5= 3.8 Hz, H-); 8.14 (bd, 1H, J8,7= 8.4 Hz, H-8-quinolinyl); 8.30 (dd, 1H, J5fi= 8.2 Hz, J5,7= 1.5 Hz, H-5-quinolinyl); 9.01 (s, 1H, H-2); 9.21 (d, 1H, J42= 2.2 Hz, H-4-quinolinyl); 9.70 (d, 1H, J2,4= 2.2 Hz, H-2-quinolinyl);31PNMR (202.4 MHz, DMSO-d6): 15.73 and 19.82 (2xd, 2xlP, JPP= 8.4 Hz, PCH2P). HR-ESI-MS: found: 535.0786 ([M - H]“, calcd for C2IH2IO9N4P2’: 535.0789).

[0653] Example 28

[0654] [(5-{[4-(Quinazolin-7-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5x)

[0655] General procedure E starting from bisphosphonate 3 (82.1 mg, 0.19 mmol) gave bisphosphonate 5x (28 mg, 28 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.28 (t, 2H, JCH2,P= 20.2 Hz, PCH2P); 4.10 - 4.19 (m, 3H, H-5',4'); 4.24 (

[0656]

[0657] dd, 1H,2= 5.2 Hz, J3 4 = 2.9 Hz, H-3'); 4.52 (

[0658]

[0659] t, 1H, J2-,7- =J= 5.7 Hz, H-2'); 6.37 (d, 1H,,2= 6.2 Hz, H-l '); 7.13 (d, 1H, J5,6= 3.8 Hz, H-5); 8.09 (d, 1H, J6,5= 3.8 Hz, H-6); 8.39 (d, 1H, J3,6 = 8.5 Hz, H-5-quinazolinyl); 8.53 (dd, 1H, Je,5 = 8.5 Hz.. As = 1.7 Hz, H-6-quinazolinyl); 8.70(bd, 1H, J8,6 = 1.6 Hz, H-8-quinazolinyl); 9.03 (s, 1H, H-2); 9.42 (bs, 1H, H-2-quinazolinyl); 9.76 (bs, 1H, H-4-quinazolinyl);31PNMR (202.4 MHz, DMSO-d6): 15.72 and 19.88 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found: 536.0737 ([M - H]“, calcd for C2oH2009N5P2“: 536.0742).

[0660] Example 29

[0661] [(5-{[4-(Isoquinolin-6-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5y)

[0662] General procedure E starting from bisphosphonate 3 (83.1 mg, 0.19 mmol) bisphosphonate 5y (32.3 mg, 32 %) as ayellow powder. ’H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2,P= 20.3 Hz, PCH2P); 4.08 -4.19 (m, 3H, H-5',4'); 4.24 (dd, 1H,

[0663]

[0664] 2= 5.1 Hz,

[0665]

[0666] = 2.8 Hz, H-3'); 4.53 (dd, 1H, J2,7= 6.2 Hz,

[0667]

[0668] J= 5.1 Hz, H-2'); 6.37 (d, 1H, Jr,2= 6.2 Hz, H-l'); 7.21 (d, 1H, Jj 6= 3.8 Hz, H-5); 8.08 (d, 1H, J6J= 3.8 Hz, H-6); 8.20 (d, 1H, J43= 5.8 Hz, H-4-isoquinolinyl); 8.37 (d, 1H, Js,7= 8.6 Hz, H-8-isoquinolinyl); 8.51 (dd, 1H, J7,8 = 8.6 Hz, J s = 1.7 Hz, H-7-isoquinolinyl); 8.63 (d, 1H, J3:4= 5.8 Hz, H-3-isoquinolinyl); 8.84 (bd, 1H, J57 = 1.6 Hz, H-5-isoquinolinyl); 9.00 (s, 1H, H-2); 9.52 (bs, 1H, H-l-isoquinolinyl);31P NMR(202.4 MHz, DMSO-d6): 15.99 and 19.43 (2xbd, 2xlP, JPP= 7.5 Hz, PCH2P). HR-ESI-MS: found-.

[0669] 535.0786 ([M - H]“, calcd for C2IH2IO9N4P2“: 535.0789).

[0670] Example 30

[0671] 4-Chloro-2-methyl-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (7)

[0672] Compound 6 (2.54 g, 5.59 mmol) was treated with 20 mL 75 % TFA according to the general procedure B. HPFC (SiO2, DCM / MeOH 1:0 —> 9:1) gave compound 7 (1.34 g, 80 %) as a white solid. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0673] Example 31

[0674] [(5-{[4-Chloro-2-methyl-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (8)

[0675] General procedure C starting from nucleoside 7 (331.4 mg, 1.11 mmol) gave bisphosphonate 8 (148.6 mg, 29 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2,P= 20.5 Hz, PCH2P); 2.66 (s, 3H, CHs-2); 4.06 - 4.16 (m, 3H, H-4',5'); 4.19 (dd, 1H, J3, = 5.1 Hz, J3-,4- = 2.8 Hz, H-3'); 4.46 (dd, 1H, J2-.i = 6.5 Hz,3= 5.1 Hz, H-2'); 6.21 (d, 1H, Jr,2= 6.5 Hz, H-l ); 6.66 (d, 1H, J5, 6 = 3.8 Hz, H-5); 7.87 (d, 1H, J6,5= 3.8 Hz, H-6);31PNMR (202.4 MHz, DMSO-d6): 15.69 and 19.83 (2xd, 2xlP, JPP= 8.2 Hz, PCH2P). HR-ESI-MS -.found: 456.0130 ([M - H]“, calcd for C13H17O9N3ClP2⁻: 456.0134).

[0676] Example 32

[0677] 2-Methyl-4-(benzofuran-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (9b) General procedure E starting from nucleoside 7 (87.5 mg, 0.29 mmol) gave nucleoside 9b (96.2 mg, 77 %) as a white powder. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0678] Example 33

[0679] 4-(Furan-2-yl)-2-methyl-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (9c)

[0680] General procedure E starting from nucleoside 7 (89.2 mg, 0.30 mmol) gave nucleoside 9c (77.7 mg, 79 %) as a pale-yellow powder.1H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0681] Example 34

[0682] 2-Methyl-4-(naphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (9d)General procedure E starting from nucleoside 7 (95.8 mg, 0.32 mmol) gave nucleoside 9d (94.6 mg, 76 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.76 (s, 3H, CH3); 3.57 (ddd, 1H, Jgem= 11.9 Hz, J5a, OH = 6.0 Hz, = 3.9 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.9 Hz, J5'b,OH= 5.1 Hz, Js= 4.1 Hz, H-5'b); 3.96 (td, 1H, J4’5 a = Jn.s'b = 4.0 H

[0683]

[0684] z, = 2.8 Hz, H-4 ); 4.14 (td, 1H, J,2- = J3,OH= 4.9 H

[0685]

[0686] z, = 2.8 Hz, H-3'); 4.52 (td, 1H, J2',r = J, OH = 6.5 Hz, J2’,3’ = 5.0 Hz, H-2'); 5.31 (t, 1H, J0H,5 a = Jons’b = 5.5 Hz, OH-5'); 5.21 (d, 1H, Jonr = 4.7 Hz, OH-3'); 5.38 (d, 1H, JOH,2' = 6.5 Hz, OH-2'); 6.27 (d, 1H, Ji7= 6.6 Hz, H-l ); 6.33 (d, 1H, J5,6= 3.7 Hz, H-5); 7.50 (ddd, 1H, J7,8= 8.5 Hz, J76= 6.8 Hz, J75= 1.4 Hz, H-7-naphthyl); 7.58 (ddd, 1H, J6,5= 8.2 Hz, J6,7= 6.8 Hz, J6,8= 1.3 Hz, H-6-naphthyl); 7.68 (dd, 1H, J3,4= 8.1 Hz, J3:2= 7.1 Hz, H-3 -naphthyl); 7.73 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.4 Hz, H-2-naphthyl); 7.77 (d, 1H, J6,5= 3.7 Hz, H-6); 8.00 (dm, 1H, J8,7= 8.5 Hz, H- 8 -naphthyl); 8.05 (bd, 1H, J5,6= 8.3 Hz, H-5-naphthyl); 8.10 (bd, 1H, J43= 8.2 Hz, J4,2= J4,5= 1.1 Hz, H-4-naphthyl); HR-ESI-MS: found: 392.1607 ([M + H]+, calcd for C22H22O4N3+: 392.1605); HR-ESI-MS: found: 414.1427 ([M + Na]+, calcd for C22H21O4N3Na+: 414.1424).

[0687] 35

[0688] [(5-{[2-Methyl-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10a)

[0689] General procedure E starting from bisphosphonate 8 (50.7 mg, 0.11 mmol) gave bisphosphonate 10a (47.8 mg, 79 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, d, JCH2,P= 20.4 Hz, PCH2P); 2.79 (s, 3H, CH3); 4.07 - 4.19 (m, 3H, H-4 ',5'); 4.23 (dd, 1H, J3y = 5.1 H

[0690]

[0691] z, = 2.7 Hz, H-3'); 4.52 (dd, 1H, J2‘,r = 6.5 Hz, J2 3= 5.1 Hz, H-2'); 6.34 (d, 1H, J.r = 6.5 Hz, H-l'); 7.12 (d, 1H, J5,6= 3.8 Hz, H-5); 7.58 - 7.66 (m, 2H, H-6,7-naphthyl); 7.93 (d, 1H, J6,s = 3.8 Hz, H-6); 8.02 (m, 1H, H-5 -naphthyl); 8.12 (d, 1H, J43= 8.7 Hz, H-4-naphthyl); 8.19 (m, 1H, H- 8 -naphthyl); 8.29 (dd, 1H, J3,4= 8.7 Hz, J3: I= 1.7 Hz, H-3 -naphthyl); 8.72 (bd, 1H, J,,3= 1.7 Hz, H-l -naphthyl);31P NMR (202.4 MHz, DMSO-d6): 19.73 and 15.78 (2xd, 2xlP, JPP= 7.9 Hz, PCH2P). HR-ESI-MS: found: 548.0989 ([M - H]“, calcd for C23H24O9N3P2-: 548.0993).

[0692] 36

[0693] [(5-{[2-Methyl-4-(benzofuran-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10b)

[0694] General procedure C starting from nucleoside 9b (77.5 mg, 0.20 mmol) gave bisphosphonate 10b (23.9 mg, 22 %) as a yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2, P = 18.1 Hz, PCH2P); 2.74 (s, 3H, CH3); 4.05 -4.18 (m, 3H, H-4', 5'); 4.22 (m, 1H, H-3'); 4.50 (dd, 1H, J2,i = J2',3' = 5.7 Hz, H-2'); 6.30(

[0695]

[0696] d, 1H,2= 6.4 Hz, H-l ); 7.21 (d, 1H,. M = 3.7 Hz, H-5); 7.36 (bt, 1H, J5= e =7.6 Hz, H-5-benzofuryl); 7.47 (bt, 1H, Js,? = 7.8 Hz, H-6-benzofuryl); 7.75 - 7.85 (m, 2H, H-4,7-benzofuryl); 7.85 -8.00 (m, 2H, H-6, H-3-benzofuryl);31PNMR (202.4 MHz, DMSO-d6): 15.78 and 19.73 (2xbd, 2xlP, JPP= 7.8 Hz, PCH2P). HR-ESI-MS: found: 538.0787 ([M - H]“, calcd for C21H22O10N3P2⁻ 538.0786).

[0697] Example 37

[0698] [(5-{[4-(Furan-2-yl)-2-methyl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10c)

[0699] General procedure C starting from nucleoside 9c (69.4 mg, 0.21 mmol) gave bisphosphonate 10c (34.6 mg, 34 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2,P= 20.5 Hz, PCH2P); 2.69 (s, 3H, CH3-2); 4.05 - 4.17 (m, 3H, H-4',5'); 4.20 (dd, 1H, J3-.2- = 5.1 Hz, J3= 2.9 Hz, H-3'); 4.47 (dd, 1H, J2'.i ■ = 6.4 Hz, J2',3' = 5.1 Hz, H-2'); 6.26 (d, 1H,,2= 6.4 Hz, H-l'); 6.79 (dd, 1H, J43= 3.5 Hz, J4.5 =1.7 Hz, H-4-fuiyl); 7.03 (d, 1H, J5,6= 3.8 Hz, H-5); 7.49 (d, 1H, J3,4= 3.5 Hz, H-3-furyl); 7.85 (d, 1H, J6,5 = 3.8 Hz, H-6); 8.07 (bd, 1H, J5,4= 1.3 Hz, H-5-fuiyl);31P NMR (202.4 MHz, DMSO-d6): 15.70 and 19.83 (2xd, 2xlP, JPP= 8.1 Hz, PCH2P). HR-ESI-MS: found: 488.0628 ([M - H]“, calcd for C17H20O10N3P2⁻: 488.0629).

[0700] Example 38

[0701] [(5-{[2-Methyl-4-(naphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10d)

[0702] General procedure C starting from nucleoside 9d (76.4 mg, 0.20 mmol) gave bisphosphonate lOd (36.4 mg, 34 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 2.24 (t, 2H, d, JCH2,P= 20.4 Hz, PCH2P); 2.80 (s, 3H, CH3); 4.07 - 4.17 (m, 3H, H-4',5'); 4.22 (bdd, 1H, J3,2= 5.1 Hz, J5 4 = 2.1 Hz, H-3'); 4.53 (dd, 1H, J2= 6.5 Hz, J2-,3- = 5.1 Hz, H-3'); 6.35 (d, 1H, J2-,r = 6.5 Hz, H-l '); 6.41 (d, 1H, J5:6= 3.7 Hz, H-5); 7.54 (ddd, 1H, J78= 8.6 Hz, J76= 6.8 Hz, J75= 1.4 Hz, H-7-naphthyl); 7.61 (ddd, 1H, J6,5= 8.2 Hz, J6,7= 6.8 Hz, J68=1.3 Hz, H-6-naphthyl); 7.71 (dd, 1H, J3,4= 8.2 Hz, J3,2= 7.1 Hz, H-3 -naphthyl); 7.78 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 7.90 (m, 1H, H-6); 7.98 (bd, 1H, J8,7= 8.6 Hz, H-8-naphthyl); 8.08 (bd, 1H, J5:6= 8.2 Hz, H-5 -naphthyl); 8.16 (d, 1H, J43= 8.2 Hz, H-4-naphthyl);31P NMR (202.4 MHz, DMSO-d6): 19.73 and 15.73 (2xd, 2xlP, JPP= 7.8 Hz, PCH2P). HR-ESI-MS: found: 548.0994 ([M - H]“, calcd for C23H24O9N3P2-: 548.0993).

[0703]

[0704] 39

[0705] [(5-{[2-Methyl-4-(5,6,7,8-tetrahydronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10e)

[0706] General procedure E starting from bisphosphonate 8 (51.3 mg, 0.11 mmol) gave bisphosphonate lOe (51.7 mg, 83 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.65 (m, 2H, H-3-CioHn); 1.76 (m, 2H, H-2-CioHn); 2.24 (t, 2H, JCH2,P= 20.4 Hz, PCH2P); 2.59 (t, 2H, J4,3= 6.4 Hz, H-4-CioHn); 2.85 (t, 2H, Ji,2= 6.4 Hz, H-l-CioHn); 4.05 - 4.16 (m, 3H, H-4',5'); 4.21 (bd, 1H, J, 2 = 5.1 Hz, H-3'); 4.51 (dd, 1H, J2 7= 6.5 Hz, Jr, 3 = 5.1 Hz, H-2'); 6.30 (d, 1H, J, 2 = 6.5 Hz, H-l ); 6.53 (bs, 1H, H-5); 7.21 - 7.33 (m, 3H, H-6,7,8-CioHn); 7.95 (bs, 1H, H-6);31P NMR (202.4 MHz, DMSO-d6): 15.74 and 19.71 (2xd, 2xlP, JPP= 7.6 Hz, PCH2P). HR-ESI-MS: found: 552.1304 ([M - H]“, calcd for C23H28O9N3P2⁻: 552.1306).

[0707]

[0708] 40

[0709] 2-Ammo-4-chloro-7-(P-D-ribofuranosyl)-77 / -pyrrolo[2,3-J]pyrimidine (12)

[0710] Compound 11 (1.58 g, 3.46 mmol) was treated with 20 mL 75 % TFA according to the general procedure B. HPFC (SiO2, DCM / MeOH 1:0 9:1) gave compound 12 (0.77 g, 74 %) as a white solid. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0711] Example 41

[0712] [(5-{[2-Ammo-4-chloro-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (13)

[0713] General procedure C starting from nucleoside 12 (335.3 mg, 1.12 mmol) gave bisphosphonate 13 (204.3 mg, 40 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.21 (t, 2H, JCH2,P= 20.5 Hz, PCH2P); 4.01 (m, 1H, H-4 ); 4.06 (ddd, 1H, Jgem= 15.5 Hz, J5■,? = 6.7 Hz, J5

[0714]

[0715] = 4.4 Hz, H-5'a); 4.12 (ddd, 1H, Jgem= 15.5 Hz, Jn,P= 6.3 Hz, Jn,r = 4.2 Hz, H-5'b); 4.14 (dd, 1H, J 3 2 = 5.1 Hz, J 3 ’,r = 3.1 Hz, H-3 '); 4.38 (dd, 1H, Jr,r = 6.5 Hz, J2,3 = 5.1 Hz, H-2'); 4.40 -5.60 (m, 5H, OH-2',3',5 ', NH2); 5.99 (d, 1H, J7,2= 6.5 Hz, H-l'); 6.36 (d, 1H, J5,6= 3.8 Hz, H-5); 7.37 (d, 1H, J6,5= 3.9 Hz, H-6);31PNMR (202.4 MHz, DMSO-d6): 15.71 and 19.78 (2xd, 2xlP, JPP= 8.1 Hz, PCH2P). HR-ESI-MS: found: 457.0083 ([M - H]“, calcd for Ci2Hi6O9N4P2“: 457.0087).

[0716] Example 42

[0717] 2-Amino-4-(naphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (14a) General procedure E starting from nucleoside 12 (82.2 mg, 0.27 mmol) gave nucleoside 14a (102.7 mg, 96 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 3.54 (ddd, 1H, Jgem= 11.8 Hz, J5a, OH =5.6 Hz, Jw = 4.1 Hz, H-5 'a); 3.62 (ddd, 1H, Jgem= 11.8 Hz, J5 b,OH= 5.5 HZ, JJ M= 4.2 Hz, H-5'b); 3.87 (q, 1H, J4’5 a = J4'5'b = J4',3' = 4.0 Hz, H-4 ); 4.10 (td, 1H, J3-,2■ = J3-,0H= 4.9 H

[0718]

[0719] z, = 3.2 Hz, H-3'); 4.38 (td, 1H, J2',i ■ = J, OH = 6.3 Hz, Jr, = 5.1 Hz, H-2'); 5.02 (t, 1H, JOH.a= JoH.sb = 5.5 Hz, OH-5'); 5.11 (d, 1H, Jon = 4.6 Hz, OH-3'); 5.30 (d, 1H, Jonr = 6.3 Hz, OH-2'); 6.13

[0720]

[0721] (d, 1H,2= 6.4 Hz, H-l ); 6.39 (bs, 2H, NH2); 6.82 (d, 1H, J5,6= 3.9 Hz, H-5); 7.45 (d, 1H, J6,5= 3.9 Hz, H-6); 7.57 - 7.63 (m; 2H, H-6, 7-naphthyl); 8.00 (m, 1H, H-5 -naphthyl); 8.07 (d, 1H, J43=8.6 Hz, H-4-naphthyl); 8.12 (m, 1H, H-8-naphthyl); 8.20 (dd, 1H, J3,4= 8.6 Hz, J3,i = 1.7 Hz, H-3-naphthyl); 8.61 (d, 1H, JIi3= 1.7 Hz, H-l-naphthyl); HR-ESI-MS: found: 393.1556 ([M + H]+, calcd for C21H21O4N4+: 393.1557); HR-ESI-MS: found: 415.1374 ([M +Na]+, calcd for C21H20O4N4Na+: 415.1377).

[0722] Example 43

[0723] 2-Amino-4-(benzofuran-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (14b) General procedure E starting from nucleoside 12 (81.8 mg, 0.27 mmol) gave nucleoside 14b (97.2 mg, 93 %) as a yellow powder. *HNMR (500 MHz, DMSO-d6): 3.54 (btd, 1H, Jgem= 11.8 Hz, J5-a,0H = Js a,4■ = 4.8 Hz, H-5'a); 3.61 (btd, 1H, Jgem= 11.8 Hz, J5-b,oH= Js -b,4 = 4.7 Hz, H-5 'b); 3.87 (td, 1H, J4-,5-fl= J4-5b= 4.1 Hz, Jr,3= 3.3 Hz, H-4'); 4.09 (m, 1H, H-3'); 4.37 (q, 1H, J2,7■=J, OH = J,3 = 5.6 Hz, H-2'); 5.02 (t, 1H, J0H a = Jo S’b = 5.4 Hz, OH-5'); 5.12 (bs, 1H, OH-3'); 5.32 (bd, 1H, J0H,2 = 5.9 Hz, OH-2'); 6.10 (d, 1H, J,2= 6.4 Hz, H-l'); 6.43 (bs, 2H, NH2); 6.96 (d, 1H, J5,6 = 3.8 Hz, H-5); 7.34 (btd, 1H, J5,6= J5,4= 7.5 Hz, J5,7= 1.0 Hz, H-5-benzofuryl); 7.44 (ddd, 1H, J6,7= 8.4 Hz, J6,s = 7.2 Hz, J6,4= 1.4 Hz, H-6-benzofuryl); 7.48 (d, 1H, J6,5= 3.8 Hz, H-6); 7.72 (d, 1H, J3,7= 1.0 Hz, H-3-benzofuiyl); 7.76 (bdq, 1H, J76= 8.4 Hz, J7,5 = J74= J73= 0.9 Hz, H-7-benzofuryl); 7.79 (dm, 1H, J45= 8.0 Hz, H-4-benzofuiyl); HR-ESI-MS: found: 383.1348 ([M + H]+, calcd for C19H19O5N4+: 383.1350); HR-ESI-MS: found: 405.1169 ([M + Na]+, calcd for Ci9Hi8O5N4Na+: 405.1169).

[0724] Example 44

[0725] 2-Amino-4-(naphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (14d)

[0726] General procedure E starting from nucleoside 12 (81.9 mg, 0.27 mmol) gave nucleoside 14d (94.7 mg, 89 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.53 (ddd, 1H, Jgem= 11.8 Hz, J5 a,OH= 5.5 Hz, J5-a,4■ = 4.1 Hz, H-5'a); 3.60 (ddd, 1H, Jgem= 11.8 Hz, J5 b,0H= 5.4 Hz, J5-b,4= 4.2 Hz, H-5'b); 3.88 (td, 1H, J4-,5-a= J4',5'b = 4.1 Hz, J4',3' = 3.1 Hz, H-4'); 4.08 (td, 1H, J3,2= J3',0H= 4.8 Hz, J3= 3.1 Hz, H-3'); 4.39 (td, 1H, J2-,! ■ = J2-, OH = 6.4 Hz, Jr, = 5.1 Hz, H-2'); 5.00 (t, 1H, J0H,5 « = Jons -b= 5.5 Hz, OH-5'); 5.11 (d, 1H, JOH,3= 4.6 Hz, OH-3'); 5.31 (d, 1H, JOH,2= 6.3 Hz, OH-2'); 6.04 (d, 1H, J5,6 = 3.8 Hz, H-5); 6.13 (d, 1H, Jr,r = 6.5 Hz, H-l'); 6.41 (s, 2H, NH2); 7.32 (d, 1H, J6,5= 3.8 Hz, H-6); 7.49 (ddd, 1H, J78= 8.3 Hz,J76= 6.8 Hz, J75= 1.5 Hz, H-7-naphthyl); 7.56 (ddd, 1H, A.s = 8.1 Hz, J6,7= 6.8 Hz, A.s = 1.3 Hz, H-6-naphthyl); 7.62 - 7.68 (m, 2H, H-2,3-naphthyl); 8.02 (dm, 1H, J8,7= 8.1 Hz, H-5-naphthyl); 8.04 (bd, 1H, J4,5 = 8.3 Hz, H-8-naphthyl); 8.05 (bd, 1H, J43= 7.4 Hz, H-4-naphthyl); HR-ESI-MS: found: 393.1556 ([M + H]+, calcd for C21H21O4N4+: 393.1557); HR-ESI-MS: found-. 415.1375 ([M + Na]+, calcd for C21H20O4N4Na+: 415.1377).

[0727] Example 45

[0728] 2-Amino-4-(5,6,7,8-tetrahydronaphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (14e)

[0729] General procedure E starting from nucleoside 12 (85.8 mg, 0.29 mmol) gave nucleoside 14e (79.1 mg, 70 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.65 (m, 2H, H-3-CioHn); 1.73 (m, 2H, H-2-CioHn); 2.64 (t, 2H, J43= 6.4 Hz, H-4-CioHn); 2.81 (t, 2H, J2= 6.4 Hz, H-l-CioHn); 3.51 (ddd, 1H,. A™, = 11.8 Hz, Jj a, off = 5.6 Hz,

[0730]

[0731] a,4= 4.1 Hz, H-5'a); 3.58 (ddd, 1H, Jgem= 11.8 Hz, J5-0H= 5.4 Hz, J5 M■ = 4.2 Hz, H-5'a); 3.86 (td, 1H, J4-5-a= J4-,5-b= 4.1 Hz, J4-3- = 3.0 Hz, H-4 ); 4.07 (td, 1H, J3-,2■ = J3-OH= 4.8 Hz, J.4 = 3.0 Hz, H-3'); 4.37 (td, 1H, A'.r = J2-,OH= 6.4 Hz, J2-,3- = 5.1 Hz, H-2'); 5.00 (t, 1H, JOH. S = JoH,5-b = 5.5 Hz, OH-5'); 5.08 (d, 1H, J0H,3- = 4.5 Hz, OH-3'); 5.28 (d, 1H, J0H,2- = 6.3 Hz, OH-2'); 6.066 (d, 1H, A.e = 3.8 Hz, H-5); 6.070 (d, 1H, J7-,2- = 6.5 Hz, H-l '); 6.27 (bs, 2H, NH2); 7.11 (dd, 1H, J6:7= 12 Hz, s = 1.8 Hz, H-6-CioHn); 7.15 (bdd, 1H, J8,7= 7.7 Hz, J86= 1.8 Hz, H-8-CioHn); 7.19 (t, 1H, A.s = J6= 7.5 Hz, H-7-CioHn); 7.28 (d, 1H, J6,5= 3.8 Hz, H-6); HR-ESI-MS -.found: 395.1728 ([M + H]+, calcd for C21H23O4N4+: 395.1725).

[0732] Example 46

[0733] [(5-{[2-Amino-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15a)

[0734] General procedure C starting from nucleoside 14a (76.6 mg, 0.20 mmol) gave bisphosphonate 15a (15 mg, 14 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.23 (t, 2H, d, JCH2,P= 20.2 Hz, PCH2P); 4.04 (m, 1H, H-4'); 4.03 - 4.16 (m, 2H, H-5'); 4.19 (bdd, 1H, J3-,2- = 4.8 Hz, J3-,4- = 2.8 Hz, H-3'); 4.46 (t, 1H, J2-,3- =J2-.i = 5.8 Hz, H-3'); 6.14 (d, 1H, J2-b= 6.5 Hz, H-l'); 6.84 (d, 1H, A,<> = 3.9 Hz, H-5); 7.51 (d, 1H, J6,5 = 3.9 Hz, H-6); 7.58 - 7.64 (m, 2H, H-6,7-naphthyl); 8.01 (m, 1H, H-5 -naphthyl); 8.09 (d, 1H, J43= 8.6 Hz, H-4-naphthyl); 8.11 - 8.20 (m, 1H, H-3,8-naphthyl); 8.61 (bs, 1H, H-l -naphthyl);31PNMR (202.4 MHz, DMSO-d6): 19.14 and 16.11 (2xs, 2xlP, PCH2P). HR-ESI-MS -.found: 549.0940 ([M - H]“, calcd for C22H23O9N4P2⁻: 549.0946).Example 47

[0735] [(5-{[2-Amino-4-(benzofuran-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15b)

[0736] General procedure C starting from nucleoside 14b (78.3 mg, 0.21 mmol) gave bisphosphonate 15b (9.8 mg, 9 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2.p = 20.3 Hz, PCH2P); 4.03 (m, IH, H-4 ); 4.03 - 4.18 (m, 2H, H-5'); 4.18 (dd, 1H,,2= 4.9 Hz,

[0737]

[0738] = 3.0 Hz, H-3'); 4.44 (dd, 1H, J2’,r = J, 3 = 5.8 Hz, H-2'); 6.11 (d, 1H, Jr,2= 6.5 Hz, H-l ); 6.98 (d, 1H, J5,6 = 3.8 Hz, H-5); 7.35 (btd, 1H, Ji, 4 = Ji, 6 =7.5 Hz, Js, 7 = 0.9 Hz, H-5 -benzofuryl); 7.45 (ddd, 1H, J6,7= 8.3 Hz, J6,5=7.2 Hz, J6,4= 1.3 Hz, H-6-benzofuryl); 7.51 (d, 1H, J6,5= 3.8 Hz, H-6). 7.76 (bs, 1H, H-3-benzofuryl); 7.77 (bd, 1H, J7,6= 8.3 Hz, H-7-benzofuryl); 7.80 (bd, 1H, J45= 7.8 Hz, H-4-benzofuryl);31PNMR (202.4 MHz, DMSO-d6): 15.89 and 19.53 (2xs, 2xlP, PCH2P). HR-ESI-MS: found: 539.0736 ([M - H]“, calcd for C2OH2IOION4P2“: 539.0738).

[0739] Example 48

[0740] [(5-{[2-Amino-4-(furan-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15c)

[0741] General procedure E starting from bisphosphonate 13 (53.6 mg, 0.12 mmol) gave bisphosphonate 15c (5.7 mg, 10 %) as a yellow powder.XH NMR (500 MHz, DMSO-d6): 2.23 (t, 2H, JCH2,p = 20.3 Hz, PCH2P); 4.01 (

[0742]

[0743] bq, 1H, = J4,5 „ = J4',s'b = 3.9 Hz, H-4'); 4.05 (dm, 1H, Jgem= 11.1 Hz, H-5'a); 4.12 (dm, 1H, Jgem= II.1 Hz, H-5'b); 4.16 (dd, 1H, J3,2= 5.1 Hz, J3= 3.0 Hz, H-3'); 4.41 (dd, 1H, J2 7= 6.4 Hz, Jr,3= 5.1 Hz, H-2'); 6.07 (d, 1H,,2= 6.4 Hz, H-l'); 6.76 (dd, 1H, J43= 3.6 Hz, J45=1.7 Hz, H-4-furyl); 6.81 (d, 1H, J5,6= 3.8 Hz, H-5); 7.35 (m, 1H, H-3-fuiyl); 7.44 (d, 1H, J6,5= 3.8 Hz, H-6); 8.02 (bd, 1H, J5,4= 1.7 Hz, H-5-furyl);31P NMR (202.4 MHz, DMSO-d6): 15.96 and 19.40 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found: 489.0579 ([M - H]“, calcd for Ci6Hi9OioN4P2’: 489.0582).

[0744] Example 49

[0745] [(5-{[2-Amino-4-(naphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15d)

[0746] General procedure C starting from nucleoside 14d (75.0 mg, 0.19 mmol) gave bisphosphonate 15d (33.8 mg, 32 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-de): 2.21 (t, 2H, d, JCH2,P= 20.3 Hz, PCH2P); 4.02 - 4.14 (m, 3H, H-4', 5'); 4.18 (dd, 1H, J3= 5.1 Hz,

[0747]

[0748] = 2.6 Hz, H-3 '); 4.46 (dd, 1H, J2= 6.6 Hz, J2„r= 5.1 Hz, H-3 '); 6.12 (d, 1H, J5,6= 3.9 Hz, H-5); 6.13 (d,

[0749]

[0750] 1H,7= 6.6 Hz, H-l '); 7.47 (d, 1H, J6,5= 3.9 Hz, H-6); 7.54 (ddd, 1H, J7.s = 8.3 Hz, J7.6= 6.8 Hz, J7,5= 1.5 Hz, H-7-naphthyl); 7.60 (ddd,

[0751]

[0752] 1H, = 8.2 Hz, J6,7= 6.8 Hz, J6,s= 1.3 Hz, H-6-naphthyl); 7.68 (dd, 1H, J3,4= 8.2 Hz, 7.1 Hz, H-3-naphthyl); 7.74 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 8.01 (d, 1H, J8,7= 8.4 Hz, H-8-naphthyl); 8.06 (bd, 1H, J5,6= 8.2 Hz, H-5 -naphthyl); 8.13 (d, 1H, J4,3= 8.2 Hz, H-4-naphthyl);31P NMR (202.4 MHz, DMSO-d6): 19.24 and 16.01 (2xs, 2xlP, PCH2P). HR-ESI-MS: found: 549.0941 ([M - H]“, calcd for C22H23O9N4P2⁻: 549.0946).

[0753] Example 50

[0754] [(5-{[2-Amino-4-(5,6,7,8-tetrahydronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / LD-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15e)

[0755] General procedure C starting from nucleoside 14e (68.3 mg, 0.17 mmol) gave bisphosphonate 15e (38.3 mg, 40 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.66 (m, 2H, H-3-CioHn); 1.74 (m, 2H, H-2-CioHn); 2.19 (t, 2H, JCH P = 20.2 Hz, PCH2P); 2.63 (t, 2H, J4,3= 6.3 Hz, H-4-CioHn); 2.83 (t, 2H, Ji,2= 6.3 Hz, H-l-CioHn); 4.00 - 4.11 (m, 3H, H-4,5); 4.16 (dd,

[0756]

[0757] 1H,2= 5.1 Hz, J3 4 = 2.5 Hz, H-3'); 4.45 (dd, 1H, J2,! = 6.6 Hz, J2,3= 5.1 Hz, H-2'); 6.07 (d, 1H,,2= 6.6 Hz, H-l ); 6.19 (d, 1H, J5,6 = 3.8 Hz, H-5); 7.18 - 7.28 (m, 3H, H-6,7,8-CioHn); 7.48 (bd, 1H, J6,5= 3.6 Hz, H-6);31PNMR (202.4 MHz, DMSO-d6): 16.19 and 18.88 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found 553.1261 ([M - H]“, calcd for C22H27O9N4P2-: 553.1259).

[0758] Example 51

[0759] 2,4-Dichloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (16)

[0760] 1) A solution of compound 11 (3.84 g, 1.31 mmol) in 130 mL DCM was treated with TMS-C1 (9.6 mL, 75.94 mmol) dropwise under argon, followed by the addition of TBN (20.1 mL, 168.75 mmol). The mixture was stirred for 1 h at rt, treated with aq. NaHCOs and extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, evaporated. HPFC (SiO2, cHex / EtOAc 1:0 — 5.7:1) gave protected 2,6-dichloro nucleoside (1.81 g, 45 %) as a yellowish oil. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093). 2) Protected 2,6-dichloro nucleoside (1.48 g, 3.13 mmol) was treated with 20 mL 75 % TFA according to the general procedure B. HPFC (SiO2, DCM / MeOH 1:0 — 9:1) gave compound 16 (1.00 g, 91 %) as a white solid. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079- 1093).

[0761] Example 52

[0762] 2-Chloro-4-(naphthalen-2-yl)-7-( / LD-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (17a)General procedure D starting from nucleoside 16 (81.1 mg, 0.25 mmol) gave nucleoside 17a (90.8 mg, 87 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.8 Hz, J5a, OH = 5.5 Hz, J5 a,4 = 3.9 Hz, H-5 'a); 3.66 (ddd, 1H, Jgem= 11.8 Hz, J5^. OH = 5.5 Hz, Jw= 4.1 Hz, H-5'b); 3.97 (q, 1H, J4',5 a = Jn.i'b=J4',3' = 3.9 Hz, H-4'); 4.14 (td, 1H, J3,2■ = J3,OH= 5.0 H

[0763]

[0764] z, = 3.1 Hz, H-3'); 4.46 (td, 1H, J,r = J2', OH = 6.3 Hz, J2, 3 = 5.0 Hz, H-2'); 5.07 (t, 1H, Jon.sa = JoH.s'b = 5.5 Hz, OH-5'); 5.25 (d, 1H, JOH,3' = 4.9 Hz, OH-3'); 5.46 (d, 1H, Jonr = 6.3 Hz, OH-2'); 6.22 (d, 1H,,2= 6.2 Hz, H-l '); 7.27 (d, 1H, J5,6= 3.9 Hz, H-5); 7.63 (m; 1H, H-7-naphthyl); 7.66 (m, 1H, H-6-naphthyl); 8.04 (m, 1H, H-5 -naphthyl); 8.06 (d, 1H, J65= 3.9 Hz, H-6); 8.14 (d, 1H, J4,3=8.6 Hz, H-4-naphthyl); 8.22 (m, 1H, H-8-naphthyl); 8.27 (dd, 1H, J34= 8.6 Hz, J3I= 1.8 Hz, H-3 -naphthyl); 8.77 (d, 1H, J = 1.8 Hz, H-l -naphthyl); HR-ESI-MS: found: 412.1057 ([M + H]+, calcd for C21H19O4N3CE: 412.1059); HR-ESI-MS: / OMM d: 434.0876 ([M + Na]+, calcd for C2iHi8O4N3ClNa+: 434.0878).

[0765] Example 53

[0766] 2-Chloro-4-(benzofuran-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo-[2,3-< / ]pyrimidine (17b) General procedure D starting from nucleoside 16 (74.3 mg, 0.23 mmol) gave nucleoside 17b (70.4 mg, 76 %) as a pale-yellow solid. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0767] Example 54

[0768] 2-Chloro-4-(furan-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17c)

[0769] General procedure D starting from nucleoside 16 (134 mg, 0.42 mmol) gave nucleoside 17c (123 mg, 84 %) as a white solid.1H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0770] Example 55

[0771] 2-Chloro-4-(naphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (17d)

[0772] General procedure D starting from nucleoside 16 (81.8 mg, 0.26 mmol) gave nucleoside 17d (92.8 mg, 88 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.4 Hz, J5 a,4= 3.9 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.9 Hz, J5’b, OH = 5.4 Hz, J5

[0773] = 4.1 Hz, H-5'b); 3.97 (q, 1H, J4',s « = J4',5'b =J4',3' = 3.9 Hz, H-4'); 4.13 (td, 1H, J3,2= J3,OH= 5.0 Hz, ^,4 = 2.9 Hz, H-3'); 4.47 (td, 1H, J.r = J, OH = 6.4 Hz, J2’,3’ = 5.0 Hz, H-2'); 5.05 (t, 1H, Jon.sa = Jons’b = 5.3 Hz, OH-5'); 5.27 (d, 1H, JOH,3’ = 4.9 Hz, OH-3'); 5.47 (d, 1H, Jonr = 6.4 Hz, OH-2'); 6.23 (d, 1H, J,r = 6.4 Hz, H-l '); 6.49 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 (ddd, 1H, J78= 8.5 Hz, J76= 6.8 Hz, J75= 1.5 Hz, H-7-naphthyl); 7.61 (ddd, 1H, J6,5= 8.2 Hz, J6,7= 6.8 Hz, J6,8= 1.3 Hz, H-6-naphthyl); 7.70 (dd, 1H, J3,4= 8.2 Hz, J3,2= 7.1 Hz, H-3 -naphthyl); 7.79 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 7.95 (d, 1H, J6,5= 3.8 Hz, H-6); 8.01 (bd, 1H, Js,7= 8.5 Hz, H-8-naphthyl); 8.08 (bd, 1H, J45= 8.3 Hz, H-5-naphthyl); 8.16 (bd, 1H, J43= 8.2 Hz, H-4-naphthyl); HR-ESI-MS: faun d. 412.1059 ([M + H]+, calcd for C2IHI9O4N3C1+: 412.1059); HR-ESI-MS: found 434.0879 ([M +Na]+, calcd for C2iHi8O4N3ClNa+: 434.0878).

[0774] Example 56

[0775] 2-Chloro-4-(5,6,7,8-tetrahydronaphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17e)

[0776] General procedure D starting from nucleoside 16 (91.8 mg, 0.29 mmol) gave nucleoside 17e (90.2 mg, 76 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 1.65 (m, 2H, H-3-CioHn); 1.75 (m, 2H, H-2- CioHn); 2.64 (t, 2H, J43= 6.4 Hz, H-4-CioHn); 2.84 (t, 2H, fa2= 6.4 Hz, H-l-CioHn); 3.56 (ddd, 1H,. A™, = 11.8 Hz, faa,oa = 5.4 Hz, = 3.9 Hz, H-5 'a); 3.63 (ddd, 1H, Jgem= 11.8 Hz, fab,OH= 5.4 Hz, fab,4- = 4.2 Hz, H-5'a); 3.95 (td, 1H, J4-,5-fl= fa,5-b= 4.0 Hz, = 2.8 Hz, H-4 ); 4.12 (td, 1H, = FA, OH = 4.9 H

[0777]

[0778] z, = 2.8 Hz, H-3'); 4.45 (td, 1H, = fa,0H= 6.4 Hz, J2-,r= 5.0 Hz, H-2'); 5.04 (t, 1H, fans « = Jou5'b= 5.4 Hz, OH-5'); 5.25 (d, 1H, J0H,3■ = 4.8 Hz, OH-3'); 5.44 (d, 1H, J0H,2= 6.4 Hz, OH-2'); 6.17 (d, 1H,,2 = 6.4 Hz, H-l '); 6.50 (d, 1H, J5,6= 3.8 Hz, H-5); 7.21 - 7.30 (m, 3H, H-6,7,8-Ci0Hn); 7.91 (d, 1H, J6,5 = 3.8 Hz, H-6); HR-ESI-MS: faun d 416.1371 ([M + H]+, calcd for C2IH23O4N3C1+: 416.1372); HR- ESI-MS -.found. 438.1190 ([M +Na]+, calcd for C2iH22O4N3ClNa+: 438.1191).

[0779] Example 57

[0780] 2-Chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (17f)

[0781] General procedure D starting from nucleoside 16 (83.5 mg, 0.26 mmol) gave nucleoside 4f 17f (65.0 mg, 60 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 1.74 - 1.82 (m, 4H, H-2,3-CioHn); 2.81 and 2.86 (2xm, 2x2H, H-l,4-CioHn); 3.57 (ddd, 1H, Jgem= 11.9 Hz, faa,0H= 5.5 Hz, faa,4- = 3.9 Hz, H-5'a); 3.64 (ddd, 1H, Jgem= 11.9 Hz, J5-b,0H= 5.4 Hz, J5-b,4- = 4.1 Hz, H-5'a); 3.95 (q, 1H, fa,5-a= fa,5-b= fa,3- = 3.9 Hz, H-4'); 4.12 (td, 1H, fa,2• = fa,OH= 5.0 Hz, J3,4= 3.0 Hz, H-3'); 4.43 (td, 1H, fa,b• = fa,OH= 6.3 Hz, fa,3- = 5.0 Hz, H-2'); 5.06 (m, 1H, OH-5'); 5.24 (d, 1H, OH-3'); 5.43 (bd, 1H, JOH. = 6.4 Hz, OH-2'); 6.17 (d, 1H, J7,2= 6.2 Hz, H-l '); 7.06 (d, 1H, fa6= 3.9 Hz, H-5); 7.28 (d, 1H, Js,7= 8.0 Hz, H-8-CioHn); 7.83 (bs, 1H, H-5-CioHn); 7.85 (dd, 1H, J7S= 8.0 Hz, J7,5= 2.0 Hz, H-7-CioHn); 7.97 (d, 1H, J6,5= 3.9 Hz, H- 6); HR-ESI-MS: faun d. 416.1371 ([M + H]+, calcd for C2IH23O4N3C1+: 416.1372); HR-ESI-MS: found.

[0782] 438.1189 ([M + Na]+, calcd for C2iH22O4N3ClNa+: 438.1191 ).Example 58

[0783] 2-Chloro-4-( / er / -butoxycarbonyl)amino)methyl)phenyl)-7-(jff-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidiiie (17g)

[0784] General procedure D starting from nucleoside 16 (82.9 mg, 0.26 mmol) gave nucleoside 17g (76.9 mg, 69 %) as a white powder.1HNMR(500 MHz, DMSO-d6): 1.41 (s,9H, (CH3)3C); 3.57 (ddd, lH, Jgem= 11.8 Hz, J5a, OH = 5.4 Hz,

[0785]

[0786] = 3.9 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.8 Hz, J. OH = 5.4 Hz, J5

[0787]

[0788] = 4.1 Hz, H-5'b); 3.95 (q, 1H, J4.5 a = J4,5 ’b = J4',3' = 3.9 Hz, H-4 ); 4.12 (td, 1H, J3,2=J3, OH = 4.9 Hz, J3y = 3.0 Hz, H-3'); 4.20 - 4.27 (m, 2H, CH2-Ph); 4.43 (td, 1H, J2’.r = J2’, OH = 6.2 H

[0789]

[0790] z, = 4.9 Hz, H-2'); 5.05 (t, 1H, Jo 5 a = JoH b = 5.4 Hz, OH-5'); 5.24 (d, 1H, JOH,3' = 4.9 Hz, OH-3'); 5.44 (d, 1H, JOH,2' = 6.3 Hz, OH-2'); 6.18 (d, 1H, Jv,r = 6.2 Hz, H-l ); 7.09 (d, 1H, J5,6= 3.9 Hz, H-5); 7.46 (m; 2H, H-w-Ph); 7.51 (bt, 1H, JN CH2= 6.2 Hz, NH); 7.99 (d, 1H, J6,5= 3.9 Hz, H-6); 8.12 (m, 2H, H-o-Ph); HR-ESI-MS: / OMM: 491.1697 ([M + H]+, calcd for C23H28O6N4C1+: 491.1692); HR-ESI-MS: found. 513.1516 ([M + Na]+, calcd for C23H27O6N4ClNa+: 513.1511).

[0791] Example 59

[0792] 2-Chloro-4-(17 / -indol-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17h)

[0793] General procedure D starting from nucleoside 16 (82.3 mg, 0.26 mmol) gave nucleoside 17h (48 mg, 95 %) as a pale-yellow powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, (m, 3H, Jgem= 11.8 Hz, J5 a,OH= 5.4 Hz, = 3.9 Hz, H-5 'a); 3.66 (dd, 1H, Jgem= 11.8 Hz, J5 b, OH = 5.5 Hz,M= 4.1 Hz, H-5'b); 3.95 (q, 1H, J4’5= J4',5'b= J4'3’ = 3.9 Hz, H-4'); 4.13 (td, 1H, J3,2■ = J3'0H= 4.9 H

[0794]

[0795] z, = 3.0 Hz, H-3'); 4.44 (td, 1H, J2,7= J2'OH = 6.3 Hz, J2,5 = 4.9 Hz, H-2'); 5.07 (t, 1H, JOH. S « = JOH. S 'b = 5.4 Hz, OH-5'); 5.24 (d, 1H, Jons' = 4.9 Hz, OH-3'); 5.44 (d, 1H, JOH,2' = 6.3 Hz, OH-2'); 6.17 (d

[0796]

[0797] , 1H,2= 6.3 Hz, H-l'); 7.08 (ddd, 1H, J5:4= 8.0 Hz, J34= 6.9 Hz, J5,7= 1.0 Hz, H-5-indolyl); 7.24 (ddd, 1H, J6,7= 8.3 Hz, J6,5= 6.9 Hz, J6:4= 1.2 Hz, H-6-indolyl); 7.31 (d, 1H, J5:6= 3.8 Hz, H-5); 7.58 (bdq, 1H, J76= 8.3 Hz, J75= J74= J73= 1.0 Hz, H-7-indolyl); 7.65 (bd, 1H, J3,NH= 2.3 Hz, J3,7= 0.9 Hz, H-3-indolyl); 7.68 (bdq, 1H, J45= 8.0 Hz, J46= J4,7 = J3= 1.0 Hz, H-4-indolyl); 8.00 (d, 1H, J6,5= 3.8 Hz, H-6); 11.86 (d, 1H, JNH,3= 2.0 Hz, NH); HR-ESI-MS: found. 401.1012 ([M + H]+, calcd for CI9HI8O4N4C1+: 401.1011); HR-ESI-MS: found.

[0798] 423.0832 ([M + Na]+, calcd for Ci9Hi7O4N4ClNa+: 423.0831).

[0799] Example 60

[0800] 2-Chloro-4-(6-fluoronaphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (17i) General procedure D starting from nucleoside 16 (80.4 mg, 0.25 mmol) gave nucleoside 17i (82.7 mg, 77 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.3 Hz,J5a.4' = 4.0 Hz, H-5 'a); 3.67 (ddd, 1H, Jgem= 11.9 Hz, Jn 0H= 5.4 Hz, J5 F4- = 4.1 Hz, H-5 'b); 3.97 (q, 1H, J4',5 a = J4',5'b =J4',3' = 3.8 Hz, H-4'); 4.14 (td, 1H, J3-,2■ = J3-,OH= 4.9 Hz, J3-,4- = 3.1 Hz, H-3'); 4.46 (td, 1H, J2-, I =J2-, OH = 6, J2,3= 4.9 Hz, H-2'); 5.07 (t, 1H, Jon.sa = JoH.s'b = 5.4 Hz, OH-5'); 5.26 (d, 1H, J0H,3- = 4.9 Hz, OH-3'); 5.46 (d, 1H, J<!n F= 6.3 Hz, OH-2'); 6.21 (d, 1H, ',2' = 6.2 Hz, H-l '); 7.28 (d, 1H, J5,6= 3.9 Hz, H-5); 7.56 (td; 1H, J78= J7F= 8.9 Hz, J75= 2.6 Hz, H-7-naphthyl); 7.85 (dd, 1H, J5,F= 10.2 Hz, J5,7= 2.6 Hz, H-5-naphthyl); 8.06 (d, 1H, J6F= 3.9 Hz, H-6); 8.13 (d, 1H, J4,3=8.7 Hz, H-4-naphthyl); 8.32 (dd, 1H, J34= 8.7 Hz, J3,i = 1.8 Hz, H-3 -naphthyl); 8.34 (dd, 1H, J8,7= 9.1 Hz, J8,F= 5.9 Hz, H-8-naphthyl); 8.82 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl);19F NMR (470.4 MHz, DMSO-d6): -107.51 (td, IF, JF5=JF7= 9.4 Hz, JF8= 5.9 Hz, F-6). HR-ESI-MS

[0801]

[0802] 430.0963 ([M + H]+, calcdfor C2iHi8O4N3ClF+: 430.0964); HR-ESI-MS: found-. 452.0781 ([M + Na]+, calcd for C2iHi7O4N3ClFNa+: 452.0784).

[0803] Example 61

[0804] 4-(4-Bromo-l-fhioronaphthalen-2-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17j)

[0805] General procedure D starting from nucleoside 16 (81.0 mg, 0.25 mmol) gave nucleoside 17j (79.9 mg, 62 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.5 Hz, J5-a,4= 3.9 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.9 Hz, J5 FOH = 5.4 Hz, J5 F4= 4.1 Hz, H-5'b); 3.97 (q, 1H, J4-.5 -a = J4-,5-b =J4-.3- = 3.9 Hz, H-4'); 4.13 (td, 1H, J3-,2= J< on = 4.9 Hz, J3-,4- = 2.9 Hz, H-3'); 4.46 (td, 1H, = J -. OH = 6.4 Hz, J2-.3- = 4.9 Hz, H-2'); 5.04 (t, 1H, JOH.a= Jou.s-b = 5.4 Hz, OH-5'); 5.27 (d, 1H, JOH.3-= 4.9 Hz, OH-3'); 5.48 (d, 1H, J0H,2- = 6.4 Hz, OH-2'); 6.21 (d, 1H, Ji -2- = 6.4 Hz, H-l'); 6.83 (bt, 1H, J5,6= A, = 4.3 Hz, H-5); 7.89 (ddd; 1H, J78= 8.3 Hz, J76= 6.9 Hz, J75= 1.0 Hz, H-7-naphthyl); 7.94 (ddd, 1H, J6F= 8.5 Hz, J6:7= 6.9 Hz, J6.s = 1.3 Hz, H-6-naphthyl); 8.03 (d, 1H, J6F= 3.9 Hz, H-6); 8.21 (d, 1H, J3,F= 6.4 Hz, H-3 -naphthyl); 8.26 (bd, 1H, J5,6= 8.4 Hz, H-5 -naphthyl); 8.31 (bd, 1H, J8,7= 8.1 Hz, H-8-naphthyl);19FNMR (470.4 MHz, DMSO-d6): -116.99 (bt, IF, JF5=JF3= 5.5 Hz, F-l). HR-ESI-MS: foun d-.

[0806] 508.0071 ([M + H]+, calcd for C2iHi7O4N3BrClF+: 508.0070); HR-ESI-MS -.foun d-. 529.9891 ([M +Na]+, calcd for C2iHi6O4N3BrClFNa+: 529.9889).

[0807] Example 62

[0808] 2-Chloro-4-(6-chloronaphthalen-2-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17k)

[0809] General procedure D starting from nucleoside 16 (79.5 mg, 0.25 mmol) gave nucleoside 17k (81.6 mg, 74 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, J,,m= 11.8 Hz, A «, OF = 5.4 Hz, A = 4.0 Hz, H-5 'a); 3.67 (ddd, 1H, Jgem= 11.8 Hz, J5 FOH = 5.4 Hz, A M = 4.1 Hz, H-5 'b); 3.97 (q, 1H,J4’5 a = J4’5’b =J4',3' = 3. HZ, H-4'); 4.14 (td, 1H, J3,2■ = J3, OH= 5.0 Hz, j, 4 = 3.1 Hz, H-3'); 4.46 (td, 1H, Jrr = Jr, OH = 6.3 H

[0810]

[0811] z,J= 5.0 Hz, H-2'); 5.07 (t, 1H, JOH.a= JoH.s’b = 5.4 Hz, OH-5'); 5.26 (d, 1H, Jon < = 4.9 Hz, OH-3'); 5.46 (d, 1H, J0H,2- = 6.3 Hz, OH-2'); 6.21 (d, 1H, Ji2= 6.2 Hz, H-l '); 7.28 (d, 1H, J5,6= 3.9 Hz, H-5); 7.65 (dd; 1H, J78= 8.8 Hz, J7,5= 2.2 Hz, H-7-naphthyl); 8.07 (d, 1H, J6,s = 3.9 Hz, H-6); 8.13 (d, 1H, J4,3 =8.7 Hz, H-4-naphthyl); 8.18 (d, 1H, J5,7= 2.2 Hz, H-5-naphthyl); 8.28 (d, 1H, J8,7= 8.9 Hz, H-8-naphthyl); 8.33 (dd, 1H, J3,4= 8.6 Hz, J3,i = 1.8 Hz, H-3 -naphthyl); 8.81 (bd, 1H, JI:3= 1.8 Hz, H- 1 -naphthyl); HR-ESI-MS: / OMM: 446.0666 ([M + H]+, calcd for C2IHI8O4N3C12+: 446.0669); HR-ESI-MS: found-. 468.0488 ([M +Na]+, calcd for C2iHi7O4N3Cl2Na+: 468.0488).

[0812] Example 63

[0813] 2-Chloro-4-(4-fluoronaphth-l-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (171) General procedure D starting from nucleoside 16 (81.6 mg, 0.26 mmol) gave nucleoside 171 (85.1 mg, 78 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.57 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.3 Hz, J5-a,4= 4.0 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.9 Hz, J5-b, OH = 5.3 Hz, Js-b,4 = 4.1 Hz, H-5 'b); 3.97 (td, 1H, J4-.5 -a = J4-,5-b = 4.0 Hz, J4-,3- = 3.0 Hz, H-4'); 4.13 (td, 1H, J3-2- = J3-, OH = 4.9 Hz, J3-,4- = 3.0 Hz, H-3'); 4.46 (td, 1H, J2'r = Jr, OH = 6.3 Hz, Jr,3' = 4.9 Hz, H-2'); 5.05 (t, 1H, J0H,5 « = Jons -b = 5.3 Hz, OH-5'); 5.28 (d, 1H, JOHS- = 4.9 Hz, OH-3'); 5.47 (d, 1H, J0H,2- = 6.3 Hz, OH-2'); 6.22 (d

[0814]

[0815] , 1H,2= 6.3 Hz, H-l'); 6.52 (d, 1H, J5,6= 3.8 Hz, H-5); 7.54 (dd; 1H, J3, F = 10.4 Hz, J3,2= 8.0 Hz, H-3 -naphthyl); 7.67 (ddd, 1H, J78= 8.6 Hz, J76= 6.8 Hz, J75= 1.4 Hz, H-7- naphthyl); 7.73 (ddd, 1H, J6,5= 8.4 Hz, J6,7= 6.8 Hz, J6,8= 1.2 Hz, H-6-naphthyl); 7.82 (dd, 1H, J2,3 = 8.0 Hz, J2, F = 5.5 Hz, H-2 -naphthyl); 7.96 (d, 1H, J6,5= 3.8 Hz, H-6); 8.11 (dm, 1H, J87= 8.6 Hz, H-8-naphthyl); 8.20 (bd, 1H, J5,6= 8.4 Hz, H-5-naphthyl);19F NMR (470.4 MHz, DMSO-d6): -115.67 (ddd, IF, JF,3 = 10.4 Hz, JF,2= 5.5 Hz, J73= 2.0 Hz, F-4). HR-ESI-MS: found-.

[0816] 430.0964 ([M + H]+, calcd for C2IHI8O4N3C1F+: 430.0964); HR-ESI-MS: faun d-. 452.0783 ([M + Na]+, calcd for C2iHi7O4N3ClFNa+: 452.0784).

[0817] Example 64

[0818] 2-Chloro-4-(6-(methoxycarbonyl)naphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3- < / ]pyrimidme (17m)

[0819] General procedure D starting from nucleoside 16 (82.3 mg, 0.26 mmol) gave nucleoside 17m (106.4 mg, 88 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.4 Hz, Js a, 4- = 4.0 Hz, H-5'a); 3.67 (ddd, 1H, Jgem= 11.9 Hz, J5-b, OH = 5.4 Hz, Jb,4- = 4.1 Hz, H-5'b); 3.95 (s, 3H, CH3O); 3.97 (m, 1H, H-4'); 4.14 (td, 1H, J3-,2= J3 -, OH = 4.9 Hz, J3-,4= 3.1 Hz, H-3'); 4.46 (td, 1H, J2-,i = Jr, OH = 62 nz, Jr,3 = 5.0 Hz, H-2'); 5.08 (t, 1H, Jonsa = Jons-b = 5.4 Hz, OH-5'); 5.26 (d, 1H, JOH,3- = 4.9Hz, OH-3'); 5.47 (d, 1H, J0H.2' = 6.3 Hz, OH-2'); 6.22 (d, 1H, J7-,2- = 6.2 Hz, H-l ); 7.29 (d, 1H, J5fi= 3.8 Hz, H-5); 8.04 - 8.13 (m; 2H, H-6, H-7-naphthyl); 8.31 - 8.39 (m, 3H, H-3,4,8-naphthyl); 8.74 (m, 1H, H-5-naphthyl); 8.83 (m, 1H, H-l -naphthyl); HR-ESI-MS: found'. 470.1111 ([M + H]+, calcd for C23H2IO6N3C1+: 470.1113); HR-ESI-MS: found. 492.0930 ([M + Na]+, calcd for C23H2o06N3ClNa+: 492.0933).

[0820] Example 65

[0821] 2-Chloro-4-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17n)

[0822] General procedure D starting from nucleoside 16 (80.6 mg, 0.25 mmol) gave nucleoside 17g (49.6 mg, 46 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 1.47 (s, 6H, CH3-CioHnO); 2.21 (t, 2H, JCH2, P = 20.0 Hz, PCH2P); 3.14 (s, 2H, H-3-CioHnO); 4.04 - 4.13 (m, 3H, H-4',5 '); 4.19 (bd, 1H, J32 = 5.0 Hz, H-3'); 4.46 (bt, 1H, J2,7= J2,3= 5.8 Hz, H-2'); 6.20 (d, 1H, J7,2= 6.5 Hz, H-l'); 6.90 (d, 1H, J76= 8.4 Hz, H-7-CioHnO); 7.06 (d, 1H, J5.6= 3.9 Hz, H-5); 7.96 (d, 1H, J6.5= 3.9 Hz, H-6); 7.98 (dd, 1H, J6,7= 8.4 Hz, J6.4 = 2.0 Hz, H-6-C10H11O); 8.03 (m, 1H, H-4-CioHnO);31P NMR (202.4 MHz, DMSO-d6): 16.32 and 18.86 (2xs, 2xlP, PCH2P). HR-ESI-MS: faun d. 432.1320 ([M + H]+, calcd for C2IH23O5N3C1+: 432.1321); HR-ESI-MS: faun d. 454.1139 ([M +Na]+, calcd for C2iH22O5N3ClNa+: 454.1140).

[0823] Example 66

[0824] 4-(6-(Benzyloxy)naphthalen-2-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17o)

[0825] General procedure D starting from nucleoside 16 (81.7 mg, 0.26 mmol) gave nucleoside 17o (91.9 mg, 70 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.9 Hz, J5'a,0H= 5.4 Hz, J5a.4' = 4.0 Hz, H-5 'a); 3.67 (ddd, 1H, Jgan= 11.9 Hz, J5 b,OH= 5.4 Hz, J5

[0826] = 4.3 Hz, H-5 'b); 3.96 (q, 1H, J4'.5'a = J4',5'b =J4',3 = 3.8 HZ, H-4 ); 4.14 (td, 1H, fa, 2 = fa,oH= 5.0 Hz, J3',4= 3.1 Hz, H-3'); 4.46 (td, 1H, fa,i =fa, OH = 6 fa,fa.3= 5.0 Hz, H-2'); 5.07 (t, 1H, Jon.sa = Jou.s'b = 5.4 Hz, OH-5'); 5.25 (d, 1H, J0H,3' = 4.9 Hz, OH-3'); 5.29 (s, 2H, CH2-Ph); 5.46 (d, 1H, fan, 2' = 6.3 Hz, OH-2'); 6.21 (d, 1H, J1',2'= 6.2 Hz, H-l'); 7.26 (d, 1H, J5,6= 3.8 Hz, H-5); 7.35 (dd; 1H, J78= 9.0 Hz, J75= 2.6 Hz, H-7-naphthyl); 7.36 (m, 1H, H- -Ph); 7.43 (m, 2H, H-w-Ph); 7.54 (m, 2H, H-o-Ph); 7.56 (d, 1H, J5,7= 2.6 Hz, H-5-naphthyl); 8.00 (d, 1H, J 4.3 =8.7 Hz, H-4-naphthyl); 8.04 (d, 1H, J6.5= 3.8 Hz, H-6); 8.15 (d, 1H, J87= 9.1 Hz, H-8-naphthyl); 8.25 (dd, 1H, J3.4= 8.6 Hz, J3.1 = 1.9 Hz, H-3 -naphthyl); 8.72 (d, 1H, J7,3= 1.9 Hz, H-l -naphthyl); HR-ESI-MS: found. 518.1473 ([M + H]+, calcd for C28H25O5N3C1+: 518.1477); HR-ESI-MS: found.

[0827] 540.1293 ([M + Na]+, calcd for C28H24O5N3ClNa+: 540.1297).Example 67

[0828] 2-Chloro-4-(6-hydroxynaphthalen-2-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidiiie (17p)

[0829] General procedure D starting from nucleoside 16 (82.2 mg, 0.26 mmol) gave nucleoside 17p (54.8 mg, 50 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 12.0 Hz, J5a, OH = 5.4 Hz, J5 a,4= 4.0 Hz, H-5 'a); 3.66 (ddd, 1H, Jgem= 12.0 Hz, J5'b,0H= 5.4 Hz, J5'b,4' = 4.3 Hz, H-5'b); 3.96 (q, 1H, J4’5 a = J4',5'b= J4’,3’ = 3.8 Hz, H-4 ); 4.14 (td, 1H, J3,2■ = J3, OH = 5.0 Hz, A, 4 = 3.1 Hz, H-3'); 4.45 (td, 1H, J2’r = J, OH = 6.3 Hz,;s' = 5.0 Hz, H-2'); 5.07 (t, 1H, JOH. S « = JOH. S ’b = 5.4 Hz, OH-5'); 5.25 (d, 1H, JOHS' = 4.9 Hz, OH-3'); 5.45 (d, 1H, JOH,2' = 6.4 Hz, OH-2'); 6.20 (d

[0830]

[0831] , 1H,2= 6.2 Hz, H-l ); 7.18 (dd; 1H, s = 8.8 Hz, J7,5= 2.4 Hz, H-7-naphthyl); 7.22 (d, 1H, J5,7= 2.4 Hz, H-5 -naphthyl); 7.24 (d, 1H, J5,6= 3.8 Hz, H-5); 7.88 (d, 1H, J43=8.7 Hz, H-4-naphthyl); 8.02 (d, 1H, J6,5= 3.8 Hz, H-6); 8.09 (d, 1H, Js,7= 8.9 Hz, H-8-naphthyl); 8.17 (dd, 1H, J3,4= 8.7 Hz, J3: I= 1.8 Hz, H-3-naphthyl); 8.66 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl); 10.12 (s, 1H, OH-6-naphthyl); HR-ESI-MS: / OMM: 428.1005 ([M + H]+, calcd for C21H19O5N3CE: 428.1008); HR-ESI-MS: found. 450.0825 ([M + Na]+, calcd for C2iHi8O5N3ClNa+: 450.0827).

[0832] Example 68

[0833] 4-(4-Aminonaphth-l-yl)-2-chloro-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17q) General procedure D starting from nucleoside 16 (91.4 mg, 0.29 mmol) gave nucleoside 17q (115.8 mg, 95 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 3.57 (ddd, 1H, Jgem= 11.8 Hz, J5 a,OH= 5.5 HZ, J5 a,4= 4.0 Hz, H-5 'a); 3.64 (ddd, 1H, Jgem= 11.8 Hz, J5'b,0H= 5.4 Hz, J5 b, 4- = 4.2 Hz, H-5'b); 3.95 (q, 1H, J4,3■ = J4’5= J4',5'b= 3.8 Hz, H-4'); 4.12 (td, 1H, J3,2■ = J3, OH = 4.9 Hz, A, 4 = 2.9 Hz, H-3'); 4.45 (td, 1H, J.r = A, OH = 6.4 Hz, A s = 5.0 Hz, H-2'); 5.04 (t, 1H, Jour, = Jons’b = 5.4 Hz, OH-5'); 5.24 (d, 1H, Jonr = 4.8 Hz, OH-3'); 5.44 (d, 1H, Jonr = 6.4 Hz, OH-2'); 6.18 (d, 1H, Jr,r = 6.4 Hz, H-l'); 6.42 (bs, 2H, NH2); 6.54 (d, 1H, J5,6= 3.8 Hz, H-5); 6.81 (d; 1H, J3,2= 8.0 Hz, H-3 -naphthyl); 7.42 - 7.50 (m, 2H, H-6,7-naphthyl); 7.63 (d, 1H, A.s = 8.0 Hz, H-2 -naphthyl); 7.86 (d, 1H, As = 3.8 Hz, H-6); 8.20 (m, 1H, H- 5-naphthyl); 8.25 (m, 1H, H-8-naphthyl); HR-ESI-MS: found 427.1170 ([M + H]+, calcd for C2IH2O04N4C1+: 427.1168); HR-ESI-MS: found 449.0990 ([M + Na]+, calcd for C2iHi9O4N4ClNa+: 449.0987).

[0834] Example 69

[0835] 2-Chloro-4-(4-cyanonaphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (17r)General procedure D starting from nucleoside 16 (81.7 mg, 0.26 mmol) gave nucleoside 17r (76.9 mg, 69 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 11.8 Hz, J5-a,0H = 5.3 Hz, J5 a,4= 3.9 Hz, H-5'a); 3.65 (ddd, 1H, Jgem= 11.8 Hz, fab,0H = 5.4 Hz, J5-b,4= 4.1 Hz, H-5 'b); 3.98 (m, 1H, H-4 ); 4.13 (td, 1H, ',2' = J3-,OH= 4.9 Hz, A = 3.0 Hz, H-3 '); 4.47 (td, 1H, Ax = J2-0H= 6.3 Hz, J2-3- = 4.9 Hz, H-2'); 5.06 (t, 1H, fans '« = JOH. S -b = 5.3 Hz, OH-5'); 5.29 (d, 1H, fans- = 4.8 Hz, OH-3'); 5.48 (d, 1H, JOH,2' = 6.3 Hz, OH-2'); 6.23 (d, 1H, A',2' = 6.3 Hz, H-l '); 6.50 (d, 1H, J5,6= 3.8 Hz, H-5); 7.74 (ddd, 1H, s = 8.6 Hz, As = 6.8 Hz, A.s = 1.3 Hz, H-7- naphthyl); 7.90 (ddd, 1H, A.s = 8.4 Hz, A.z = 6.9 Hz, As = 1.2 Hz, H-6-naphthyl); 7.94 (d, 1H, J23= 7.4 Hz, H-2 -naphthyl); 8.00 (d, 1H, A.5 = 3.8 Hz, H-6); 8.10 (dm, 1H,.z = 8.6 Hz, H- 8 -naphthyl); 8.28 (dm, 1H, J5,6= 8.4 Hz, H-5-naphthyl); 8.36 (d; 1H, J3,2= 7.4 Hz, H-3-naphthyl); HR-ESI-MS: found. 437.1013 ([M + H]+, calcd for C22H18O4N4CA: 437.1011); HR-ESI-MS -.found. 459.0834 ([M +Na]+, calcd for C22Hi7O4N4ClNa+: 459.0831).

[0836] Example 70

[0837] 2-(2-Chloro-4-(6-methoxynaphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (17s) General procedure D starting from nucleoside 16 (109.7 mg, 0.34 mmol) gave nucleoside 17s (125.2 mg, 83 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.8 Hz, J5 a,OH= 5.4 Hz, A = 4.0 Hz, H-5'a); 3.67 (ddd, 1H, Jgem= 11.8 Hz, J5'b:0H= 5.4 Hz, J5-b,4- = 4.1 Hz, H-5'b); 3.93 (s, 3H, CH3O); 3.93 (q, 1H,,5 « =. ft = A.s = 3.8 Hz, H-4'); 4.14 (td, 1H, J3-,2■ = J3-OH= 5.0 Hz, A, 4 = 3.1 Hz, H-3'); 4.46 (td, 1H, Ax = A = 6.3 Hz, A.s = 4.9 Hz, H-2'); 5.06 (t, 1H, Jons '« = JoH.s-b = 5.4 Hz, OHS'); 5.24 (d, 1H, JOH.3- = 5.0 Hz, OH-3'); 5.45 (d, 1H,.z = 6.4 Hz, OH-2'); 6.21 (d, 1H, A, 2 = 6.2 Hz, H-l'); 7.26 (d, 1H, J5,6= 3.9 Hz, H-5); 7.27 (dd; 1H, A.s = 9.1 Hz, J75= 2.5 Hz, H-7-naphthyl); 7.44 (d, 1H, J5,7= 2.5 Hz, H-5-naphthyl); 8.02 (d, 1H, J43=8.6 Hz, H-4-naphthyl); 8.03 (d, 1H, A.s = 3.9 Hz, H-6); 8.13 (d, 1H, A.z = 9.1 Hz, H-8-naphthyl); 8.25 (dd, 1H, J3,4= 8.6 Hz, A,7= 1 9 Hz, H-3 -naphthyl); 8.71 (d, 1H, A.s = 1.9 Hz, H-l -naphthyl); HR-ESI-MS: faun d. 442.1165 ([M + H]+, calcd for C22H21O5N3CE: 442.1164); HR-ESI-MS: found. 464.0986 ([M +Na]+, calcd for C22H2o05N3ClNa+: 464.0984).

[0838] Example 71

[0839] [(5-{[2-Chloro-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18a)

[0840] General procedure C starting from nucleoside 17a (81.9 mg, 0.2 mmol) gave bisphosphonate 18a (39.2 mg, 35 %) as a yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.28 (t, 2H, d, JCH P = 20.5 Hz, PCH2P); 4.11 - 4.17 (m, 3H, H-4', 5'); 4.22 (dd, 1H, A, 2 = 5.1 Hz, Ax = 2.6 Hz, H-3'); 4.49 (dd, 1H, Ax = 6.4 Hz, A,3 = 5.1 Hz, H-2'); 6.25 (d, 1H, A,2 = 6.4 Hz, H-l '); 7.26 (d, 1H, J5,6= 3.9 Hz, H-5); 7.60 - 7.68 (m, 2H,H-6,7-naphthyl); 8.04 (m, 1H, H-5 -naphthyl); 8.06 (d, 1H,.f3= 3.9 Hz, H-6); 8.14 (d, 1H, J43= 8.3 Hz, H-4-naphthyl); 8.23 (m, 1H, H-8-naphthyl); 8.27 (dd, 1H, J3,4= 8.6 Hz, J3,i = 1.8 Hz, H-3-naphthyl); 8.77 (d, 1H, J = 1.8 Hz, H-l-naphthyl);31P NMR (202.4 MHz, DMSO-de): 19.83 and 15.71 (2xd, 2xlP, A> = 8.2 Hz, PCH2P). HR-ESI-MS -.found. 568.0443 ([M - H]“, calcd for C22H2IO9N3C1P2“: 568.0447).

[0841] Example 72

[0842] [(5-{[2-Chloro-4-(benzofuran-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18b)

[0843] General procedure C starting from nucleoside 17b (65.8 mg, 0.16 mmol) gave bisphosphonate 18b (36.8 mg, 40 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.28 (t, 2H, JCH2.p = 20.5 Hz, PCH2P); 4.10 - 4.17 (m, 3H, H-4',5 '); 4.21 (dd, 1H, J3-2- = 5.1 Hz, J3-4- = 2.7 Hz, H-3 '); 4.47 (dd, 1H, J2-,i = 6.4 Hz, J2-3-= 5.1 Hz, H-2'); 6.21 (d, 1H,,2= 6.4 Hz, H-l '); 7.32 (d, 1H, J5,6= 3.8 Hz, H-5); 7.38 (ddd, 1H, J5,4= 8.0 Hz, A.e =7.2 Hz, J5,7= 0.9 Hz, H-5-benzofuryl); 7.51 (ddd, 1H, J6.7= 8.4 Hz, J6,5=7.2 Hz, J6.4= 1.3 Hz, H-6-benzofuryl); 7.83 (dm, 1H, J43= 8.0 Hz, H-4-benzofuryl); 7.84 (bdq, 1H, J s = 8.4 Hz, J3= J74= J3= 0.8 Hz, H-7-benzofuryl); 8.01 (d, 1H, J37= 1.0 Hz, H-3 -benzofuryl); 8.07 (d, 1H, J6.s = 3.8 Hz, H-6);31P NMR (202.4 MHz, DMSO-d6): 14.56 and 18.74 (2xbd, 2xlP, JPP= 7.4 Hz, PCH2P). HR-ESI-MS -.faun d.

[0844] 558.0236 ([M - H]“, calcd for C2OHI9OION3C1P2“: 558.0240).

[0845] Example 73

[0846] [(5-{[2-Chloro-4-(furan-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18c)

[0847] General procedure C starting from nucleoside 17c (42.3 mg, 0.12 mmol) gave bisphosphonate 18c (24.6 mg, 40 %) as a brownish powder.1H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.08 - 4.14 (m, 3H, H-4',5'); 4.19

[0848]

[0849] (dd, 1H,2= 5.1 Hz, A = 2.6 Hz, H-3'); 4.44 (dd, 1H, Ax = 6.4 Hz, J2-,3- = 5.1 Hz, H-2'); 6.17 (d, 1H, Jp,2- = 6.4 Hz, H-l '); 6.82 (dd, 1H, J43= 3.6 Hz, J45=1.8 Hz, H-4-fuiyl); 7.10 (d, 1H, J56= 3.7 Hz, H-5); 7.54 (dd, 1H, J3,4= 3.6 Hz,.5 = 0.8 Hz, H-3-fuiyl); 7.97 (d, 1H, J6:5= 3.8 Hz, H-6); 8.11 (d, 1H, J5,4= 1.8 Hz, J5,3= 0.8 Hz, H-5-furyl);31PNMR (202.4 MHz, DMSO-d6): 14.63 and 18.60 (2xbd, 2×1P, JPP= 5.7 Hz, PCH2P). HR-ESI-MS: found: 508.0081 ([M - H]“, calcd for C16H17O10N3CIPA 508.0083).

[0850] Example 74

[0851] [(5-{[2-Chloro-4-(naphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18d)General procedure C starting from nucleoside 17d (83.3 mg, 0.20 mmol) gave bisphosphonate 18d (34 mg, 30 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, d, JCH2,P= 20.5 Hz, PCH2P); 4.09 - 4.17 (m, 3H, H-4',5'); 4.21 (dd, 1H, J3,2= 5.1 Hz, Jr, 4 = 2.5 Hz, H-3'); 4.49 (dd, 1H, J2,i = 6.5 Hz,,3 = 5.1 Hz, H-2'); 6.26 (d, 1H, Ji = 6.5 Hz, H-l '); 6.47 (d, 1H, J5fi= 3.8 Hz, H-5); 7.55 (ddd, 1H, J7:8= 8.4 Hz, J7:6= 6.8 Hz, J75= 1.5 Hz, H-7-naphthyl); 7.61 (ddd, 1H, J6.s = 8.1 Hz, J6,7= 6.8 Hz, J6,8= 1.3 Hz, H-6-naphthyl); 7.70 (dd, 1H, J3,4= 8.3 Hz, J3,2= 7.1 Hz, H-3 -naphthyl); 7.80 (dd, 1H, J2,3= 7.1 Hz, J2:4= 1.3 Hz, H-2-naphthyl); 7.95 (d, 1H, J6,5= 3.8 Hz, H-6); 8.03 (dm, 1H, J8,7= 8.4 Hz, H-8 -naphthyl); 8.08 (dm, 1H, J5,6= 8.2 Hz, H-5-naphthyl); 8.16 (bd, 1H, J43= 8.3 Hz, H-4-naphthyl);nP NMR (202.4 MHz, DMSO-d6): 18.88 and 14.67 (2xd, 2xlP, JPP= 8.2 Hz, PCH2P). HR-ESI-MS: / OMM: 568.0443 ([M - H]“, calcd for C22H2IO9N3C1P2-: 568.0447).

[0852] Example 75

[0853] [(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18e)

[0854] General procedure C starting from nucleoside 17e (59.3 mg, 0.14 mmol) gave bisphosphonate 18e (32.5 mg, 40 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.66 (m, 2H, H-3-CioHn); 1.75 (m, 2H, H-2-CioHn); 2.25 (t, 2H, JCH2,P= 20.4 Hz, PCH2P); 2.64 (t, 2H, J43= 6.4 Hz, H-4-CioHn); 2.84 (t, 2H, J1:2= 6.4 Hz, H-l-CioHn); 4.07 - 4.11 (m, 3H, H-4',5'); 4.19 (bd, 1H,,2= 5.1 Hz, H-3'); 4.47 (dd, 1H, J2,7= 6.5 Hz, J2,3 = 5.1 Hz, H-2'); 6.21 (d, 1H,,2= 6.5 Hz, H-l '); 6.49 (d, 1H, J5,6= 3.8 Hz, H-5); 7.21 - 7.29 (m, 3H, H-6,7,8-CioHn); 7.91 (d, 1H, J6,5= 3.8 Hz, H-6);31P NMR (202.4 MHz, DMSO-d6): 15.77 and 19.72 (2xbd, 2xlP, JPP= 6.1 Hz, PCH2P). HR-ESI-MS: found. 572.0758 ([M - H]“, calcd for C22H25O9N3C1P2-: 572.0760).

[0855] Example 76

[0856] [(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18f)

[0857] General procedure C starting from nucleoside 17f (53.9 mg, 0.13 mmol) gave bisphosphonate 18f (28.2 mg, 38 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.75 - 1.82 (m, 4H, H-2,3-CioHn); 2.25 (t, 2H, JCH2. P = 19.7 Hz, PCH2P); 2.81 (m, 2H, H-4-CioHn); 2.87 (m, 2H, H-l-CioHn); 4.07 - 4.15 (m, 3H, H-4', 5'); 4.20 (m, 1H, H-3'); 4.46 (t, 1H, J2,7= J2,3 = 5.7 Hz, H-2'); 6.21 (d, 1H, J7,2= 6.4 Hz, H-l'); 7.05 (d, 1H, 75,6 = 3.8 Hz, H-5); 7.28 (d, 1H, J87= 8.0 Hz, H-8-C10H11); 7.83 (bd, 1H, J5,7= 1.9 Hz, H-5-CioHn); 7.86 (dd, 1H, J78= 7.9 Hz, J75= 2.0 Hz, H-7-CioHn); 7.97 (d, 1H, J6.s = 3.8 Hz, H-6);31P NMR (202.4MHz, DMSO-d6): 15.85 and 19.60 (2xs, 2xlP, PCH2P). HR-ESI-MS: / OMM: 572.0756 ([M - H]“, calcdfor C22H25O9N3C1P2-: 572.0760).

[0858] Example 77

[0859] [(5-{[4-(4-(Ammomethyl)phenyl)-2-chloro-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18g)

[0860] General procedure C starting from nucleoside 17g (302.6 mg, 0.62 mmol) gave bisphosphonate 18g (140.8 mg, 42 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 2.25 (bt, 2H, JCH2.p = 18.7 Hz, PCH2P); 3.94 - 4.04 (m, 2H, H-5'); 4.09 (bs, 1H, H-4 ); 4.05 - 4.17 (vbs, 2H, CH2Ph); 4.21 (bs, 1H, H-3'); 4.48 (bs, 1H, H-2'); 6.22 (d, 1H, J7 2= 6.1 Hz, H-l ); 6.97 (bs, 1H, H-5); 7.59 - 7.69 (m, 2H, H-w-Ph); 8.04 - 8.18 (m, 3H, H-6, H-o-Ph); 8.38 (vbs, 3H, NH3+);31PNMR (202.4 MHz, DMSO-d6): 16.05 and 17.85 (2xs, 2xlP, PCH2P). HR-ESI-MS: found. 547.0559 ([M - H]“, calcd for Ci9H22O9N4ClP2’: 547.0556).

[0861] Example 78

[0862] |(5-;|2-( hloro-4-(l / / -indol-2-yl)-7H-pyrrolo|2.3-7|pyriniidin-7-yl|- / / -D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18h)

[0863] General procedure C starting from nucleoside 17h (38.2 mg, 0.095 mmol) gave bisphosphonate 18h (27.1 mg, 51 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.28 (t, 2H, JCH2,p = 20.4 Hz, PCH2P); 4.09 - 4.17 (m, 3H, H-4', 5 '); 4.21 (dd, 1H, J32 = 5.1 Hz, J3= 2.6 Hz, H-3 '); 4.47 (dd, 1H, J2,1 = 6.4 Hz, J2,5 = 5.1 Hz, H-2'); 6.20 (d, 1H, J7,2= 6.4 Hz, H-l'); 7.08 (ddd, 1H, J5,4= 8.0 Hz, J5,6= 6.9 Hz, J5,7= 1.0 Hz, H-5-indolyl); 7.24 (ddd, 1H, J6,7= 8.3 Hz, J6,5= 6.9 Hz, J6,4= 1.2 Hz, H-6-indolyl); 7.30 (d, 1H, J5fi= 3.8 Hz, H-5); 7.58 (bdq, 1H, J76= 8.3 Hz, J75= J74= J73= 1.0 Hz, H-7-indolyl); 7.65 (bd, 1H, J3,NH= 2.3 Hz, H-3-indolyl); 7.68 (dq, 1H, J45= 8.0 Hz, J46= J7= J3= 1.0 Hz, H-4-indolyl); 7.99 (d, 1H, J6,5= 3.8 Hz, H-6); 11.86 (d, 1H, Jm,3= 1.9 Hz, NH);31PNMR (202.4 MHz, DMSO-d6): 15.80 and 19.74 (2xbd, 2xlP, JPP= 6.5 Hz, PCH2P). HR-ESI-MS -.found: 557.0399 ([M - H]“, calcd for C20H2O09N4C1P2“: 557.0400).

[0864] Example 79

[0865] [(5-{[2-Chloro-4-(6-fhioronaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18i)

[0866] General procedure C starting from nucleoside 17i (51.3 mg, 0.12 mmol) gave bisphosphonate 18i (23.5 mg, 33 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.25 (bt, 2H, JCH P = 19.9 Hz, PCH2P); 4.07 - 4.17 (m, 3H, H-4', 5'); 4.22 (m, 1H, H-3'); 4.49 (bt, 1H, J2,i = J2'.3' = 5.7 Hz, H-2'); 6.25 (d, 1H, J7,2 = 6.4 Hz, H-l '); 7.27 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 (td; 1H, J78= J7F= 8.9 Hz, J75= 2.6 Hz, H-7-1

[0867] naphthyl); 7.84 (dd, 1H,. A / = 10.2 Hz, J5,7= 2.6 Hz, H-5-naphthyl); 8.07 (d, 1H, J6E= 3.8 Hz, H-6); 8.12

[0868]

[0869] (d, 1H, =8.7 Hz, H-4-naphthyl); 8.32 (bdd, 1H, J3,4= 8.6 Hz, J3,i = 1.9 Hz, H-3 -naphthyl); 8.34 (dd, 1H, Js. = 9.1 Hz,. A / = 5.8 Hz, H-8-naphthyl); 8.82 (bd, 1H,J= 1.8 Hz, H-l -naphthyl);31P NMR (202.4 MHz, DMSO-d6): 16.06 and 19.25 (2xbs, 2xlP, PCH2P);19F NMR (470.4 MHz, DMSO-d6): -107.52 (td, IF, JE5= JE7= 9.5 Hz, JE8= 5.9 Hz, F-6). HR-ESI-MS: found. 586.0358 ([M - H]“, calcd for C22H2O09N3C1FP2-: 586.0353).

[0870] Example 80

[0871] [(5-{[2-Chloro-4-(4-bromo-l-fluoronaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / AD- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18j)

[0872] General procedure C starting from nucleoside 17j (50.0 mg, 0.10 mmol) gave bisphosphonate 18j (23.9 mg, 36 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.15 (t, 2H, JCH2,p = 19.9 Hz, PCH2P); 4.03 - 4.08 (m, 2H, H-5'); 4.10 (m, 1H, H-4 ); 4.21 (bdd,

[0873]

[0874] 1H,2= 5.0 Hz,

[0875]

[0876] = 2.7 Hz, H-3'); 4.49 (bdd, 1H, J2,7= 6.5 Hz, J2,3 = 5.0 Hz, H-2'); 6.24 (d, 1H,,2= 6.5 Hz, H-l '); 6.80 (bt, 1H, J5,6= J5,E= 4.4 Hz, H-5); 7.86 (bddd; 1H, J78= 8.3 Hz, J76= 7.0 Hz, J75= 1.1 Hz, H-7-naphthyl); 7.94 (ddd, 1H, J6E= 8.5 Hz, J67= 7.0 Hz, J6E= 1.2 Hz, H-6-naphthyl); 8.08 (d, 1H, J6,5= 3.8 Hz, H-6); 8.21 (d,

[0877]

[0878] 1H, = 6.3 Hz, H-3- naphthyl); 8.25 (bd, 1H, J5,6= 8.5 Hz, H-5 -naphthyl); 8.31 (bd, 1H, J87= 8.3 Hz, H-8-naphthyl);31PNMR (202.4 MHz, DMSO-d6): 16.71 and 18.08 (2xbs, 2x IP, PCH2P);19FNMR (470.4 MHz, DMSO-d6): -116.80 (bm, IF, F-l). HR-ESI-MS -.found: 663.9467 ([M - H]“, calcd for C^HisOgNsBrClFP: 663.9458).

[0879] Example 81

[0880] [(5-{[2-Chloro-4-(6-diloronaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / AD- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18k)

[0881] General procedure C starting from nucleoside 17k (50.7 mg, 0.11 mmol) gave bisphosphonate 18k (25.6 mg, 37 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.24 (t, 2H, JCH2,p = 20.2 Hz, PCH2P); 4.07 - 4.16 (m, 3H, H-4', 5 '); 4.22 (dd, 1H, J3y = 5.1 H

[0882]

[0883] z, = 2.2 Hz, H-3 '); 4.49 (dd, 1H, J2,i = 6.4 Hz, J2,3 = 5.1 Hz, H-2'); 6.25 (d, 1H, J7.2= 6.4 Hz, H-l'); 7.27 (d, 1H, J5,6 = 3.9 Hz, H-5); 7.64 (dd; 1H, J7S= 8.8 Hz, J75= 2.2 Hz, H-7-naphthyl); 8.08 (d, 1H, J6E= 3.9 Hz, H-6); 8.12 (d, 1H, J43=8.8 Hz, H-4-naphthyl); 8.17 (d, 1H, J5,7= 2.2 Hz, H-5-naphthyl); 8.28 (d, 1H, J8,7= 8.9 Hz, H- 8 -naphthyl); 8.32 (dd, 1H, J3,4= 8.7 Hz, J31= 1.8 Hz, H-3 -naphthyl); 8.80 (d, 1H, JE3= 1.8 Hz, H-l -naphthyl);31PNMR (202.4 MHz, DMSO- d6): 16.10 and 19.18 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found 602.0059 ([M - H]“, calcd for C22H2O09N3C12P2-: 602.0057).Example 82

[0884] [(5-{[2-Chloro-4-(4-fhioronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (181)

[0885] General procedure C starting from nucleoside 171 (50.6 mg, 0.12 mmol) gave bisphosphonate 181 (25.6 mg, 37 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.24 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.09 -4.25 (m, 3H, H-4',5'); 4.21 (dd, 1H, J,2- = 5.1 Hz,

[0886]

[0887] = 2.4 Hz, H-3'); 4.49 (dd,

[0888]

[0889] 1H, = 6.4 Hz, J2-, = 5.1 Hz, H-2'); 6.26 (d, 1H,,2= 6.4 Hz, H-l ); 6.50 (d, 1H, J5,6 = 3.8 Hz, H-5); 7.54 (dd; 1H, F= 10.4 Hz, Jj 2= 8.0 Hz, H-3-naphthyl); 7.67 (ddd, 1H, J7,s = 8.6 Hz, J76= 6.8 Hz, J75= 1.2 Hz, H-7-naphthyl); 7.73 (ddd, 1H, J6:5= 8.3 Hz, J6:7= 6.8 Hz, J6:8= 1.2 Hz, H-6-naphthyl); 7.83 (dd, 1H, J2:3= 8.0 Hz, J2: E= 5.5 Hz, H-2-naphthyl); 7.96 (d, 1H, J6.5 = 3.8 Hz, H-6); 8.12 (dm, 1H, J8,7= 8.6 Hz, H-8-naphthyl); 8.20 (bd, 1H, J5:6= 8.3 Hz, H-5-naphthyl);31P NMR (202.4 MHz, DMSO-d6): 15.84 and 19.59 (2xbs, 2xlP, PCH2P);19F NMR (470.4 MHz, DMSO-d6): -115.63 (bdd, IF, JE3= 10.4 Hz, JE2= 5.5 Hz, F-4). HR-ESI-MS: found. 586.0353 ([M - H]“, calcd for C^HisOgNsBrClFPE: 586.0353).

[0890] Example 83

[0891] [(5-{[2-Chloro-4-(6-(methoxycarbonyl)naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18m)

[0892] General procedure C starting from nucleoside 17m (50.2 mg, 0.11 mmol) gave bisphosphonate 18m (23.2 mg, 35 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2,p = 19.9 Hz, PCH2P); 3.95 (s, 3H, CH3O); 4.09 - 4.19 (m, 3H, H-4',5'); 4.22 (m, 1H, H-3'); 4.50 (bt, 1H, J2-,E= J2-,3- = 5.7 Hz, H-2'); 6.26 (d, 1H, J,2- = 6.4 Hz, H-l '); 7.28 (d, 1H, J5,6= 3.8 Hz, H-5); 8.06 - 8.11 (m; 2H, H-7-naphthyl, H-6); 8.32 - 8.38 (m, 3H, H-3,4,8-naphthyl); 8.74 (m, 1H, H-5-naphthyl); 8.84 (bs, 1H, H-l -naphthyl);31P NMR (202.4 MHz, DMSO-d6): 15.83 and 19.69 (2xbs, 2xlP, PCH2P). HR-ESI-MS: / oz: 626.0499 ([M - H]“, calcd for C24H23OIIN3C1P2-: 626.0502).

[0893] Example 84

[0894] [(5-{[2-Chloro-4-(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18n)

[0895] General procedure C starting from nucleoside 17g (23.6 mg, 0.055 mmol) gave bisphosphonate 18g (13.5 mg, 19 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 1.47 (s, 6H, CH3-Ci0HnO); 2.21 (t, 2H, JCH2, P = 20.0 Hz, PCH2P); 3.14 (s, 2H, H-3-CioHnO); 4.04 - 4.13 (m, 3H, H-4',5'); 4.19 (bd, 1H, J3 2= 5.0 Hz, H-3'); 4.46 (bt, 1H, J2-.i = J2-,3= 5.8 Hz, H-2'); 6.20 (d, 1H, JE,2= 6.5 Hz, H-l'); 6.90 (d, 1H, J6= 8.4 Hz, H-7-CioHnO); 7.06 (d, 1H, J5,6= 3.9 Hz, H-5); 7.96 (d, 1H, J6E= 3.9 Hz, H-6); 7.98 (dd, 1H,J6:7= 8.4 Hz, J64= 2.0 Hz, H-6-CioHnO); 8.03 (m, 1H, H-4-CioHnO);31P NMR (202.4 MHz, DMSO-d6): 16.32 and 18.86 (2xs, 2x IP, PCH2P). HR-ESI-MS: / OMM: 588.0711 ([M-H]“, calcdfor C22H25OION3C1P2’: 588.0709).

[0896] Example 85

[0897] [(5-{[4-(6-(Benzyloxy)naphthalen-2-yl)-2-diloro-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18o)

[0898] General procedure C starting from nucleoside 17o (48.2 mg, 0.093 mmol) gave bisphosphonate 18o (23.4 mg, 37 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.12 (t, 2H, JCH2, P = 19.7 Hz, PCH2P); 3.99 - 4.07 (m, 2H, H-5'); 4.10 (m, 1H, H-4 ); 4.22 (m, 1H, H-3'); 4.50 (bt, 1H, J2,7= J2,3 = 5.8 Hz, H-2'); 5.28 (s, 2H, CH2-Ph); 6.24 (d, 1H,,2= 6.4 Hz, H-l '); 7.24 (d, 1H, J56= 3.9 Hz, H-5); 7.33 (dd; 1H, J7,s= 9.0 Hz, J75 = 2.6 Hz, H-7-naphthyl); 7.36 (m, 1H, H- -Ph); 7.43 (m, 2H, H-w-Ph); 7.52 - 7.56 (m, 3H, H-o-Ph, H-5-naphthyl); 7.99 (d, 1H, J43=8.7 Hz, H-4-naphthyl); 8.09 (d, 1H, J6,5= 3.9 Hz, H-6); 8.15 (d, 1H, J8:7= 9.1 Hz, H-8-naphthyl); 8.24 (dd, 1H, J3,4= 8.6 Hz, J3: I= 1.8 Hz, H-3 -naphthyl); 8.71 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl);nP NMR (202.4 MHz, DMSO-d6): 17.29 and 17.43 (2xbs, 2xlP, PCH2P). HR-ESI-MS: / OMMJ: 674.0871 ([M - H]“, calcd for C29H27OION3C1P2’: 674.0866).

[0899] Example 86

[0900] [(5-{[2-Chloro-4-(6-hydroxynaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18p)

[0901] General procedure C starting from nucleoside 17p (51.4 mg, 0.12 mmol) gave bisphosphonate 18p (21.7 mg, 31 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JC 2,p = 20.4 Hz, PCH2P); 4.09 -4.16 (m, 3H, H-4', 5'); 4.21 (dd, 1H, J3,2= 5.1 Hz, J3,4= 2.4 Hz, H-3'); 4.48 (dd, 1H, J2 7= 6.4 Hz, J2 3= 5.1 Hz, H-2'); 6.24 (d, 1H, J7,2= 6.4 Hz, H-l'); 7.18 (dd; 1H, J78= 8.8 Hz, J75= 2.4 Hz, H-7-naphthyl); 7.21 (d, 1H, J5,7= 2.4 Hz, H-5 -naphthyl); 7.23 (d, 1H, J5,6= 3.9 Hz, H-5); 7.88 (d, 1H, J43=8.7 Hz, H-4-naphthyl); 8.01 (d, 1H, J65= 3.8 Hz, H-6); 8.07 (d, 1H, J87= 8.9 Hz, H- 8 -naphthyl); 8.17 (dd, 1H, J3,4= 8.7 Hz, J3:1= 1.8 Hz, H-3 -naphthyl); 8.66 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl); 10.11 (vbs, 1H, OH-6-naphthyl);31P NMR (202.4 MHz, DMSO-d6): 15.80 and 19.71 (2xbd, 2xlP, JPP= 7.6 Hz, PCH2P). HR-ESI-MS -.found. 584.0398 ([M - H]“, calcd for C22H2IOI0N3C1P2“: 584.0396).

[0902] Example 87

[0903] [(5-{[4-(4-Aminonaphth-l-yl)-2-chloro-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18q)General procedure C starting from nucleoside 17q (48.5 mg, 0.11 mmol) gave bisphosphonate 18q (27.5 mg, 41 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.09 - 4.15 (m, 3H, H-4',5'); 4.20 (dm, 1H, J3,2= 5.1 Hz, H-3'); 4.46 (dd, 1H, J2,i = 6.5 Hz, J2, 3 = 5.1 Hz, H-2'); 6.22

[0904]

[0905] (d, 1H,2= 6.5 Hz, H-l ); 6.53 (d, 1H, J5,6= 3.8 Hz, H-5); 6.82 (d, 1H, J3,2= 8.0 Hz, H-3-naphthyl); 7.45 (ddd; 1H, JP7= 8.3 Hz, J6,7= 6.7 Hz,

[0906]

[0907] = 1.6 Hz, H-6-naphthyl); 7.48 45 (ddd; 1H, J7,s= 8.4 Hz, J7:6= 6.7 Hz, J75= 1.5 Hz, H-7-naphthyl); 7.64 (d, 1H, J2,3=8.0 Hz, H-2-naphthyl); 7.86 (d, 1H, J6,5 = 3.8 Hz, H-6); 8.20 (m, 1H, H-5-naphthyl); 8.26 (m, 1H, H- 8 -naphthyl);31PNMR (202.4 MHz, DMSO-d6): 15.71 and 19.80 (2xd, 2xlP, JPP= 7.9 Hz, PCH2P). HR-ESI-MS: / OMM: 583.0551 ([M - H]“, calcd for C22H22O9N4C1P2“: 583.0556).

[0908] Example 88

[0909] [(5-{[2-Chloro-4-(4-cyanonaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18r)

[0910] General procedure C starting from nucleoside 17r (48.6 mg, 0.11 mmol) gave bisphosphonate 18r (36.0 mg, 54 %) as a white powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2.p = 20.4 Hz, PCH2P); 4.10 - 4.16 (m, 3H, H-4',5 '); 4.22 (dd, 1H, J3y = 5.1 Hz, J3= 2.5 Hz, H-3 '); 4.50 (dd, 1H, J2-,7- = 6.4 Hz, J2,5 = 5.1 Hz, H-2'); 6.27 (d, 1H, J7,2= 6.4 Hz, H-l '); 6.49 (d, 1H, J5,6= 3.8 Hz, H-5); 7.75 (ddd; 1H, J78= 8.6 Hz, J76= 6.9 Hz, J75= 1.3 Hz, H-7-naphthyl); 7.90 (ddd; 1H, J6,5= 8.4 Hz, J6,7= 6.9 Hz, J6,8= 1.2 Hz, H-6-naphthyl); 7.93 (d, 1H, J2,3= 7.4 Hz, H-2-naphthyl); 8.00 (d, 1H, J65= 3.8 Hz, H-6); 8.12 (bdt, 1H, J87= 8.6 Hz, J 6 = J8,5 = 1.0 Hz, H-8-naphthyl); 8.28 (bdt, 1H, J7P= 8.4 Hz, J3,7= Js.s = 1.0 Hz, H-5 -naphthyl); 8.36 (d, 1H, J3,2 = 7.4 Hz, H-3-naphthyl);31PNMR (202.4 MHz, DMSO-d6): 15.78 and 19.69 (2xbs, 2xlP, PCH2P). HR-ESI-MS: found. 593.0396 ([M - H]“, calcd for C23H2O09N4C1P2“: 593.0400).

[0911] Example 89

[0912] [(5-{[2-Chloro-4-(6-methoxynaphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18s)

[0913] General procedure C starting from nucleoside 17s (52.7 mg, 0.12 mmol) gave bisphosphonate 18s (29.4 mg, 41 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2, P = 20.3 Hz, PCH2P); 3.93 (s, 3H, CH3O); 4.10 - 4.16 (m, 3H, H-4',5'); 4.22 (dd, 1H, J3'2' = 5.4 Hz, J3^ = 2.4 Hz, H-3'); 4.49 (bdd, 1H, J2,7= 6.4 Hz, J2,5 = 5.3 Hz, H-2'); 6.24 (d, 1H, J7,2= 6.4 Hz, H-l '); 7.26 (d, 1H, J5,6= 3.8 Hz, H-5); 7.27 (dd; 1H, J78= 9.0 Hz, J75= 2.5 Hz, H-7-naphthyl); 7.44 (d, 1H, J5,7= 2.5 Hz, H-5 -naphthyl); 8.02 (d, 1H, J4.3 =8.6 Hz, H-4-naphthyl); 8.03 (d, 1H, J6.s = 3.7 Hz, H-6); 8.14 (d, 1H, J87= 9.0 Hz, H-8-naphthyl); 8.25 (dd, 1H, J3.4 = 8.6 Hz, J3.1 = 1.9 Hz, H-3 -naphthyl); 8.71 (d, 1H, J7 J= 1.9 Hz, H-l -naphthyl);31PNMR(202.4 MHz, DMSO-d6): 15.79 and 19.73 (2xbs, 2xlP, PCH2P). HR-ESI-MS: / OMM: 598.0546 ([M - H]“, calcd for C23H23OI0N3C1P2-: 598.0553).

[0914] Example 90

[0915] 4-Chloro-2-fluoro-7-( / LD-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (19)

[0916] Protected nucleoside 11 (1.58 g, 3.46 mmol) was treated with 20 mL 75 % TFA according to the general procedure B. HPFC (SiO2, DCM / MeOH 1:0 — 9:1) gave 2-amino-4-chloro-7-(P-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (0.77 g, 74 %) as a white solid.1H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093). The nucleoside was dissolved in pyridine (1 mL) and added dropwise to a solution of 5 mL 70 % HF-Py at - 30 °C, followed by the addition of TBN (0.8 mL, 6.37 mmol). The mixture was stirred for 20 min and then the solution was poured out to a cold solution of saturated aq. NaHCOs containing CaCO3. It was extracted with EtOAc, evaporated in vacuo. HPFC (SiO2, DCM / MeOH 1:0 —► 9:1) and lyophilization from H2O / LBuOH gave 19 (0.39 g, 61 %) as a white powder. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0917] Example 91

[0918] 2-Fluoro-4-(naphthalen-2-yl)-7-( / LD-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (20a) General procedure E starting from nucleoside 19 (88.3 mg, 0.29 mmol) gave nucleoside 20a (58.8 mg, 51 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.8 Hz, J5-a,0H= 5.4 Hz,

[0919]

[0920] = 3.9 Hz, H-5 'a); 3.67 (ddd, 1H, Jgan= 11.8 Hz, J5'b,OH= 5.4 Hz, J5= 4.1 Hz, H-5 'b); 3.97 (q, 1H, T « = T * =7^,5 = 3.8 Hz, H-4 ); 4.14 (td, 1H, J3,2= J3-,OH= 5.0 Hz,^ = 3.2 Hz, H-3'); 4.45 (td, 1H, J2-,r = J, OH = 6.3 Hz, J2,5 = 5.0 Hz, H-2'); 5.07 (t, 1H, Jon.sa = JoH.s’b = 5.4 Hz, OH-5'); 5.24 (d, 1H, JOH,3-= 5.0 Hz, OH-3'); 5.45 (d, 1H, JOH, i = 6.4 Hz, OH-2'); 6.17 (d, 1H, Ji3= 6.1 Hz, H-l ); 7.28 (d, 1H, J5,6= 3.9 Hz, H-5); 7.63 and 7.66 (2xm, 2xlH, H-6,7-naphthyl); 8.02 (d, 1H, J6,s = 3.9 Hz, H-6); 8.04 (dm, 1H, J5,6= 7.7 Hz, H-5 -naphthyl); 8.14 (d, 1H, J43= 8.7 Hz, H-4-naphthyl); 8.22 (dm, 1H, J8,7= 7.7 Hz, H-8-naphthyl); 8.29 (dd, 1H, J3,4= 8.7 Hz, J3: I= 1.8 Hz, H-3 -naphthyl); 8.80 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl);19F NMR (470.4 MHz, DMSO-d6): -53.64 (s, IF, F-2). HR-ESI-MS: found: 396.1357 ([M + H]⁺, calcd for C21H19O4N3F⁺: 396.1354); HR-ESI-MS: found: 418.1175 ([M + Na]⁺, calcd for C21H18O4N3FNa⁺: 418.1174).

[0921] Example 92

[0922] 4-(Benzofuran-2-yl)-2-fhioro-7-( / LD-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (20b)General procedure E starting from nucleoside 19 (83.2 mg, 0.27 mmol) gave nucleoside 20b (45.6 mg, 43 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.59 (ddd, 1H, Jgem= 11.9 Hz, J5-a,0H = 5.3 Hz, J5a, = 3.9 Hz, H-5 'a); 3.67 (ddd, 1H, Jgem= 11.9 Hz, J5-b, OH = 5.4 Hz, J5-b,4- = 4.0 Hz, H-5 'b); 3.96 (q, 1H, J4,5 a = J.s’b = J4’,3' = 3.8 Hz, H-4 ); 4.13 (td, 1H, J3-,2- = J3-. OH = 4.9 Hz, J3-,4- = 3.2 Hz, H-3'); 4.43 (q, 1H, J2-,r = J, OH = J2',3' = 5.9 Hz, H-2'); 5.07 (t, 1H, Jon.sa = Jons’b = 5.3 Hz, OH-5'); 5.24 (d, 1H, Jonr = 4.6 Hz, OH-3'); 5.46 (d, 1H, JOH,2 = 5.1 Hz, OH-2'); 6.13 (d, 1H, J7 2= 6.1 Hz, H-l ); 7.33 (d, 1H, J5,6 = 3.8 Hz, H-5); 7.39 (ddd, 1H, J5,4= 7.9 Hz, J56= 7.2 Hz, J5,7= 0.9 Hz, H-5 -benzofuryl); 7.52 (ddd, 1H, J6,7= 8.6 Hz, J6,5 = 7.2 Hz, J6,4= 1.3 Hz, H-6-benzofuryl); 7.81 - 7.86 (m, 2H, H-4,7-benzofuryl); 8.01 (d, 1H, J3 7= 0.9 Hz, H-3 -benzofuryl); 8.03 (d, 1H,.f3= 3.8 Hz, H-6);19F NMR (470.4 MHz, DMSO-d6): -53.69 (s, IF, F-2). HR-ESI-MS: found: 386.1149 ([M + H]⁺, calcd for C19H17O5N3F⁺: 386.1147). HR-ESI-MS: found: 408.0968 ([M + Na]⁺, calcd for C19H16O5N3FNa⁺: 408.0966).

[0923] Example 93

[0924] 2-Fluoro-4-(furan-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (20c)

[0925] General procedure E starting from nucleoside 19 (87.7 mg, 0.29 mmol) gave nucleoside 20c (50.8 mg, 52 %) as a pale-yellow powder. ’H NMR spectra is in agreement with the literature (Malnuit, V. ChemMedChem 2015, 10, 1079-1093).

[0926] Example 94

[0927] 2-Fluoro-4-(naphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (20d)

[0928] General procedure E starting from nucleoside 19 (82.2 mg, 0.27 mmol) gave nucleoside 20d (94.7 mg, 89 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 3.58 (ddd, 1H, Jgem= 11.9 Hz, J5 a,OH= 5.3 Hz, J5-a,4- = 3.9 Hz, H-5 'a); 3.65 (ddd, 1H, Jgem= 11.9 Hz, Jb. OH = 5.3 Hz, J5-b,4- = 4.1 Hz, H-5'b); 3.97 (btd, 1H,,5 « = J4',5 'b = 4.0 Hz, J4= 3.2 Hz, H-4'); 4.13 (td, 1H, J3= J3',0H= 4.7 Hz, = 3.1 Hz, H-3 '); 4.46 (q, 1H, J2',i ■ = J2-, OH = J2-,3 = 6.1 Hz, H-2'); 5.05 (t, 1H, JOH5a = Jon b = 5.3 Hz, OH-5'); 5.26 (d, 1H, JOH,3’ = 4.8 Hz, OH-3'); 5.47 (d, 1H, JOH,2- = 6.4 Hz, OH-2'); 6.18 (d, 1H,,2= 6.3 Hz, H-l '); 6.50 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 (ddd, 1H, J78= 8.5 Hz, J76= 6.8 Hz, J75= 1.4 Hz, H-7-naphthyl); 7.61 (ddd, 1H, J6,5 = 8.0 Hz, J6,7= 6.8 Hz, J6,8 = 1.3 Hz, H-6-naphthyl); 7.70 (dd, 1H, J3,4= 8.3 Hz, J3,2= 7.1 Hz, H-3-naphthyl); 7.81 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 7.91 (d, 1H, J65= 3.8 Hz, H-6); 8.06 - 8.10 (m, 2H, H-5,8-naphthyl); 8.16 (bd, 1H, J43= 8.3 Hz, H-4-naphthyl);19F NMR (470.4 MHz, DMSO- d6): -53.61 (s, IF, F-2). HR-ESI-MS: found: 396.1356 ([M + H]⁺, calcd for C21H19O4N3F⁺: 396.1354); HR-ESI-MS: found: 418.1172 ([M + Na]⁺, calcd for C21H18O4N3FNa⁺: 418.1174).Example 95

[0929] 2-Fluoro-4-(5,6,7,8-tetrahydronaphth-l-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (20e)

[0930] General procedure E starting from nucleoside 19 (102.4 mg, 0.34 mmol) gave nucleoside 20e (60.2 mg, 45 %) as a white powder. ‘H NMR (500 MHz, DMSO-d6): 1.66 (m, 2H, H-3-CioHn); 1.75 (m, 2H, H-2- CioHn); 2.66 (t, 2H, J43= 6.4 Hz, H-4-CioHn); 2.84 (t, 2H, Jp2= 6.4 Hz, H-l-CioHn); 3.56 (ddd, 1H, Jgem= 11.8 Hz, Ja,OH= 5.4 Hz,

[0931]

[0932] = 3.9 Hz, H-5 'a); 3.63 (ddd, 1H, Jgem= 11.8 Hz, J5'b,OH= 5.4 Hz, Jsl,4= 4.1 Hz, H-5 'a); 3.95 (q, 1H, J4,5■« = J4,5'b = J4’,3’ = 3.9 Hz, H-4 ); 4.12 (td, 1H, J3,2■ = J3, OH = 4.9 Hz, J3’,4’ = 3.0 Hz, H-3'); 4.44 (td, 1H, J2',r= J2'0H= 6.3 Hz, J2^ = 5.0 Hz, H-2'); 5.04 (t, 1H, J0H a= Jon^b = 5.4 Hz, OH-5'); 5.23

[0933]

[0934] (d, 1H, = 4.8 Hz, OH-3'); 5.44 (d, 1H, JOH,2' = 6.4 Hz, OH-2'); 6.13

[0935]

[0936] (d, 1H,2= 6.3 Hz, H-l '); 6.50 (d, 1H, J5,6= 3.8 Hz, H-5); 7.22 - 7.30 (m, 3H, H-6,7,8-CioHn); 7.87 (d, 1H, J6,5= 3.8 Hz, H-6);19FNMR (470.4 MHz, DMSO-d6): -53.79 (s, IF, F-2). HR-ESI-MS: found: 400.1669 ([M + H]⁺, calcd for C21H23O4N3F⁺: 400.1667); HR-ESI-MS: found: 422.1489 ([M + Na]⁺, calcd for C21H22O4N3FNa⁺: 422.1487).

[0937] Example 96

[0938] [(5-{[2-Fluoro-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21a)

[0939] General procedure C starting from nucleoside 20a (48.5 mg, 0.12 mmol) gave bisphosphonate 21a (29.8 mg, 44 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-de): 2.28 (t, 2H, d, JCH2, P = 20.5 Hz, PCH2P); 4.11 - 4.18 (m, 3H, H-4', 5'); 4.23 (dd, 1H, J3,2= 5.1 Hz, J3,4= 2.8 Hz, H-3'); 4.49 (dd, 1H, J2,7= 6.3 Hz, J2,3= 5.1 Hz, H-2'); 6.21 (d, 1H, Jr,2= 6.3 Hz, H-l'); 7.28 (d, 1H, J5.6=.9 Hz, H-5); 7.60 - 7.68 (m, 2H, H-6,7-naphthyl); 8.02 (d, 1H, J6.5 = 3.9 Hz, H-6); 8.04 (m, 1H, H-5-naphthyl); 8.14 (d, 1H, J43= 8.7 Hz, H-4-naphthyl); 8.23 (m, 1H, H- 8 -naphthyl); 8.30 (dd, 1H, J3= 8.6 Hz, J3= 1.8 Hz, H-3-naphthyl); 8.81 (d, 1H, JI:3= 1.8 Hz, H-l -naphthyl);nP NMR (202.4 MHz, DMSO-d6): 19.76 and 15.76 (2xd, 2xlP, JP: P= 8.1 Hz, PCH2P);19F NMR (470.4 MHz, DMSO-d6): -53.56 (s, IF, F-2). HR-ESI-MS: found: 552.0741 ([M - H]“, calcd for C22H2IO9N3FP2-:552.0743).

[0940] Example 97

[0941] [(5-{[4-(Benzofuran-2-yl)-2-fhioro)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D- ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21b)

[0942] General procedure C starting from nucleoside 20b (46.5 mg, 0.12 mmol) gave bisphosphonate 21b (13.3 mg, 20 %) as a pale-yellow powder.1H NMR (500 MHz, DMSO-d6): 2.27 (t, 2H, JCH2, P = 20.3 Hz, PCH2P);4.09 - 4.17 (m, 3H, H-4',5'); 4.21

[0943]

[0944] (dd, 1H,2= 5.1 Hz, J3 4 = 2.7 Hz, H-3'); 4.46 (dd, 1H, J2-,7- = 6.2 Hz, J2,3= 5.1 Hz, H-2'); 6.17 (d, 1H, J, 2 = 6.2 Hz, H-l ); 7.32 (d, 1H, J5,6= 3.8 Hz, H-5); 7.38 (bid, 1H, Ji, 4 = Ji, 6 = 7.6 Hz, J5,7 = 0.9 Hz, H-5-benzofuryl); 7.52 (ddd, 1H, J6,7= 8.3 Hz, J6,5= 7.2 Hz, J6,4= 1.3 Hz, H-6-benzofuryl); 7.82 - 7.86 (m, 2H, H-4,7-benzofuryl); 8.00 (d, 1H, J3, LR = 0.9 Hz, H-7-benzofuryl); 8.03 (d, 1H, J6,s = 3.8 Hz, H-6);19F NMR (470.4 MHz, DMSO-d6): -53.63 (s, IF, F-2). HR-ESI-MS: found:

[0945] 542.0536 ([M - H]“, calcd for C20HI9OION3FP2- 542.0535).

[0946] Example 98

[0947] [(5-{[2-Fluoro-4-(furan-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21c)

[0948] General procedure C starting from nucleoside 20c (43.4 mg, 0.13 mmol) gave bisphosphonate 21c (27.2 mg, 43 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, JCH2, P = 20.4 Hz, PCH2P); 4.07 -4.14 (m, 3H, H-4',5'); 4.19 (dd, 1H, J3,2= 5.1 Hz, J3,4= 2.7 Hz, H-3'); 4.43 (dd, 1H, J2.7= 6.3 Hz, J2.2= 5.1 Hz, H-2'); 6.13 (d, 1H, Jr,2= 6.3 Hz, H-l'); 6.83 (dd, 1H, J4,3= 3.6 Hz, J45=1.7 Hz, H-4-furyl); 7.10 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 (bd, 1H, J3,4= 3.6 Hz, H-3-furyl); 7.92 (d, 1H, J6,5= 3.8 Hz, H-6); 8.12 (bd, 1H, J5,4 = 1.7 Hz, H-5-furyl);31PNMR (202.4 MHz, DMSO-d6): 15.92 and 19.49 (2xbd, 2xlP, JPP= 5.1 Hz, PCH2P);19FNMR (470.4 MHz, DMSO-d6): -53.70 (s, IF, F-2). HR-ESI-MS -.found: 492.0377 ([M - H]“, calcd for CieHnOioNsFPE: 492.0379).

[0949] Example 99

[0950] [(5-{[2-Fluoro-4-(naphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21d)

[0951] General procedure C starting from nucleoside 20d (46.4 mg, 0.12 mmol) gave bisphosphonate 21d (31.9 mg, 49 %) as a yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.25 (t, 2H, d, JCH2, P = 20.5 Hz, PCH2P); 4.09 - 4.17 (m, 3H, H-4',5'); 4.21 (dm, 1H, J3,2= 5.1 Hz, H-3'); 4.48 (dd, 1H, J2,i = 6.4 Hz, Jr,3= 5.1 Hz, H-2'); 6.21 (d, 1H, J7-,2- = 6.4 Hz, H-l'); 6.49 (d, 1H, J5,6= 3.8 Hz, H-5); 7.55 (ddd, 1H, J78= 8.3 Hz, J6= 6.8 Hz, J75= 1.4 Hz, H-7-naphthyl); 7.61 (ddd, 1H, J6,5= 8.2 Hz, J6,7= 6.8 Hz, J6,s = 1.3 Hz, H-6-naphthyl); 7.70 (dd, 1H, J3,4= 8.2 Hz, J3,2= 7.1 Hz, H-3 -naphthyl); 7.82 (dd, 1H, J2,3= 7.1 Hz, J2,4= 1.3 Hz, H-2-naphthyl); 7.90 (d, 1H, J6,5= 3.8 Hz, H-6); 8.06 - 8.11 (m, 2H, H-5,8-naphthyl); 8.16 (dt, 1H, J4,3= 8.3 Hz, J4,2= J4s = 1.0 Hz, H-4-naphthyl);31P NMR (202.4 MHz, DMSO-d6): 19.85 and 15.69 (2xd, 2xlP, JPP= 8.3 Hz, PCH2P);19F NMR (470.4 MHz, DMSO-d6): -53.51 (s, IF, F-2). HR-ESI-MS: found:

[0952] 552.0737 ([M - H]“, calcd for C22H2IO9N3FP2-: 552.0743).

[0953]

[0954] 100

[0955] [(5-{[2-Fluoro-4-(5,6,7,8-tetrahydronaphth-l-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21e)

[0956] General procedure C starting from nucleoside 20e (53.9 mg, 0.14 mmol) gave bisphosphonate 21e (35.9 mg, 48 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.66 (m, 2H, H-3-CioHn); 1.75 (m, 2H, H-2-CioHn); 2.24 (t, 2H, JCH2, P = 20.4 Hz, PCH2P); 2.67 (t, 2H, J43= 6.4 Hz, H-4-CioHn); 2.84 (t, 2H, Jp2= 6.4 Hz, H-l-CioHn); 4.06 - 4.15 (m, 3H, H-4',5'); 4.19 (bd, 1H, J3 2= 5.1 Hz, H-3'); 4.46 (dd, 1H, J2-,i = 6.4 Hz,J= 5.1 Hz, H-2'); 6.16 (d, 1H,,2= 6.4 Hz, H-l ); 6.49 (d, 1H, J5,6= 3.8 Hz, H-5); 7.22 - 7.31 (m, 3H, H-6,7,8-CioHn); 7.86 (d, 1H,J= 3.8 Hz, H-6);31P NMR (202.4 MHz, DMSO-d6): 15.76 and 19.72 (2xs, 2xlP, PCH2P);19F NMR (470.4 MHz, DMSO-d6): -53.70 (s, IF, F-2). HR-ESI-MS: found-.

[0957] 556.1053 ([M - H]“, calcd for C22H25O9N3FP2- 556.1056).

[0958]

[0959] 101 2-Methoxy-4-(naphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (22) Compound 17a (40.4 mg, 0.098 mmol) was treated with 3 mL 0.5 M NaOMe and let to stir overnight at 60 °C. HPFC purification (SiO2, DCM / MeOH 1:0 —> 5.7:1) and lyophilization from H2O / t-BuOH gave 22 (34.9 mg, 87 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 3.57 (bdt, 1H, Jgem= 11.8 Hz, J5 a,oH= J5-a,4- = 4.5 Hz, H-5 'a); 3.65 (bdt, 1H, Jgem= 11.8 Hz, Jb,OH= J5-b,4- = 4.5 Hz, H-5'b); 3.93 (q, 1H, J4-5= J4-,5'b= J4-3- = 3.9 Hz, H-4 ); 4.12 (bq, 1H, J3-2 = J3, OH = J3.4- = 4.1 Hz, H-3'); 4.45 (q, 1H, J2-,i = J. OH = J2-.3- = 5.7 Hz, H-2'); 2.93 (d, 3H, JCH3. NH = 4.8 Hz, CH3NH);5.00 (t, 1H, JOH,5 a= JOH. S I, = 5.3 Hz, OHS'); 5.16 (bs, 1H, OH-3'); 5.33 (d, 1H, JOH,2- = 6.3 Hz, OH-2'); 6.13 (d, 1H, J7-,2- = 6.1 Hz, H-l'); 6.82 (d, 1H, J5:6= 3.9 Hz, H-5); 6.83 (m, 1H, CH3NH); 7.42 (d, 1H, J6,5= 3.9 Hz, H-6); 7.56 - 7.63 (m; 2H, H-6, 7-naphthyl); 7.99 (m, 1H, H-5 -naphthyl); 8.07 (d, 1H, J43=8.6 Hz, H-4-naphthyl); 8.13 (m, 1H, H-8-naphthyl); 8.21 (bd, 1H, J3,4= 8.6 Hz, H-3 -naphthyl); 8.62 (s, 1H, H-l -naphthyl); HR-ESI-MS: found'.

[0960] 408.1552 ([M + H]+, calcd for C22H22O5N3+: 408.1554); HR-ESI-MS: found: 430.1370 ([M + Na]+, calcd for C22H2iO5N3Na+: 430.1373).

[0961] 102

[0962] [(5-{[2-Methoxy-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidm-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (23a)

[0963] General procedure C starting from nucleoside 22 (56.8 mg, 0.14 mmol) gave bisphosphonate 23 (8.6 mg, 11 %) as a pale-yellow powder. ’H NMR (500 MHz, DMSO-d6): 2.26 (t, 2H, d, JCH2, P = 20.4 Hz, PCH2P); 4.05 (s, 3H, CH3O); 4.07 - 4.18 (m, 3H, H-4',5'); 4.23 (dd, 1H, = 5.2 Hz, J3 4 = 2.9 Hz, H-3'); 4.51(dd, 1H, J2,i ■ = J2^ = 5.7 Hz, H-2'); 6.22 (d

[0964]

[0965] , 1H, = 6.2 Hz, H-l ); 7.08 (d, 1H, J5,6= 3.9 Hz, H-5); 7.58 - 7.66 (m, 2H, H-6,7-naphthyl); 7.76 (d, 1H, J6.s = 3.9 Hz, H-6); 8.02 (m, 1H, H-5-naphthyl); 8.11 (d, 1H, J4,3 = 8.6 Hz, H-4-naphthyl); 8.19 (m, 1H, H- 8 -naphthyl); 8.30 (dd, 1H, J3,4= 8.6 Hz, J3,i = 1.8 Hz, H-3-naphthyl); 8.75 (bd, 1H, JI:3= 1.7 Hz, H-l -naphthyl);31PNMR (202.4 MHz, DMSO-d6): 15.80 and 19.69 (2xbd, 2xlP, JP: P= 7.5 Hz, PCH2P). HR-ESI-MS: found. 564.0938 ([M - H]“, calcd for C23H24O10N3P2-: 564.0942).

[0966] Example 103

[0967] 2-(Methylammo)-4-(naphthalen-2-yl)-7-(P-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (24) Compound 17a (34.1 mg, 0.083 mmol) was treated with 2 mL MeNH2(33 % in EtOH), 0.02 mL TEA and let to stir overnight at 80 °C. HPFC purification (SiO2, DCM / MeOH 1:0 —> 5.7:1) and lyophilization from H2O / t-BuOH gave 24 (27.4 mg, 81 %) as a pale-yellow powder. HR-ESI-MS: found. 407.1711 ([M + H]+, calcd for C22H23O4N4+: 407.1714); *HNMR (500 MHz, DMSO-d6): 2.93 (d, 3H, JCH3. NH = 4.8 Hz, CH3NH); 3.54 (dt, 1H, Jgem= 11.7 Hz, Jsa, OH=Jsw = 4.8 Hz, H-5 a); 3.66 (bdt, 1H, Jgem= 11.7 Hz, d bou = Jsw=4.8 Hz, H-5'b); 3.88 (td, 1H, J4'5'a= J4^b= 4.1 Hz, J4,3= 3.7 Hz, H-4 ); 4.12 (bq, 1H, J3,2■ = J3. OH = J3'4' = 4.1 Hz, H-3'); 4.45 (q, 1H, Jr.i ■ = J2, OH = J2.3 = 5.7 Hz, H-2'); 5.00 (t, 1H, Jonp = JOH. S ’b = 5.3 Hz, OHS'); 5.16 (bs, 1H, OH-3'); 5.33 (d, 1H, JOH,2' = 6.3 Hz, OH-2'); 6.13 (d, 1H,,2= 6.1 Hz, H-l'); 6.82 (d, 1H, J5,6= 3.9 Hz, H-5); 6.83 (m, 1H, CH3NH); 7.42 (d, 1H, J6,5= 3.9 Hz, H-6); 7.56 - 7.63 (m; 2H, H-6, 7-naphthyl); 7.99 (m, 1H, H-5 -naphthyl); 8.07 (d, 1H, J43=8.6 Hz, H-4-naphthyl); 8.13 (m, 1H, H-8-naphthyl); 8.21 (bd, 1H, J34= 8.6 Hz, H-3 -naphthyl); 8.62 (s, 1H, H-l -naphthyl); HR-ESI-MS: found.

[0968] 429.1530 ([M +Na]+, calcd for C22H22O4N4Na+: 429.1533).

[0969] Example 104

[0970] [(5-{[2-(Methylamino)-4-(naphthalen-2-yl)-77 / -pyrrolo[2,3-< / ]pyrimidin-7-yl]- / LD-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (25a)

[0971] General procedure C starting from nucleoside 24 (51.4 mg, 0.13 mmol) gave bisphosphonate 25 (18.7 mg, 26 %) as a yellow powder.1H NMR (500 MHz, DMSO-d6): 2.24 (t, 2H, d, Ja.p = 20.4 Hz, PCH2P); 2.95 (s, 3H, CH3NH); 4.01 - 4.17 (m, 3H, H-4', 5'); 4.21 (dd, 1H, J3,2= 5.2 H

[0972]

[0973] z, = 3.0 Hz, H-3'); 4.41 (t, 1H, J2 7=J2,5 = 5.7 Hz, H-2'); 6.16 (d, 1H, J2 7= 6.3 Hz, H-l'); 6.83 (d, 1H, J5fi= 3.9 Hz, H-5); 7.46 (d, 1H, J6:5= 3.9 Hz, H-6); 7.56 - 7.64 (m, 2H, H-6,7-naphthyl); 8.00 (m, 1H, H-5-naphthyl); 8.08 (d, 1H, J43= 8.6 Hz, H-4-naphthyl); 8.14 (m, 1H, H-8-naphthyl); 8.21 (bd, 1H, J2,4= 8.6 Hz, H-3 -naphthyl); 8.62 (s 1H, H-l -naphthyl);31PNMR (202.4 MHz, DMSO-d6): 15.91 and 19.49 (2xbd, 2xlP, JP: P= 5.5 Hz, PCH2P). HR-ESI-MS: found: 563.1098 ([M - H]“, calcd for C23H25O9N4P2’: 563.1102).Example 105

[0974] 2-Amino-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7-(2,3-(?-isopropylidene-5-(?-tert-butyldimethylsilyl- / LD-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidine (26)

[0975] General procedure E starting from nucleoside 11 (203.0 mg, 0.45 mmol) gave nucleoside 26 (180.2 mg, 73 %) as a yellow oil. ’H NMR (500 MHz, DMSO-d6): -0.02 and -0.03 (2xs, 2x3H, (CH3)2Si); 0.83 (s, 9H, (CH3)3C); 1.33 and 1.54 (2xs, 2x3H, (CH3)2C); 1.73 - 1.81 (m, 4H, H-2,3-CioHn); 2.79 (m, 2H, H-4-CioHn); 2.82 (m, 2H, H-l-CioHn); 3.71 (dd, 1H, Jgem= 11.2 Hz, Jw = 5.6 Hz, H-5'a); 3.74 (dd, 1H, Jgem= 11.2 Hz, J5'b,4= 4.7 Hz, H-5'b); 4.08 (btd, 1H, J4^a= J.s'b = 5.1 Hz, J3= 3.5 Hz, H-4 ); 4.97 (dd, 1H, J3'2' = 6.4 Hz, J3,4 = 3.5 Hz, H-3'); 5.18 (dd, 1H, J2 3= 6.4 Hz,

[0976]

[0977] 7= 2.8 Hz, H-2'); 6.21 (d, 1H,,2= 2.8 Hz, H-l '); 6.38 (s, 2H, NH2); 6.66 (d, 1H, J5,6= 3.8 Hz, H-5); 7.20 (d, 1H, J8,7= 8.0 Hz, H-8-CioHn); 7.29 (d, 1H, J6,5 = 3.8 Hz, H-6); 7.72 - 7.76 (m, 2H, H-5,7-CioHn); HR-ESI-MS: found: 551.3050 ([M + H]+, calcd for C30H43O4N4Si+: 551.3048); HR-ESI-MS: found 573.2870 ([M + Na]+, calcd for C30H42O4N4NaSi+: 573.2868).

[0978] Example 106

[0979] 2-Iodo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7-( / ?-D-ribofuranosyl)-77 / -pyrrolo[2,3-< / ]pyrimidme (27)

[0980] Isopentyl nitrite (0.07 mL, 0.50 mmol) was added to a stirred mixture of 26 (92.5 mg, 0.17 mmol), Cui (35.2 mg, 0.19 mmol), I2(46.9 mg, 0.19 mmol) and CH2I2(0.14 mL, 1.70 mmol) in 3 mL THE After the completion of the reaction, volatiles were evaporated. HPFC purification (SiO2, cH / EA 1:0 — 9:1) gave 2-iodo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7-(2,3-O-isopropylidene-5-(9-terLbutyldimethylsilyl- / LD-ribofuranosyl)-7H-pyrrolo[2,3-<7]pyrimidine (25.6 mg, 23 %) as a yellow oil. ’H NMR (500 MHz, DMSO-d6): -0.03 (s, 6H, (CH3)2Si); 0.81 (s, 9H, (CH3)3C); 1.34 and 1.56 (2xs, 2x3H, (CH3)2C); 1.75 - 1.82 (m, 4H, H-2,3-CioHn); 2.81 (m, 2H, H-4-CioHn); 2.86 (m, 2H, H-l-CioHn); 3.72 (dd, 1H, Jgem= 11.2 Hz, J5^ = 5.8 Hz, H-5'a); 3.77 (dd, 1H, Jgem= 11.2 Hz, J5b,4= 4.9 Hz, H-5'b); 4.17 (btd, 1H, J4,5■« = J4,5-b = 5.4 Hz, = 3.4 Hz, H-4'); 4.94 (dd, 1H, J3 2= 6.3 Hz, J5 4 = 3.4 Hz, H-3'); 5.27 (dd, 1H, J2 3= 6.3 Hz, J2,7 = 2.5 Hz, H-2'); 6.30 (d, 1H,,2= 2.5 Hz, H-l'); 7.02 (d, 1H, J5,6= 3.8 Hz, H-5); 7.26 (d, 1H, J8,7= 8.0 Hz, H-8-C10H11); 7.775 (d, 1H, J65= 3.8 Hz, H-6); 7.779 (bd, 1H, J5,7= 2.0 Hz, H-5-CioHn); 7.81 (dd, 1H, J78= 7.9 Hz, J7:5= 2.0 Hz, H-7-CioHn); HR-ESI-MS: found 662.1903 ([M + H]+, calcd for C30H4iO4N3ISi+: 662.1906); HR-ESI-MS: found 684.1722 ([M + Na]+, calcd for C30H40O4N3INaSi+: 684.1725).

[0981] The obtained nucleoside (50.8 mg, 0.077 mmol) was dissolved in 4 mL 75 % TFA and let to stir for 1 h at rt. After the completion of the reaction, it was co-evaporated 3 times with MeOH. HPFC (SiO2,DCM / MeOH 1:0 —> 9:1) and lyophilization from H2O / i-BuOH gave compound 27 (31.3 mg, 80 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.75 - 1.82 (m, 4H, H-2,3-CioHn); 2.81 and 2.86 (2xm, 2x2H, H-l,4-CioHn); 3.55 (ddd, 1H, Jgem= 11.8 Hz, J5 a,OH= 5.5 Hz, J5 fl,4= 3.9 Hz, H-5 'a); 3.63 (ddd, 1H, Jgem = 11.8 Hz, Js'b,0H = 5.5 Hz, Js'b,4‘ = 4.3 Hz, H-5 a); 3.94 (td, 1H, J 4', 5a=J4',5'b = 4.1 Hz, J 4 -i3- = 2.9 Hz, H-4 ); 4.11 (td, 1H, J3.2=JJ= 5.0 H

[0982]

[0983] z, = 2.9 Hz, H-3'); 4.44 (

[0984]

[0985] td, 1H, ■ = J2, OH= 6.5 Hz, J2,3= 5.0 Hz, H-2'); 5.03 (t, 1H, JOH,5a= JoH.s'b = 5.5 Hz, OH-5'); 5.25 (d, 1H, JOH.3 = 4.9 Hz, OH-3'); 5.42 (d, I H..W?= 6.5 HZ, OH-2 ); 6.15 (d, 1H, J7,2= 6.4 Hz, H-l ); 7.01 (d, 1H, J56= 3.8 Hz, H-5); 7.27 (d, 1H, Js, 7= 8.0 Hz, H-8-C10H11); 7.78 (d, 1H, J5,7= 1.9 HZ, H-5-CIOHH); 7.81 (dd, 1H, J78= 7.9 Hz, J75= 1.9 Hz, H-7-CioHn); 7.87 (d, 1H, J6,5= 3.8 Hz, H-6); HR-ESI-MS: found. 508.0729 ([M + H]+, calcd for C2iH23O4N3I+: 508.0728); HR-ESI-MS: / oz: 530.0549 ([M +Na]+, calcd for C2iH22O4N3INa+: 530.0547).

[0986] Example 107

[0987] [(5-{[2-Iodo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-77Z-pyrrolo[2,3-< / ]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (28f)

[0988] General procedure C starting from nucleoside 27 (27.5 mg, 0.054 mmol) gave bisphosphonate 28f (18.2 mg, 50 %) as a white powder. ’H NMR (500 MHz, DMSO-d6): 1.74 - 1.83 (m, 4H, H-2,3-Ci0Hn); 2.25 (t, 2H, Ja,? = 20.4 Hz, PCH2P); 2.81 (m, 2H, H-4-CioHn); 2.86 (m, 2H, H-l-CioHn); 4.07 - 4.13 (m, 3H, H-4', 5'); 4.19 (dm, 1H, J3.2= 5.1 Hz, H-3'); 4.46 (dd, 1H, J2-,7= 6.6 Hz, J2,3= 5.1 Hz, H-2'); 6.20 (d, 1H, J7,2= 6.6 Hz, H-l '); 7.00 (d, 1H, J5,6= 3.8 Hz, H-5); 7.27 (d, 1H, J8,7= 8.0 Hz, H-8-C10H11); 7.78 (d, 1H, J5,7= 1.9 Hz, H-5-CioHn); 7.81 (dd, 1H, J78= 7.9 Hz, J75= 1.9 Hz, H-7-CioHn); 7.88 (d, 1H, J65= 3.8 Hz, H-6);31P NMR (202.4 MHz, DMSO-d6): 15.83 and 19.61 (2xs, 2xlP, PCH2P). HR-ESI-MS: found 664.0118 ([M - H]“, calcd for C22H25O9N3IP2-: 664.0116).

[0989] Results of Biological Activity Screening

[0990] The inhibitory activity of target compounds was tested on recombinant human CD73 as well as on CD73-expressing cell line MDA-MB-231.

[0991] Description of the method

[0992] Cloning, expression, and purification of recombinant CD73 extracellular domain

[0993] DNA sequences encoding the enzymatic domain of human CD73 was subcloned into the expression plasmid. Expi293F™ cells (Thermo Fisher Scientific) in 100 mL of Expi293™ Met (-) medium were transiently transfected with 100 pg of expression plasmid coding rhCD73 using ExpiFectamine™ 293 Transfection Kit (Thermo Fisher Scientific) according to the manufacturer’s instructions. After six days of incubation (37 °C, 8% CO2, 120 rpm), the medium was collected, and the proteins were purified in twosteps: by affinity chromatography using cOmplete His-Tag Purification Resin (Sigma- Aldrich) and using a HiLoad Superdex 200 prepgrade column (GE Healthcare Life Sciences). The purified proteins were dialyzed against storage buffer (120 mM NaCl, 20 mM Tris, 4 mM CaCl2, 20% glycerol, pH = 7.5) and stored at -80 °C until use.

[0994] Testing of CD73 activity

[0995] The PiColorLock Gold kit (Novus Biologicals) was used to determine the inhibition constants of the tested compounds. We followed the standard protocol with specific conditions as follows: 1.25 ng of rhCD73 of TBST was mixed with a dilution series of the tested compound in 10 pL of TBST. The reaction was initiated by adding 10 pL of 2 mM AMP. After 30 minutes at room temperature, 25 pL of PiColorLock Gold was added, followed by 10 pL of Stabilizer after 5 minutes. After a further 30 minutes, absorbance was measured at 635 nm using an Infinite M1000 plate reader (Tecan). The phosphate calibration curve was used to calculate the conversion rate for each well. The percentage of activity was calculated as the ratio of the sample well to the average of the uninhibited reaction (maximum conversion did not exceed 20%). The resulting values were plotted, and IC50 and Ki values were calculated using GraphPad Prism 9 (Morrison fit).

[0996] Cellular assay for testing CD73 activity

[0997] A modified PiColorLock Gold protocol was used to determine the inhibition constants of the tested compounds on a CD73 -endogenously expressing cell line (MDA-MB-231). On the day of the experiment, an aliquot of cells stored at -80 °C was thawed at 37 °C and immediately diluted into 10 mL of assay buffer (20 mM HEPES, 137 mM NaCl, 5.4 mM KC1, 1.3 mM CaCl2, 4.2 mM NaHCOs, 0.1% glucose). The cells were then washed twice in 1 mL of the same buffer. Afterward, cells were counted using an automatic cell counter. 6000 MDA-MB-231 cells in 70 pL of assay buffer were mixed with a dilution series of the tested compound in 10 pL of assay buffer. After 1 hour of incubation at 37 °C, the reaction was initiated by adding 20 pL of 1 mM AMP for MDA-MB-231 cells. After 30 minutes at room temperature, the plate with cells was centrifuged and 80 pL of the supernatant was mixed with 20 pL of PiColorlock Gold, followed by the addition of 8 pL of Stabilizer after 5 minutes. The subsequent procedure was the same as for the recombinant protein.

[0998] All the tested compounds showed potent activity against CD73, best inhibitors have Ki in sub-picomolar range.Table 2. Inhibition of recombinant human CD73 (rhCD73)

[0999] Compound Ki (rhCD73) Compound Ki (rhCD73) Compound Ki (rhCD73)

[1000] 5a B 5v C 18h A 5b B 5w C 18i A 5c B 5x B 18j A 5d A 5y B 18k A 5e A 10a A 181 A 5f C 10b A 18m A 5g B 10c B 18n A 5h C lOd A 18o A 5i D lOe A 18p A 5j B 15a A 18q A 5k B 15b A 18r A 51 B 15c B 18s A 5m C 15d A 21a A 5n B 15e A 21b A 5o B 18a A 21c B 5p C 18b A 21d A 5q B 18c A 21e A 5r B 18d A 23a B 5s C 18e A 25a C 5t A 18f A 28f A 5u A 18g A PSB12379 D A: [<0.1] nM, B: [0.1-0.5] nM, C: [0.5-1] nM, D: [1-10] nMTable 3. CD73 activity measured on CD73 -expressing cell line MDA-MB-231

[1001] Compound MDA-MB-231 Compound MDA-MB-231 Compound ^D^MB

[1002]

[1003] 5a C 5v C 18h A 5b C 5w C 18i A 5c C 5x C 18j A 5d A 5y B 18k B 5e A 10a A 181 A 5f D 10b A 18m B 5g C 10c B 18n A 5h C lOd B 18o D 5i E lOe A 18p A 5j D 15a B 18q A 5k B 15b B 18r A 51 B 15c B 18s A 5m D 15d B 21a B 5n D 15e B 21b A 5o D 18a A 21c B 5p C 18b A 21d A 5q B 18c A 21e A 5r B 18d A 23a C 5s C 18e A 25a D 5t A 18f A 28f A 5u A 18g A PSB12379 D A: [<0.1] nM, B: [0.1-0.5] nM, C: [0.5-1] nM, D: [1-10] nM, E: [>10] nMTable 4. CD-I Mouse pharmacokinetic data for selected compounds after IV administration (1 mg / kg) Compound T1 / 2 (min) Clearance (mL / min / kg) 5a 252 4.1 lOd 316 0.32 AB680 210 0.42

[1004] Pharmacokinetic study was performed by Bienta (Enamine Biology Services) using male CD-I mice (3 animals, 9 weeks old, body weight ranged from 29.2 g to 33.7 g) following intravenous administration. Levels of the test compound were determined by LC-MS / MS in blood plasma over time (seven sampling time points: 5, 15, 30, 60, 120, 240, and 480 min) after a single dose.

[1005] Industrial Applicability

[1006] The compounds disclosed in this patent are useful as pharmaceuticals or components of drugs effective against cancer and other diseases connected with CD73 overexpression or mediated by adenosine.

Claims

CLAIMS(I),n is 0 or 1;X, Y, Z and W are independently C, 0, N or S; with the proviso that at most two of X, Y, Z and W are other than C, and with the proviso that R1is only present when the valency allows that;R1is the same or different from each other and independently selected from H; –NR2; NR2–(C1–C3)alkyl–, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; halogen; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group;and / orone or two pairs of two neighbouring substituents R1together with the atoms to which they are bound form a five-membered or a six-membered aromatic, heteroaromatic, cycloalkyl or heterocycloalkyl ring, or a nine-membered or a ten-membered bicyclic hetero aromatic ring;wherein said five-membered or the six-membered aromatic, hetero aromatic, cycloalkyl or heterocycloalkyl ring, or said nine-membered or the ten-membered bicyclic heteroaromatic ring may optionally be substituted with one or more substituents independently selected from the group consisting of -NR2; NR2-(C1-C3)alkyl-, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; halogen; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group;andR2is selected from the group comprising hydrogen; halogen; -NR2, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; (Cl-C5)alkyl; (Cl-C5)alkoxy; and (Cl-C5)alkylamino;and pharmaceutically acceptable salt thereof.

2. Compounds of general formula I according to claim 1, wherein R2is selected from the group comprising hydrogen, halogen, -NH2, (Cl-C3)alkyl, (Cl-C3)alkoxy, and (Cl-C3)alkylamino; preferably R2is selected from the group comprising Cl, F, Br, I, -NH2, -CH3, -CH2CH3, CH3-O-, CH3CH2-O-, CH3-NH-, and CH3CH2-NH-.

3. Compounds of general formula I according to claim 1 or 2, wherein the structural unit (II)whereinring C is selected from a 6-membered aryl, 6-membered heteroaryl containing at least one heteroatom selected from 0, N, S; 6-membered cycloalkyl, and 6-membered heterocycloalkyl containing at least one heteroatom selected from 0, N, S;ring D is selected from a 5 -membered heteroaryl and 5 -membered heterocycloalkyl containing at least one heteroatom selected from 0, N, S;and wherein the structural unit (II) may optionally be substituted with one or more substituents independently selected from the group consisting of -NRz; NRz-(Cl-C3)alkyl-, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; -C00H; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group.

4. Compounds of general formula I according to claim 1 or 2, wherein the structural unit (II) is selectedwhereinring C is selected from a 6-membered aryl, 6-membered heteroaryl containing at least one heteroatom selected from 0, N, S; 6-membered cycloalkyl, and 6-membered heterocycloalkyl containing at least one heteroatom selected from 0, N, S;ring D is selected from a 5 -membered heteroaryl and 5 -membered heterocycloalkyl containing at least one heteroatom selected from 0, N, S;and wherein the structural unit (II) may optionally be substituted with one or more substituents independently selected from the group consisting of -NR2; NR2-(C1-C3)alkyl-, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; halogen; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group.

5. Compounds of general formula I according to claim 1 or 2, wherein the structural unit (II) is selectedwherein ring A is a 6-membered aryl or 6-membered heteroaryl containing at least one heteroatom selected from 0, N, S; and X is 0, S or NH;and wherein the structural unit (II) may optionally be substituted with one or more substituents independently selected from the group consisting of -NR2; NR2-(C1-C3)alkyl-, wherein R are the same or different from each other and selected from H and (Cl-C3)alkyl; -OH; -CN; phenyl; halogen; -COOH; (Cl-C5)alkyl; (Cl-C5)alkyloxycarbonyl; (Cl-C5)alkoxy; (C2-C3)alkynyl; benzyloxy group.

6. Compounds of general formula I according to any one of the preceding claims, wherein the structural unit (II) is selected from phenyl, naphthyl, naphthalenyl, furanyl, benzofuranyl, thiophenyl, pyridinyl, 1H-indolyl, dibenzofuranyl, biphenyl, phenanthrenyl, quinolinyl, isoquinolinyl, quinazolinyl, tetrahydronaphthyl, tetrahydronaphthalenyl, dihydrobenzofuranyl, and chromanyl;which may further be substituted with one or more substituents selected from the group comprising -NH2, -CN, -CH2NH2, -F, -Br, -Cl, CH3O-C(=O)-, benzyloxy, -OH, CH3O-, ethynyl, and CH3-.

7. Compounds of general formula I according to any one of the preceding claims, wherein said compound of general formula I is selected from:[(5 - { 14-(N aph th alcn-2-y I )-7 / / -py rrolo [2,3 - 1 / 1 py r i m i d i n - 7-y l | - / > - D -ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5a),[(5 - { [4-(Benzofuran-2-yl)-7H-pyrrolo [2,3 -<7]pyrimidin-7-yl]ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5b),|(5-{|4-(Furan-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5c),|(5-{|4-(Naphth-l-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5d),[(5-{[4-(5,6,7,8-Tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5e),[(5 - { [4-(p-Aminomethylphenyl)-7H-pyrrolo [2,3 -<7|pyrimidin-7-yl| - / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5g),[(5-{[4-Phenyl-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5h),[(5 - { [4-(5 -Ethynylbenzofuran-2-yl)-7H-pyrrolo [2,3 -t / |pyrim idin-7-yl | - / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5j),[(5 - { [4-(Thiophen-3 -y 1 )-7Z7-py rrolo [2,3 -<7|pyrim idi n-7-y l | - / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5k),|(5-{|4-(Thiophcn-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (51),[(5-{[4-(Dibenzofuran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-P-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5n)[(5-{[4-(Phenanthren-9-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-P-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5o)[(5-{[4-(Chroman-8-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5p),[(5 - { [4-(Benzofuran-7-yl)-7H-pyrrolo [2,3 -<7]pyrimidin-7-yl]ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5q),[(5-{[4-(2,3-Dihydrobenzofuran-5-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5r),[(5-{[4-(Quinolin-4-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5t),[(5-{[4-(Isoquinolin-8-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5u),[(5-{[4-(Quinolin-6-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5v),[(5-{[4-(Quinolin-3-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5w),[(5 - { [4-(Quinazolin-7 -y 1 )-7Z7-py rrolo 12.3 -<7| py ri m idin -7 -yl] - / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5x),[(5-{[4-(Isoquinolin-6-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5y),[(5-{[2-Methyl-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10a),[(5-{[2-Methyl-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10b),[(5-{[2-Methyl-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10c),[(5-{[2-Methyl-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10d),[(5-{[2-Methyl-4-(5,6,7,8-tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10e),[(5-{[2-Amino-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15a),[(5-{[2-Amino-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15b),[(5 - { [2-Amino-4-(furan-2-yl)-7H-pyrrolo [2,3 -<7]pyrimidin-7-yl]ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15c),[(5-{[2-Amino-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15d),[(5-{[2-Amino-4-(5,6,7,8-tefrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (15e),[(5-{[2-Chloro-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18a),[(5-{[2-Chloro-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18b),[(5-{[2-Chloro-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18c),[(5-{[2-Chloro-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18d),[(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18e),[(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18f),[(5-{[4-(4-(Aminomethyl)phenyl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18g),[(5-{[2-Chloro-4-(177-indol-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]-?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18h),[(5-{[2-Chloro-4-(6-fluoronaphthalen-2-yl)-7H-pyrrolo[2,3- / pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18i),[(5-{[2-Chloro-4-(4-bromo-l-fluoronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]-y?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18j),[(5-{[2-Chloro-4-(6-chloronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18k),[(5-{[2-Chloro-4-(4-fluoronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (181),[(5-{[2-Chloro-4-(6-(methoxycarbonyl)naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18m),[(5-{[2-Chloro-4-(2,2-dimethyl-2, 3 -dihydrobenzo furan-5- l)-7H-pyrrolo|2.3-<7|p rimidin-7- l |- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18n),[(5-{[4-(6-(Benzyloxy)naphthalen-2-yl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18o),[(5-{[2-Chloro-4-(6-hydroxynaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18p),[(5-{[4-(4-Aminonaphth-l-yl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18q),|(5-{ |2-Oiloro-4-(4-cyanonaplUh-l -yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18r),[(5-{[2-Chloro-4-(6-methoxynaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18s),[(5-{[2-Fluoro-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21a),[(5-{[2-Fluoro-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21b),[(5-{[2-Fluoro-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21c),[(5-{[2-Fluoro-4-(naphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21d),[(5-{[2-Fluoro-4-(5,6,7,8-tetrahydronapht-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21e),[(5-{[2-Methoxy-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (23a),[(5-{[2-A-Methylamino-4-(naphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (25a),[(5-{[2-Iodo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (28f).

8. Compounds of general formula I according to any one of the preceding claims, wherein said compound of general formula I is selected from:[(5 - { 14-(N aph th alcn-2-y I )-7 / / -py rrolo [2,3 -<7]pyrimidin-7-yl]-?-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (5a)|(5-{|2-Mcthyl-4-(naphth-l-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (10d)|(5-{ |2-Chloro-4-(naphthalcn-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18a)[(5-{[2-Chloro-4-(benzofuran-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18b)[(5-{[2-Chloro-4-(furan-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18c)|(5-{|2-Oiloro-4-(naphth-l-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18d)[(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18e)[(5-{[2-Chloro-4-(5,6,7,8-tetrahydronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18f)[(5-{[4-(4-(Aminomethyl)phenyl)-2-chloro-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18g)[(5-{[2-Chloro-4-(177-indol-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]-?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18h)[(5-{[2-Chloro-4-(4-bromo-l-fluoronaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofiiranosyl}oxy)phosphonomethyl]phosphonic acid (18j)[(5-{[2-Chloro-4-(4-fluoronaphth-l-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (181)[(5-{[2-Chloro-4-(2,2-dimethyl-2, 3 -dihydrobenzo furan-5- l)-7H-pyrrolo|2.3-<7|p rimidin-7- l |- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18n)[(5-{[2-Chloro-4-(6-hydroxynaphthalen-2-yl)-7H-pyrrolo[2,3-<7]pyrimidin-7-yl]- / ?-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (18p)|(5-{ |2-Fhioro-4-(5.6.7.8-tctrahydronapht-l-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7- l|- / >-d-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (21e)|(5-{ |2-Iodo-4-(5.6.7.8-tctraliydronaplitlialcn-2-yl)-7H-pyrrolo|2.3-<7|pyrimidin-7-yl|- / >-D-ribofuranosyl}oxy)phosphonomethyl]phosphonic acid (28f).

9. A pharmaceutical composition, characterized in that it comprises the compound of general formula I according to any one of the preceding claims 1 to 8; and at least one pharmaceutically acceptable excipient.

10. Compounds of general formula I according to any one of the preceding claims 1 to 8 for use as medicaments.

11. Compounds of general formula I according to any one of the preceding claims 1 to 8 for use in the treatment of diseases involving pathological cell proliferation and CD73 overexpression, preferably for use in the treatment of diseases selected from the group comprising bladder cancer, leukemia, glioblastoma, breast cancer including TNBC, prostate cancer, colorectal cancer, ovarian cancer, lung cancer, pancreatic cancer, papillary thyroid cancer, gastric cancer, melanoma, autoimmune diseases, inflammation, pain management, cardiovascular diseases, and transplantation and neurological disorders.

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