NZ790347A - Ectonucleotidase inhibitors and methods of use thereof - Google Patents

Abstract

The invention relates to novel heterocyclic compounds and pharmaceutical preparations thereof. The invention further relates to methods of treating or preventing cancer using the novel heterocyclic compounds of the invention.

Description

Ectonucleotidase Inhibitors and Methods of Use Thereof RELATED APPLICATIONS This application claims the benefit of US. Provisional Application No. 62/688,225, filed June 21, 2018, and US. Provisional Application No. ,505, filed April 1, 2019, each of which is hereby incorporated by reference in its entirety.

BACKGROUND CD73, also referred to as 5’-nucleotidase ) or ecto-5’-nucleotidase (Ecto ’NTase), is a ne-bound cell surface enzyme whose primary role is to ze the conversion of extracellular nucleotides (e.g., AMP) to their corresponding nucleosides (e.g., adenosine), CD73 is found in most tissues and expressed on lymphocytes, endothelial cells, and epithelial cells. It is also widely expressed in many tumor cell lines and, notably, is upregulated in cancerous tissues (Antonioli er al., Nat. Rev. Cancer, 13: 842-857, 2013).

In tandem with CD39 (ecto-ATPase), CD73 generates adenosine from ATP/AMP, which is often released from d or inflamed cells into the extracellular nment.

Extracellular adenosine produced by CD73 cts with G-protein coupled receptors on target cells. An important downstream effect of this signaling is increased immunosuppression via a number of pathways. For example, CD73 is a co-signaling molecule on T cytes. Under normal circumstances, extracellular adenosine levels promote a self-limiting immune response that prevents excessive inflammation and tissue damage. For tumors, an advantage of ally increased CD73 is that the resulting increased CD73-catalyzed adenosine levels yield inhibition of anti—tumor immune system responses.

Even though CD73 plays a role in cancer immunosuppression, higher expression of CD73 is associated with a variety of stages of tumor progression, including tumor vascularization, veness, and metastasis, and with shorter breast cancer patient survival time. Some of these observations result from CD73’s enzyme-independent function as an on molecule required for lymphocyte binding to the endothelium.

Overall, CD73 has become an important target for developing new cancer therapies, either as single agents or in combination with other cancer therapies. Indeed, combining CD73 monoclonal dies with antibodies for other chemotherapy targets enhances response and survival in animal cancer models (Allard et al., Clin. Cancer Res., 19:5626-35, 2013).

Many of the current cancer treatments and chemotherapeutic agents fail to successfully treat all patients or all symptoms in treated patients, and many of these ies are associated with rable side effects. As certain cancers develop resistance to various chemotherapeutic agents, ate cancer therapies are needed. Thus, there is a need for additional compounds and methods for treating cancer and other diseases.

SUMMARY Disclosed herein are compounds of Formula (I): Y 0 Het R2b R1 b R23 R1a or a pharmaceutically acceptable salt and/or prodrug thereof, wherein R4 o o R5 || II \P p_§_ 5i R15/ V/ Y is R6 or R15 Het is heterocyclyl or heteroaryl; Rlais ed from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyCi- 6alkyl, amino-Ci-salkyl, -O-C(O)-O-C1-6alkyl, Cmacyloxy, C1-6alkoxy, C2.6alkenyl, and kynyl; R1b is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; Rzais selected from halo, y, cyano, azido, amino, kyl, hydroxy-C1-6alkyl, amino-Ci—salkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; R21) is selected from halo, C1-6alkyl, C2-6alkenyl, and C2.6alkynyl, preferably substituted or tituted Czalkynyl, most preferably unsubstituted Czalkynyl; R3 is selected from H and alkyl, R4 is selected from H, alkyl, CN, aryl, heteroaryl, -C(O)OR9, RHR12, - S(O)2R10, -P(O)(OR”)(OR12), and -P(O)(OR”)(NR13R14); R5 is ed from H, cyano, alkyl, lkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9; R6 is selected from —C(O)OR9, -C(O)NR16R17, and —P(O)(OR11)(OR12); R9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; R10 is independently selected from alkyl, alkenyl, alkynyl, amino, lkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R11 and R12, together with the en atom to which they are attached, form a 5- to 7-membered heterocyclyl, R13 is H or alkyl, R14 is alkyl or aralkyl, each R15 is independently selected from y, alkoxy acyloxy and NR13R14, each R16 and R17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, cyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R16 and R17, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

In certain preferred embodiments of Formula I, the included compounds meet the terms of a) and b); or a) and c); wherein: W0 46403 O NH2 NH2 0 GE </N '\N EtO 0:0N 0 NA Nn a) the compound is not To“ 0 ”81:1 0 o v.

)LN Ho‘ HN\\) \N o N//'\CI “1:56 /=N \N 0 O <’ I Eto O N / HO CAL-7‘NW N/kCI “0 ”OH ”3/“ . .

Cl Ho‘ ’OH , ,or O NH2 b) if R4 and R6 are each -C(O)OH and R5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, then the phenyl ring substituent is selected from unsubstituted or substituted pyrrolidinyl, piperazinonyl, piperidonyl, tetrahydropyrimidonyl, nyl, and pyridyl; and c) if R4 is H or tetrazolyl, R6 is -C(O)OH, and R5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with -C(O)OR9 where R9 is H or alkyl.

R6 In some embodiments, Y is . In other embodiments, Y is O O R” || II > p—;— R15 V/ In certain preferred embodiments: W0 20192946403 O NH2 NH2 0 GE </N '\N EtO 0:0N 0 NA Nn a) the nd is not To“ 0 ”81:1 0 o v.

)LN Ho‘ HN\\) \N o N//'\CI N; \,N o NH2 N o OEt N O 0%O N/=N NH </ l1 2 / HO ”OH ”3/“ . .

Cl Ho‘ ’OH ,or O NH2 0 OH N </ 1‘” b) R2b is selected from halo, C2-6alkyl, C2-6alkenyl, and kynyl, preferably substituted or unsubstituted Czalkynyl, most preferably unsubstituted Czalkynyl, and either c) R5 is benzyl substituted on the phenyl ring with a substituent selected from unsubstituted or substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl, or d) R5 is benzyl substituted on the phenyl ring with a second phenyl ring substituted with -C(O)OR9 Where R9 is H or alkyl.

In certain embodiments, the present invention provides a ceutical composition suitable for use in a subject in the treatment or prevention of cancer comprising an effective amount of any of the compounds described herein (e. g., a nd of the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more ceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein.

Disclosed herein are methods of treating diseases and conditions that benefit from the inhibition of CD73, comprising administering to a subject in need thereof an effective amount of a nd as disclosed herein (e.g., a compound of Formula (I) or any of the embodiments thereof sed herein). In certain embodiments, the human t is in need of such treatment. These diseases include, but are not limited to cancers, such as lung cancer, WO 46403 kidney cancer, skin cancer, breast cancer, and ovarian cancer. Other diseases and conditions that can be treated using the methods described herein include, but are not limited to, neurological, neurodegenerative and CNS disorders and diseases such as sion and son’s disease, cerebral and c ischemic diseases, sleep disorders, fibrosis, immune and inflammatory disorders.

Provided herein are combination therapies of compounds of formula (I) with onal antibodies and other chemotherapeutic agents that can enhance the therapeutic benefit beyond the ability of the adjuvant therapy alone.

BRIEF DESCRIPTION OF THE FIGURES depicts the increase in %CD8+ cells of CD45+ cells in EG7 tumors from mice treated with Compound 9. depicts the reversal of efficacy using Compound 9 when CD8+ cells are ed with an anti-CD8 antibody. depicts the al of AMP-mediated suppression of CD8+ T cells using the CD73 inhibitor Compound 9, including the EC50=11.6nM for CD8+ T cell proliferation. depicts the EC50=9.6 nM for CD8+ T cell activation. depicts the .5 nM for [FN—gamma production. depicts the ECso=5.6nM for Granzyme B tion. depicts the effect of Compound 9 on proliferation of certain cell lines, including the comparable % cell survival of EG7 cells, a mouse T cell lymphoma cell line. depicts the comparable % cell al of A375 cells, a human melanoma cell line. depicts the comparable % divided cells of human CD8+ T cells. depicts the potency of Compound 9 as evaluated against CD73 and CD73- expressing SK-lVIEL—28 cells. depicts the IC50=0.17 nM for human recombinant CD73. depicts the ICso=0.38 nM for human plasma CD73. depicts the 1C50=0.21 nM for human CD73 cell surface assay. depicts the level of Compound 9 in mouse plasma. depicts the inhibition of CD73 in mouse plasma. s the efficacy of Compound 9 against EG7 tumors. depicts the efficacy of Compound 9 against CT26 tumors. depicts the reduction in tumor volume with single agent Compound 9 and combination therapy with anti-PD—Ll antibody.

FIGs. 7B-7E show dual replications of this measurement for each dosing. is vehicle. is anti- PD-Ll antibody. is Compound 9. is Compound 9 + Anti—PD-Ll. depicts the reduction in tumor volume with single agent Compound 9 and combination therapy with oxaliplatin.

FIGs. 8B-8E show individual ations of this ement for each dosing. is vehicle. is oxaliplatin. is Compound 9. FIG. SE is Compound 9 + latin. depicts the reduction in tumor volume with single agent Compound 9 and combination therapy with doxorubicin.

FIGs. 9B-9E show individual replications of this measurement for each dosing. is vehicle. is doxorubicin. is Compound 9. is Compound 9 + doxorubicin.

A depicts the sub-nanomolar inhibition of CD73 activity in head and neck squamous cell oma (HNSCC) serum by Compound 9.

B s the sub—nanomolar tion of CD73 activity in ovarian cancer serum by Compound 9.

C depicts the sub-nanomolar inhibition of CD73 activity in triple—negative breast cancer (TNBC) serum by compound 9.

D depicts the sub-nanomolar inhibition of CD73 activity in esophageal cancer serum by Compound 9. depicts normalized mRNA expression levels of CD73 in tumor and normal A depicts the reduction in tumor volume with single agent Compound 9 and combination therapy with docetaxel in EG7 tumor model.

FIGs. 12B-12E depict individual replications of the reduction in tumor .

B shows vehicle. C is Compound 9. D is docetaxel. E is Compound 9 + docetaxel.

A depicts Compound 9 reduced the growth of established EG7 tumors.

FIGs. 13B-13D depict individual replications of the reduction in tumor growth.

B is vehicle. C is dosing of nd 9 started on day 1. D is Compound 9 started on day 6.

DETAILED DESCRIPTION Definitions Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by a person skilled in the art of the t disclosure. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular y (2nd ed. 1994), The Cambridge Dictionary of e and Technology (Walker ed, 1988), The Glossary of Genetics, 5th Ed, R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

In some embodiments, chemical structures are disclosed with a corresponding chemical name. In case of conflict, the al structure controls the meaning, rather than the name.

In this disclosure, "comprises, comprising, containing" and "having" and the like " includes," can have the meaning ascribed to them in US. Patent law and can mean "including," and the like, "consisting essentially of" or "consists ially" likewise has the meaning ed in US. Patent law and the term is open-ended, allowing for the presence of more than that which is recited so long as basic or novel characteristics of that which is recited are not substantially changed by the presence of more than that which is recited, but excludes prior art embodiments.

Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context otherwise, as used herein, the terms "a", "an", and "the" are understood to be ar or plural.

The term “acyl” is cognized and refers to a group represented by the l formula arble(O)—, preferably alkle(O)-.

The term mino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarble(O)NH-.

The term “acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarble(O)O-, preferably alkle(O)O-.

The term “alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups e methoxy, ethoxy, propoxy, utoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term “alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more s that are included or not included in one or more double bonds. Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is plated.

An “alkyl” group or “alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely ted. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise . Examples of straight chained and branched alkyl groups include , ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also ed to as a "lower alkyl" group.

Moreover, the term " (or "lower ) as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and ituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a ate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the es substituted on the hydrocarbon chain can themselves be substituted, if appropriate.

For instance, the tuents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, oryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and ate), and silyl groups, as well as ethers, alkylthios, yls (including ketones, des, carboxylates, and esters), -CF3, -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further tuted with alkyls, ls, alkoxys, alkylthios, aminoalkyls, carbonyl- substituted , —CF3, -CN, and the like.

The term “Cx.y” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from X to y s in the chain. For example, the term “Cx—yalkyl” refers to substituted or unsubstituted saturated hydrocarbon , including straight-chain alkyl and branched-chain alkyl groups that n from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-tirfluoroethyl, etc. Co alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms “C2.yalkenyl” and “C2.yalkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term “alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

The term “alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term “alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both stituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds. Moreover, such substituents include all those contemplated for alkyl groups, as sed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term “amide”, as used herein, refers to a group WO 46403 wherein each R30 independently represents a hydrogen or hydrocarbyl group, or two R30 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms ” and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be ented by R31 R31 / / é—N\ §—N{—R31 R31 or R31 wherein each R31 independently represents a hydrogen or a hydrocarbyl group, or two R31 are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure. The term “aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

The term “aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably, the ring is a 5- to 7- membered ring, more preferably a 6—membered ring. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings n at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term “carbamate” is art-recognized and refers to a group O O fr‘\OJkN/R32 or 5‘:\NiO/R32 R53 [233 wherein R32 and R33 ndently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R32 and R33 taken together with the intervening atom(s) te a heterocycle having from 4 to 8 atoms in the ring structure.

WO 46403 The terms “carbocycle”, and cyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.

The term “carbocycle” includes 5-7 membered clic and 8-12 membered bicyclic rings. Each ring of a bicyclic ycle may be ed from saturated, unsaturated and ic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared n the two rings. The term “fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring.

Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a ted or unsaturated ring, e. g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2. l]heptane, 1,5-cyclooctadiene, l,2,3,4-tetrahydronaphthalene, o[4.2.0]octene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, l,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro- lH—indene and bicyclo[4.1.0]heptene. “Carbocycles” may be tuted at any one or more positions capable of bearing a hydrogen atom.

A “cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.

“Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term “fused cycloalkyl” refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.

The second ring of a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. A alkenyl” group is a cyclic hydrocarbon containing one or more double bonds.

The term “carbocyclylalkyl”, as used , refers to an alkyl group substituted with a carbocycle group.

The term “carbonate” is art—recognized and refers to a group —OC02—R34, wherein R34 represents a hydrocarbyl group.

The term “carboxy”, as used herein, refers to a group represented by the formula -C02H.

The term “ester”, as used herein, refers to a group -C(O)OR35 wherein R35 represents a hydrocarbyl group.

The term “ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.

Examples of ethers e, but are not limited to, cycle-O-heterocycle and aryl-O- heterocycle. Ethers include “alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

The terms “halo” and “halogen” as used herein means n and includes chloro, fluoro, bromo, and iodo.

The terms “hetaralkyl” and oaralkyl”, as used herein, refers to an alkyl group substituted with a l group.

The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

The terms “heteroaryl” and “hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two atoms. The terms “heteroaryl” and yl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e. g., the other cyclic rings can be cycloalkyls, lkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term “heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred atoms are nitrogen, oxygen, and sulfur.

The terms “heterocyclyl”, “heterocycle”, and ocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to lO-membered rings, more preferably 3— to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and “heterocyclic” also include clic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or cyclyls. Heterocyclyl groups include, for e, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

The term “hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =0 or :8 substituent, and typically has at least one carbon- hydrogen bond and a ily carbon backbone, but may optionally include heteroatoms.

Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the es of this application, but tuents such as acetyl (which has a =0 substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations f.

The term “hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a y group.

The term “lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, l, or alkoxy is meant to e groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A “lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In n embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when ng the carbon atoms in the alkyl sub stituent).

The terms “polycyclyl”, “polycycle”, and “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining Iings, e.g., the rings are “fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term “silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

The term “substituted” refers to moieties having tuents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the it proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, ation, etc. As used herein, the term “substituted” is contemplated to include all permissible tuents of organic nds. In a broad aspect, the permissible substituents include acyclic and cyclic, ed and unbranched, carbocyclic and cyclic, aromatic and omatic substituents of organic compounds.

The permissible substituents can be one or more and the same or different for appropriate organic nds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a ate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a oyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” nces to chemical moieties herein are tood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and tituted variants.

The term “sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof.

The term “sulfonamide” is art—recognized and refers to the group represented by the l formulae 0' IR36 OQSIR é—S—N or , “O .. s—N. wherein R36 and R37 independently represent hydrogen or hydrocarbyl, such as alkyl, or R36 and R37 taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “sulfoxide” is art—recognized and refers to the group -S(O)-R38, wherein R38 represents a hydrocarbyl.

The term “sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

The term ne” is art-recognized and refers to the group -S(O)2-R39, wherein R39 represents a hydrocarbyl.

The term “thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

The term “thioester”, as used herein, refers to a group -C(O)SR40 or -SC(O)R40 n R10 represents a hydrocarbyl.

The term “thioether”, as used , is equivalent to an ether, wherein the oxygen is ed with a .

The term “urea” is art-recognized and may be represented by the general formula s’S\NJLN,R42 R41 R41 wherein R41 and R42 independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R41 taken together with R42 and the intervening atom(s)complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term “protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed, 1999, John Wiley & Sons, NY and on et al., Compendium ofSynthetic Organic Methods, Vols. 1—8, 1971—1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ), tert-butoxycarbonyl (“Boo”), trimethylsilyl (“TMS”), 2—trimethylsilyl—ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9—fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxyl protecting groups e, but are not limited to, those where the hydroxyl group is either acylated ified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS ), glycol , such as ethylene glycol and ene glycol derivatives and allyl ethers.

In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one omer. For example, a compound of the invention may have greater than about 30% ee, about 40% ee, about 50% ee, about 60% ee, about 70% ee, about 80% ee, about 90% ee, or even about 95% or r ee. In certain embodiments, nds of the invention may have more than one stereocenter. In certain such embodiments, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the ion may have greater than about 30% de, about 40% de, about 50% de, about 60% de, about 70% de, about 80% de, about 90% de, or even about 95% or greater de.

In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula (1)). An omerically enriched mixture may comprise, for example, at least about 60 mol percent of one enantiomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent. In certain embodiments, the nd enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a ition or compound mixture contains about 98 grams of a first enantiomer and about 2 grams of a second enantiomer, it would be said to contain about 98 mol percent of the first enantiomer and only about 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula (1)). A diastereomerically enriched mixture may comprise, for example, at least about 60 mol percent of one diastereomer, or more preferably at least about 75, about 90, about 95, or even about 99 mol percent.

The term "subject" to which administration is contemplated es, but is not d to, humans (i.e., a male or female of any age group, e. g., a pediatric subject (e. g., infant, child, adolescent) or adult t (e.g., young adult, middle—aged adult or senior adult)) and/or other primates (e. g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs; and/or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and/or turkeys. Preferred subjects are humans.

As used herein, a therapeutic that “prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the er or condition in the treated sample relative to an ted control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated The term ing” includes prophylactic and/or therapeutic treatments. The term ylactic or therapeutic” treatment is art-recognized and includes administration to the subject of one or more of the disclosed compositions. If it is stered prior to clinical station of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, rate, or stabilize the existing unwanted condition or side effects f).

The term ug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of Formula (1)). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the subject. For example, esters or carbonates (e,g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain ments, some or all of the compounds of Formula (I) in a formulation represented above can be replaced With the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid.

An “effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired biological effect. A “therapeutically effective amount”, as used herein, refers to an amount that is sufficient to achieve a desired therapeutic effect. For example, a therapeutically effective amount can refer to an amount that is sufficient to improve at least one sign or symptom of cancer.

A “response” to a method of ent can include a decrease in or amelioration of negative symptoms, a decrease in the ssion of a disease or ms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, ization of disease, partial or complete remedy of e, among others.

In some embodiments, the ion provides a compound of formula (I): Y 0 Het R2b R1 b RZa R1 a or a pharmaceutically acceptable salt and/or prodrug thereof, n R4 O O R \IF!15 R5 L|_§_ 555\ R15/ v/ Y is R6 or R15 Het is heterocyclyl or heteroaryl, Rlais selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyCi— 6alkyl, amino-C1-6alkyl, -O-C(O)-O—C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl; R11) is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-Ci-salkyl, Cmalkenyl, and C2-6alkynyl, Rzais selected from halo, hydroxy, cyano, azido, amino, C1.6alkyl, hydroxy—Ci-salkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, Cmalkoxy, C2-6alkenyl, and C2-6alkynyl, R21) is ed from halo, C1-6alkyl, C2-6alkenyl, and C2.6alkynyl, preferably substituted or unsubstituted Czalkynyl, most preferably unsubstituted Czalkynyl, R3 is selected from H and alkyl; R4 is selected from H, alkyl, CN, aryl, heteroaryl, R9, -C(O)NRHR12, - S(O)2R10, OR”)(OR12), and OR”)(NR13R14); R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9; R6 is selected from —C(O)OR9, -C(O)NR16R17, and —P(O)(OR11)(OR12), R9 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl; each R11 and R12 is independently selected from H, alkyl, cycloalkyl, lkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or R11 and R12, together with the en atom to which they are attached, form a 5- to 7-membered heterocyclyl; R13 is H or alkyl; R14 is alkyl or aralkyl; each R15 is independently selected from hydroxy, alkoxy acyloxy and NR13R14, each R16 and R17 is independently selected from H, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R16 and R17, er with the en atom to which they are attached, form a 5- to 7-membered heterocyclyl.

In certain preferred embodiments of Formula I, the included compounds meet the terms of a) and b); or a) and c); wherein: W0 20192946403 2019/038245 O NH2 NH2 0 GE </N '\N EtO 0:0N 0 NA Nn a) the compound is not To“ 0 ”81:1 0 o v.

)LN Ho‘ HN\\) \N o N//'\CI “1:56 /=N \N 0 CAL-7‘NO <’ I EtC) (3 “' / fiC) PJ”L‘C: C- TT/ “0 ”OH ”3/“ . .

Cl HO“ "OH , ,or O NH2 b) if R4 and R6 are each -C(O)OH and R5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, then the phenyl ring substituent is selected from unsubstituted or substituted pyrrolidinyl, piperazinonyl, piperidonyl, tetrahydropyrimidonyl, pyridonyl, and l; and c) if R4 is -C(O)OH or tetrazolyl, R6 is -C(O)OH, and R5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with -C(O)OR9 where R9 is H or alkyl.

In some embodiments, the invention provides a compound of formula (11): F24 F13 C3 flet RZb R1 b R23 R1 a or a pharmaceutically acceptable salt and/or prodrug thereof, wherein Het is heterocyclyl or heteroaryl, Rlais selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyCi- , amino-C1-6alkyl, )-O-C1-6alkyl, C1-6acyloxy, C1-6alkoxy, C2.6alkenyl, and Czsdkynyh R1b is selected from H, halo, C1-6alkyl, hydroxy-Crsalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl; Rzais selected from halo, hydroxy, cyano, azido, amino, C1.6alkyl, hydroxy-C1-6alkyl, amino-Ci-salkyl, Cmacyloxy, -O-C(O)-O-C1-6alkyl, C1-6alkoxy, C2-6alkenyl, and C2-6alkynyl, R21) is selected from H, halo, C1-6alkyl, C2-6alkenyl, and C2—6alkynyl, R3 is selected from H and alkyl, R4 is selected from alkyl, aryl, aryl, R9, -C(O)NR”R12, -S(O)2R10, -P(O)(OR”)(OR12), and -P(O)(OR”)(NR13R14), R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9, R6 is ed from -C(O)OR9, -C(O)NR“R12 and -P(O)(OR”)(OR12), R9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, and heteroaralkyl; R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, aralkyl, or R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl, R13 is H or alkyl, and R14 is alkyl or aralkyl, provided that a), b) and c); or a), b) and d); o NH2 NH2 0 GE <NI EtO 'Nim 0:00 HO 0:2:o <IN<Nf:N*0 a) the compound is not H6 I 0 BEIf/im HZOHOO\é’ifikm N C' N 00 m oWit </ I\N HO 0 N o CI 0 M No OWNAI<NfN1H2 ON C b) sz is selected from halo, C2-6alkyl, C2-6alkenyl, and C2.6alkynyl, ably substituted or unsubstituted Czalkynyl, most preferably unsubstituted Czalkynyl, c) if R4 and R6 are each -C(O)OH and R5 is benzyl substituted on the phenyl ring with a heterocyclyl or aryl substituent, then the phenyl ring substituent is selected from unsubstituted or substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl; and d) if R4 is -C(O)OH or tetrazolyl, R6 is -C(O)OH, and R5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with -C(O)OR9 where R9 is H or alkyl.

In certain preferred embodiments: o NHZ NH2 0 CE EtO o *0 a) the nd is not H0 0::0o (NjiqiN<N HO OwN NACI HO [RE/km o 0 _ V. w H)“ F HN)LN Hd H:{in HoWt”: HO OWN NACI 0 OH </N 0 [\N F HO o N ~_ NA OH O “0 "0“ ”Y“ “0 '6“ ”Y“ Cl CI O NH2 0 NH2 0 CE /N O OH < \N /N \N l A < l A EIO 0—: N HO 0—: N O N CI O N CI Hd 90H or HOc I(OH 7 ; and b) R2b is selected from halo, C2-6alkyl, C2-6alkenyl, and C2.6alkynyl, preferably substituted or unsubstituted Czalkynyl, most preferably unsubstituted Czalkynyl; and either c) R5 is benzyl substituted on the phenyl ring with a tuent selected from unsubstituted or substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl, or d) R5 is benzyl substituted on the phenyl ring with a second phenyl ring substituted with -C(O)OR9 Where R9 is H or alkyl.

The following paragraphs describe various embodiments of compounds of Formula I or II, which may be combined in any combination as consistent with the formulas as defined above.

In certain embodiments, Rla is H or hydroxy. In certain embodiments, R113 is H or yl. In other embodiments, R121 is hydroxy and R11) is H.

In some ments, R2a is hydroxy or C1.6alkyl. In certain embodiments, R2b is C2- , C2-6alkenyl or C2-6alkynyl, preferably substituted or unsubstituted C2alkynyl, such as ethynyl. In certain preferred ments, R2a is Me and R2b is ethynyl. In some embodiments, R2a is hydroxy and R21) is ethyl or Vinyl. In other preferred embodiments, R221 is hydroxy and R21) is ethynyl. In some embodiments, R2b is yl, butynyl, _ / \NH % j, or unsubstituted or substituted / In certain preferred embodiments, R3 is H.

In certain embodiments, the compound of Formula (I) has the ing structure: Y X Het R2b R1b R23 R1a In certain embodiments, the compound of Formula (II) has the following structure: R5>1\ X Het R2b R1b R23 R13 In certain such embodiments, R1a is in the guration. For example, the compound of Formula (I) may have the structure (IA): RZb a, Rlb R23 ’l/R1a Further, the compound of Formula (II) may have the structure (IIAa): R4 R3 R5>l\ Het (IIAa) In alternative embodiments, R1a is in the B-configuration. In some such ments, the compound of Formula (I) has the structure (I3): Y X Het sz "’III/R1b R22 R16 (113) In some such ments, the compound of Formula (II) has the structure (IIBa): (IIBa) In further embodiments of nds of Formula (I), e.g., as described above, R221 is in the u-configuration. For example, the compound of Formula (I) may have the structure (IC): (IICa) In alternative embodiments, R2a is in the B-configuration. In some such embodiments, the compound of Formula (I) has the structure (ID): Y X Het R2b\\“ R1b R22 R13 (113) In further preferred embodiments, the compound of Formula (II) has the structure (IIDa): R4 R3 R2b\\" R1b R23 R13 (IIDa) In certain red embodiments, the compound of Formula (I) has the structure (IE): In further preferred embodiments, the compound of Formula (II) has the ure (IIEa): (IIEa) In particularly preferred such embodiments, R1a is hydroxy and R2“1 is hydroxy and R2b is selected from methyl, ethyl, Vinyl, and ethynyl, most preferably ethynyl. In most preferred embodiments of the compound of Formula (IE), R1a is hydroxy, R2a is hydroxy, and R21) is ethynyl. In some preferred embodiments of the nd of Formula (IIEa), R1a is hydroxy, R2a is y, and R2b is ethynyl.

In certain embodiments, Y is R6 In n embodiments, R4 is selected from R9, -C(O)NR”R12, -S(O)2R10, and -P(O)(OR”)(OR12). In some embodiments, R4 is -C(O)OR9 and R9 is H or alkyl. In other embodiments, R4 is -C(O)NR”R12, In certain embodiments, each R11 and R12 is independently selected from H and alkyl, or R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl. In other embodiments, R4 is -S(O)2R10 and R10 is alkyl or aryl.

In some embodiments, R6 is -C(O)OR9 and R9 is H or alkyl, e.g., H or C1-6alkyl. In other embodiments, R6 is -C(O)NR“R12. In certain such embodiments, each R11 and R12 is independently selected from H and alkyl, or R11 and R12, er with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl.

In certain preferred embodiments, R4 and R6 are each -C(O)OH, most preferably wherein R5 is benzyl, e. g., as discussed in greater detail below.

In certain embodiments, R5 is selected from H, alkyl, aralkyl and heteroaralkyl. In certain such ments, each alkyl, aralkyl and aralkyl at R5 is unsubstituted or substituted with one or more substituents selected from halo, alkyl, alkoxy, carbonyl, amino, amido, cycloalkyl, heterocyclyl, and aryl. In other embodiments, the substituents on the alkyl, aralkyl and heteroaralkyl at R5 are selected from halo, haloalkyl, alkoxy, carbonyl, aryl, heterocyclyl, and aryl. In certain embodiments, R5 is aralkyl, e.g., substituted on the aryl ring with a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl. In certain ular embodiments, R5 is selected from H, methyl, ethyl, -CH2—ethynyl, and - CHz-Vinyl. In other embodiments, R5 is selected from benzyl, -CH2-pyridyl, -CH2- pyridazinyl, -CH2-oxazolyl, -CH2-thiophenyl, -CH2-furanyl, -CH2-thiazolyl, and -CH2- benzothiazolyl, preferably benzyl and -CH2-thiophenyl.

In certain preferred embodiments, R5 is benzyl tuted on the phenyl ring (e.g., at a para position) with a heterocyclyl or heteroaryl sub stituent, preferably wherein the phenyl ring substituent is selected from substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyn'dyl. In some embodiments, the phenyl ring substituent is piperazinonyl. In certain such embodiments, the donyl, tetrahydropynmidonyl, pyridonyl, or pyridyl is substituted with one or more of alkyl, hydroxyalkyl or alkoxyalkyl.

In certain embodiments, R5 is aralkyl or heteroaralkyl with a para substituent on the aryl or heteroaryl ring selected from heterocyclyl, aryl, and aryl, and R21) is methyl, ethyl, or C2-6alkynyl.

In certain preferred ments, R5 is benzyl substituted on the phenyl ring (e.g., at o o “be“be\| | 7 3 O O “bkwax or\ OMe I I , ,Orl / ~ In certain embodiments, certain preferred embodiments, R5 is benzyl substituted on O O NELL/ HNiNk the phenyl ring (e.g., at the 4—position) with v , , W0 20192’246403 2019/038245 \Nifi; \/\NJ\N}{ K) K) \N Hz/\N WES/Y o 0 “ON\/\ \o/N /O\/\N 3: N \ N \ ”I: \ ,l / I Insomeenmodhnmua W0 46403 0 OH 0 NH2 HO HO R6 represents 0 O 0 NH2 0 NH N H2N jg HO 0 o3‘; HO 0% O O 7 7 /OH /OH O O 0 Me \ \ P—OH P—OH O§s/ MeO jg EtO HO O O}{ 0 o o j 7 H O OH ph O OH O§8/ HO HO 0% HO oj; O O 7 7 o OH OH O OH HO 0% // o W0 246403 o OEt 0 OH 0 0H EtO ){ HO jg HO O O Ojg OH \\ //0 OH o;%; HO o;%; 7 7 O OH O O 9 3 F3C F30 O OH O OEt HO HO Ojg O}{ O 0 M60 CI 0 OH \ / O OH W0 246403 0 (DH W0 246403 W0 46403 In some embodiments, Y is R15 . In certain embodiments, each R15 is hydroxy.

In certain ments, Het is selected from a 6- to bered aryl, a 5- to 8- membered heterocyclyl, a 5— to 8-membered monocyclic or 5- to lO-membered bicyclic heteroaryl, and may be unsubstituted or substituted with one or more substituents selected from halo, alkyl, haloalkyl, alkoxy, yl, amino, amido, alkylthio, alkoxycarbonyl, cycloalkyl, aryl, heterocyclyl and heteroaryl. In some embodiments, the Het substituents are selected from halo, haloalkyl, amino, and heterocyclyl. In certain embodiments, Het is a nitrogen-containing heterocyclyl or heteroaryl, preferably attached to the core ring Via a nitrogen atom of the heterocyclyl or heteroaryl ring. In some ments, Het is o NH2 / /NH NH /\N 7H0 :5; A . In other embodiments, Het is In other embodiments, Het is {f2 Ra N( I\ 75: NAijys N/ wherein Z is CH or N; Ra is ed from H, halo, hydroxy, alkyl, thiophenyl, -NR7R8, aralkyl, aryl, and heteroaryl, preferably from H, Cl, -NR7R8, and phenyl; Rb is selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkylthio, amido, carbonyl, amido, and heteroaryl, R7 is selected from H, y, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl; and R8 is H or alkyl, or R7 and R8, together with the nitrogen atom to which they are attached, form a 4- to 7- membered cyclyl ring.

In some embodiments, Het is ~76: «Am In certain embodiments, Z is CH. In other embodiments, Z is N.

In certain embodiments, Ra is selected from H, halo, alkyl, thienyl, -NR7R8, aryl, and heteroaryl, preferably from H, Cl, —NR7R8, and . In some embodiments, R3 is -NR7R8.

In certain embodiments, Rb is selected from halo, alkyl, hydroxyalkyl, haloalkyl, amido, carbonyl, amido, and aryl. In some embodiments, Rb is selected from C1, -CF3, carbonyl and -CONH2.

NR7R8 </ \N 7‘» NA In some embodiments, Het is Cl In some embodiments, R7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl. In certain embodiments, R7 is alkyl or cycloalkyl, e. g, where the alkyl or cycloalkyl is unsubstituted or substituted with one or more tuents selected from hydroxy, alkoxy, aryl, amino, and cycloalkyl. In other embodiments, R7 is aralkyl or heteroaralkyl, e.g., where the aralkyl or heteroaralkyl is unsubstituted or substituted with halo or alkyl.

In some embodiments, R8 is ed from H, methyl, and ethyl.

In other embodiments, R7 and R8, together with the nitrogen atom to which they are attached, form a heterocyclyl ring, e.g., selected from azetidinyl, morpholino, pyrrolidinyl, and azepanyl.

Methods of Use Provided herein are methods of inhibiting CD73 in a cell, comprising contacting the cell with a compound of the invention, such as a compound of formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, contacting the cell occurs in a subject in need thereof, thereby ng a disease or disorder mediated by ine.

Also, disclosed herein are methods of treating a disease or a disorder mediated by adenosine comprising administering a compound the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, disclosed herein are s of treating cancer comprising administering a compound the invention, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Adenosine acts on a variety of immune cells to induce immunosuppression, and the suppressive effects of cleotidases that enhance adenosine levels are also associated with enhanced infections of mammalian cells by parasites, fungi, ia, and viruses. Apart from immunosuppressive effects, adenosine also has a role in ting the cardiovascular system (as a vasodilator and cardiac depressor), the l nervous system (CNS) (inducing sedative, anxiolytic and antiepileptic effects), the respiratory system (inducing bronchoconstriction), the kidney (having ic action; inducing vasoconstriction at low concentrations and vasodilation at high doses), fat cells iting lipolysis), and platelets (as an anti-aggregant). Furthermore, adenosine also promotes fibrosis (excess matrix production) in a variety of tissues. Therefore, improved treatments targeting CD73 would provide therapies for treating a wide range of conditions in addition to cancer, ing cerebral and cardiac ischemic disease, is, immune and inflammatory disorders (e.g., atory gut motility disorder), ogical, neurodegenerative and CNS disorders and diseases (e.g., depression, Parkinson’s disease), and sleep disorders.

In some embodiments, the disease or the disorder mediated by adenosine is selected from cerebral ischemic e, cancer, cardiac ischemic disease, depression, s, an immune er, an inflammatory disorder (e.g., inflammatory gut motility disorder), neurological disorder or disease, neurodegenerative disorder or disease (e.g., Parkinson’s disease), CNS ers and diseases, and sleep disorders.

The methods described herein are useful for the treatment of a wide variety of cancers, ing bladder cancer, bone cancer, brain cancer (including glioblastoma), breast cancer, cardiac cancer, cervical , colon , colorectal cancer, esophageal cancer, f1brosarcoma, gastric cancer, gastrointestinal cancer, head & neck cancer, ’s sarcoma, kidney cancer (including renal cell adenocarcinoma), leukemia, liver cancer, lung cancer (including non-small cell lung cancer, small cell lung cancer, and mucoepidermoid pulmonary carcinoma), lymphoma, melanoma, myeloma, ovarian cancer (including ovarian adenocarcinoma), pancreatic cancer, penile , prostate cancer, testicular germcell cancer, thymoma and thymic carcinoma.

In some embodiments, the subject has a cancer selected from breast cancer, brain , colon cancer, f1brosarcoma, kidney cancer, lung cancer, melanoma, ovarian cancer, and prostate . In certain embodiments, the subject has a cancer selected from breast cancer, colon cancer, f1brosarcoma, melanoma, ovarian cancer, and prostate cancer. In other embodiments, the subject has a cancer selected from brain cancer, breast cancer, kidney cancer, lung cancer, melanoma, and ovarian cancer. In some embodiments, the subject has head and neck squamous cell oma, ovarian cancer, breast cancer or esophageal cancer.

In other embodiments, the subject has atic cancer, esophageal cancer, stomach cancer, head and neck cancer, colon cancer, lung cancer or kidney cancer. In yet other embodiments, the subject has breast cancer. In some embodiments, the breast cancer is breast adenocarcinoma. In n embodiments, the breast cancer is triple-negative breast cancer.

In certain embodiments, the methods for treating or preventing cancer can be demonstrated by one or more responses such as increased apoptosis, inhibition of tumor , reduction of tumor asis, tion of tumor metastasis, reduction of microvessel density, decreased cularization, inhibition of tumor ion, tumor regression, and increased survival of the subject.

In certain embodiments, the disease or the disorder mediated by adenosine is a disease or er mediated by CD73 activity. In some ments, the compounds of the invention, such as nds of Formula (I), are useful as inhibitors of CD73.

In some embodiments, the methods described herein treat or prevent cardiovascular disease using inhibitors of CD73. Mutant genes encoding CD73 lead to extensive calcification of lower-extremity arteries and small joint capsules, which is associated with increased risk of cardiovascular disease (Hilaire et 51]., N. Engl. J. Med, 364(5): 432-442, 2011).

In some embodiments, the methods disclosed herein treat or prevent cancer using inhibitors of CD73. A CD73 small interfering RNA and anti-CD73 onal antibodies showed a significant effect in treating or preventing cancer (Antonioli el al., Nat. Rev.

Cancer, 13: 842-857, 2013). A tight correlation exists between CD73 expression and the ability of cancer cells to e, invade, and adhere to the extracellular matrix (ECM) (Antonioli 2013, Antonioli et 61]., Trends Cancer, 2(2): 95-109, 2016).

In some embodiments, the treatment or prevention of cancer by inhibitors of CD73 can be demonstrated by one or more responses selected from activation, clonal expansion, and homing of specific T cells (Antonioli 2016). In other embodiments, the methods sed herein increase the number of effector T lymphocytes (e.g., cytolytic effector T lymphocytes).

Combination Treatments In some embodiments, the method of treating or preventing cancer may comprise administering a CD39 inhibitor conj ointly with one or more other chemotherapeutic agent(s).

In one embodiment, the CD73 inhibitor is a compound of the invention, such as a compound of Formula (I). Other chemotherapeutic agents can include CD73-specific monoclonal antibodies which enhance the effects of other dies and therapies because of increased overall immune system activity (lower T-regulatory function and higher T-effector function, etc.) (Antonioli 2016).

In certain embodiments, the method of treating or preventing cancer may se administering a compound of the invention conjointly with one or more other chemotherapeutic agent(s). herapeutic agents that may be conjointly administered with compounds of the invention include: 1—amino-4—phenylamino—9,10-dioxo-9,10—dihydroanthracene-2—sulfonate (acid blue 25), l-amino[4-hydroxyphenyl-amino]-9, lO-dioxo-9,lO-dihydroanthracene-Z- sulfonate, 1-amino[4-aminophenylamino]-9,10-dioxo-9,lO-dihydroanthracenesulfonate, l-amino[l -naphthylamino]—9, lO—dioxo-9, lO-dihydroanthracene—2-sulfonate, l-amino[4- fluorocarboxyphenylamino]-9,10-dioxo—9,10-dihydroanthracenesulfonate, 1-amino—4- [2-anthracenylamino]-9, l 0-dioxo-9, l O-dihydroanthracene—2-sulfonate, ABT-263, afatinib dimaleate, ib, aminoglutethimide, amsacrine, anastrozole, APCP, asparaginase, AZD5363, Bacillus Calmette—Guérin vaccine (bcg), bicalutamide, bleomycin, omib, B- methylene-ADP (AOPCP), buserelin, busulfan, cabazitaxel, ntinib, hecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatin, bine, clodronate, cobimetinib, colchicine, crizotinib, hosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, bicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, stim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gefltinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, rexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK-2206, mutamycin, N—(4-sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, nilutamide, nocodazole, octreotide, ib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemexetred, pentostatin, perifosine, PF-O4691502, plicamycin, pomalidomide, porflmer, PPADS, bazine, quercetin, rexed, ramucirumab, reactive blue 2, rituximab, rolofylline, romidepsin, rucapaiib, selumetinib, sirolimus, sodium nitrobenzenesulfonate, sorafenib, ozocin, sunitinib, suramin, talazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, tonapofylline, topotecan, trametinib, trastuzumab, tretinoin, veliparib, stine, vincristine, Vindesine, vinorelbine, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5- fluorouracil, PF-O4691502, romidepsin, and vorinostat (SAHA). In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: l—amino-4—phenylamino—9,10-dioxo-9, 10—dihydroanthracene-2—sulfonate (acid blue 25), o[4-hydroxyphenyl-amino]-9, lO-dioxo-9,lO-dihydroanthracene-Z- sulfonate, 1-amino[4-aminophenylamino]-9,10-dioxo-9,10-dihydroanthracenesulfonate, l-amino[1-naphthylamino]—9,lO—dioxo-9,10-dihydroanthracene—Z-sulfonate, l-amino[4- fluoro-Z-carboxyphenylamino]-9,10-dioxo—9,10-dihydroanthracene-Z-sulfonate, 1-amino—4- [2-anthracenylamino]-9,10-dioxo-9,lO-dihydroanthracene—2-sulfonate, APCP, B-methylene- ADP (AOPCP), capecitabine, cladribine, cytarabine, fludarabine, doxorubicin, gemcitabine, N-(4—sulfamoylphenylcarbamothioyl) pivalamide, NF279, NF449, PPADS, tin, ve blue 2, rolofylline sodium 2,4-dinitrobenzenesulfonate, sumarin, and tonapofylline.

Many combination therapies have been developed for the treatment of cancer. In certain ments, nds of the invention (e.g., compounds of Formula (I)) may be ntly administered with a combination therapy. es of combination therapies with which compounds of the invention may be conjointly stered are included in Table 1.

Table 1: Exemplary atorial therapies for the treatment of cancer Therapeutic agents V Doxorubicin, Bleomycin, Vinblastine ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine AC t) Doxorubicin, Cyclophosphamide AC (Sarcoma) Doxorubicin, Cisplatin AC blastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide, Doxorubicin, Etoposide ACe Cyclophosphamide, Doxorubicin fififlfifilllllllll fififififlflilllllll wwwwwnllllllll MMWK fiwwwwwulllllll Eww fiwwmwwwwwmwwlll BCVPP Carmustine, Cyclophosphamide, Vinblastine, Procarbazine, Prednisone P Bleomycin, ide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, Filgrastim EMMfiwwwwllllll EWWWWWWWWWIIII wwwwwwWMWIllO> flwwfiwwllllllll 00 O EWWWWWWWWWWIII EWWWEWWWWWWIII Cyclophosphamide, Daunorubicin, Vincristine, Prednisone, Asparaginase Cyclophosphamide, Doxorubicin, Methotrexate, Procarbazine E EWWWWWWWWWIIII mv EWWWWWWWWWEIII CMWD EWWWWIIIIIIIII mww QWWWEWWWWWEIII O0 EWWWEWWWIIIIII cmmw EWWWWIIIIIIIII cw EMWWWWWWWWEIII CEPP(B) Cyclophosphamide, Etoposide, Prednisone, with or Without/ cin CEV hosphamide, Etoposide, Vincristine CF Cisplatin, Fluorouracil or Carboplatin Fluorouracil Name Therapeutic agents CHAP Cyclophosphamide or Cyclophosphamide, Altretamine, Doxorubicin, Cisplatin ChlVPP mbucil V1nblast1ne Procarbazme Prednlsone 7 7 CHOP-BLEO Add Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, Cisplatln CLD-BOMP Bleomycin, tln Vlncristlne Mltomycm CMF rexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide, Methotrexate, Fluorouracil, CMFVP Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone COMLA Cyclophosphamide, Vincristine, Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamlde, stine Methotrexate Prednlsone Cooper Regimen Cyclophosphamide, Methotrexate, Fluorouracil, stine, Prednisone COP Cyclophosphamide, Vincristine Prednisone COPE Cyclophosphamide, Vlncrlstlne, Cisplatin, EtopOSIde COPP Cyclophosphamide, Vincristine, Procarbazine, Prednisone CP(Chronic mbucil, Prednisone lymphocytic leukemia) CP (Ovarian Cancer) Cyclophosphamide, Cisplatin Cisplatin, Vinblastine, Dacarbazine Carboplatin, Etoposide, Ifosfamide, Mesna ilTherapeutic agentsCyclophosphamide, Vincristine, Prednisome g Lornustine, Procarbazine, Prednisone CYVADIC Cyclophosphamide, Vincristine, Doxorubicin, Dacarbazine Daunorubicin, bine Daunorubicin, Cytarabine, Thioguanine Daunorubicin, Cytarabine, Etoposide Daunorubicin, Cytarabine, Thioguanine Cisplatin, Cytarabine, Dexamethasone IiillE Doxorubicin, Ifosfamide DTIC/Tamoxifen Dacarbazine, fen Daunorubicin, Vincn'stine, Prednisone m Etoposide, Doxorubicin, Cisplatin [T]O Etoposide, Carboplatin Etoposie, Fluorouracil, Cisplatin Etoposide, Leucovorin, uracil Mitoxantrone, Etoposide, Cytarabine ide, Cisplatin Etoposide, Vinblastine Fluorouracil, Doxorubicin, Cyclophosphamide Fluorouracil, bicin, cin Methotrexate, Leucovorin, Doxorubicin ’fi Fluorouracil, Doxorubicin, Cisplatin Fluorouracil, Leucovorin uracil, Cyclophosphamide, Epirubicin Fluorouracil, Etoposide, Cisplatin Flutamide, Leuprolide Flutamide, Goserelin acetate implant Methotrexate, Leucovorin WO 46403 Altretamine, Cyclophosphamide, Methotrexate, Fluorouracil N Vincristine, Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-III Methotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MACC Methotrexate, Doxorubicin, Cyclophosphamide, Lomustine MACOP-B Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone Z>5 Mesna, Doxorubicin, Ifosfamide, Dacarbazine Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Dexamethasone, rexate, Leucovorin Methotrexate, Bleomycin, tin Z0 Mitoxantrone, bine rexate, Fluorouracil, Leucovorin Ifosfamide, Carboplatin, Etoposide, Mesna Mesna, Ifosfamide, Mitoxantrone, Etoposide EAM Carmustine, Etoposide, Cytarabine, lan MOBP Bleomycin, Vincristine, Cisplatin, Mitomycin MOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine, Vincristine, Procarbazine, Prednisone MOPP/ABV Mechlorethamine, Vincristine, bazine, Prednisone, Doxorubicin, Bleornycin, Vinblastine MP (multiple Melphalan, Prednisone myeloma) g5 Therapeutic agents VIP (prostate cancer) Mitoxantrone, Prednisone Methotrexate, Mercaptopurine ?s:HP] E5)é Methotrexate, Mercaptopurine, Vincristine, Prednisone UUfi-U>& Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breast ) Mitomycin, Vinblastine VIV (acute myelocytic Mitoxantrone, Etoposide M-VAC Methotrexate Vinblastine, Doxorubicin, Cisplatin MVP cin Vinblastine, Cisplatin MVPP Mechlorethamine, stine, Procarbazine, Prednisone Mitoxantrone, Fluorouracil, orin %é Mitoxantrone, Vinblastine, Vincn'stine OPA Vincristine, Prednisone, Doxorubicin OPPA Add Procarbazine to OPA.

PAC Cisplatin, Doxorubicin PAC-I Cisplatin, Doxorubicin, Cyclophosphamide PA-CI Cisplatin, Doxorubicin PCV ine, Procarbazine, Vincristine PFL Cisplatin, Fluorouracil, Leucovorin POC Prednisone, Vincristine, Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Etoposide ProMACE/cytaBOM sone, Doxorubicin, Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine, Methotrexate, Leucovorin, Cotrimoxazole PROMACE/MOPP Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine, Procarbazine, Methotrexate, Leucovorin Cisplatin, Teniposide sone, Vincristine, Asparaginase Mechlorethamine, Doxorubicin, Vinblastine, stine, cin, Etoposide, Prednisone TTT Methotrexate, Cytarabine, Hydrocortisone Topo/CTX Cyclophosphamide, Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, Cisplatin, Bleomycin VACAdr stine, Cyclophosphamide, Doxorubicin, Dactinomycin, Vincristine Vincristine, Doxorubicin, Dexamethasone Vinblastine, Doxorubicin, Thiotepa, Flouxymesterone Vincn'stine, Carmustine, Doxorubicin, Prednisone Vincristine, Camustine, Melphalan, Cyclophosphamide, Prednisone <O Vinorelbine, tin Vincfistine, Cyclophosphamide, Doxorubicin, Prednisone Vinorelbine, Doxorubicin Vinblastine, Cisplatin, Ifosfamide, Mesna Etoposide, Cisplatin, Ifosfamide, Mesna Mitomycin, Vinblastine tine, Melphalan, Cyclophosphamide, Prednisone Etoposide, tin < Etoposide, Thioguanine, Daunorubicin, bine U‘I Cytarabine, Daunorubicin, Mitoxantrone \] Cytarabine with/, Daunorubicin or Idarubicin or Mitoxantrone prednisolone, Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine In some embodiments, the chemotherapeutic agents that may be conjointly administered with nds of the invention, such as a compound of Formula (I), e a CD39 inhibitor. CD39 or ecto-nucleoside triphosphate diphosphohydrolase 1 (E-NTPDasel or ENTPD 1) is a membrane-bound enzyme that zes the conversion of extracellular adenosine sphate (ATP) and/or ADP (adenosine diphosphate) to adenosine monophosphate (AMP). In one embodiment, the CD39 inhibitor is polyoxometalate-l (POM-l).

In other embodiments, the chemotherapeutic agents that may be conjointly administered with compounds of the invention, such as a compound of Formula (I), include known CD73 inhibitors. In some embodiments, the CD73 inhibitor is an anthraquinone tive (Baqi el al., J. Med. Chem, 53(5): 2076-2086, 2010, herein incorporated by reference). In other embodiments, the CD73 inhibitor is an sulfonic acid derivative (Raza et al., Med. Chem, 8: 1133-1139, 2012, herein incorporated by reference). In yet other embodiments, the CD73 inhibitor is selected from l-amino—4-phenylamino-9,lO-dioxo-9,lO- dihydroanthracenesulfonate (acid blue 25), 1-amino[4-hydroxyphenyl-amino]-9,10- dioxo-9, l 0—dihydroanthracenesulfonate, 1-amino[4-aminophenylamino]-9,10-dioxo— 9, l 0—dihydroanthracenesulfonate, l-amino[1—naphthylamino]—9,lO-dioxo-9,10- dihydroanthracenesulfonate, 1-amino[4-fluorocarboxyphenylamino]-9,10-dioxo- 9, l droanthracenesulfonate, l-amino[2-anthracenylamino]-9,lO-dioxo-9,10- dihydroanthracenesulfonate, sodium 2,4—dinitrobenzenesulfonate, N—(4— oylphenylcarbamothioyl) pivalamide, APCP, B-methylene-ADP (AOPCP), PPADS, NF279, NF449, quercetin, reactive blue 2, and sumarin (Baqi 2010, Raza 2012).

In certain ments, the combination of a compound of the invention, such as a compound of Formula (I), with a second CD73 inhibitor or a CD39 inhibitor may have a synergistic effect in the treatment of cancer and other diseases or disorders mediated by adenosine. Without wishing to be bound by any theory, this synergy may be observed because CD39 and CD73 are often on different cell types. The hypoxic tumor microenvironment also s greater levels of CD39 and CD73.

In some embodiments, the chemotherapeutic agents that may be conjointly stered with nds of the invention, such as a compound of Formula (I), include an adenosine receptor tor. In other embodiments, the adenosine receptor inhibitor is selected from rolofylline, tonapofylline, ATL-444, istradefylline, MSX-3, preladenant, SCH- 58,261, SCH-412,348, SCH-442,416, ST-1535, VER-6623, VER—6947, VER-7835, vipadenant, and ZM-241,3 85. In some embodiments, the adenosine receptor tor targets the AZA receptor as this subtype is inantly expressed in most immune cells.

In other embodiments, the chemotherapeutic agents that may be conjointly administered with compounds of the invention, such as a compound of Formula (I), include a nucleoside-based drug. In certain embodiments, the nucleoside-based drug is selected from gemcitabine, capecitabine, bine, fludarabine and cladribine.

In further embodiments, the combination therapy comprises a nd of the invention, such as a compound of Formula (I), conj ointly administered with an anthracycline.

In other ments, the combination therapy comprises a compound of the invention, such as a compound of Formula (I), conj ointly administered with doxorubicin. Combination treatment with an anti-CD73 antibody and doxorubicin has trated a significant chemotherapeutic effect (Young et 61]., Cancer Discov., 4(8): 1-10, 2014, herein incorporated by reference).

In certain embodiments, the combination therapy comprises a compound of the invention, such as a compound of Formula (I), conj ointly administered with an A2A receptor inhibitor and an anthracycline. In some embodiments, the anthracycline is doxorubicin.

Combination treatment with an anti—CD73 antibody, an A2A receptor tor, and doxorubicin has demonstrated an increased chemotherapeutic effect (Antonioli 2013).

In certain embodiments, the nt therapies of the invention comprise conjoint administration with other types of herapeutic agents, such as immuno-oncology agents. Cancer cells often have c cell surface ns that can be recognized by the immune system. Thus, -oncology agents, such as monoclonal antibodies, can selectively bind to cancer cell antigens and effect cell death. Other immuno-oncology agents can suppress tumor—mediated inhibition of the native immune response or otherwise activate the immune response and thus facilitate recognition of the tumor by the immune system.

Exemplary antibody immuno—oncology agents, include, but are not limited to, omab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, umomab, EMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED1473 6, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, zumab, rituXimab, ticilimumab, samalizumab, and tremelimumab. In some embodiments, the antibody immune-oncology agents are selected from anti-CD73 monoclonal antibody (mAb), anti—CD39 mAb, anti—PD-l mAb, and anti- CTLA4 mAb. Thus, in some embodiments, the methods of the invention comprise conjoint administration of one or more immuno-oncology agents, such as the agents mentioned above.

In some ments, the combination therapy comprises a compound of the invention, such as a nd of Formula (I), conj ointly administered with anti-PD-l therapy and anti-CTLA4 therapy. Combination treatment with an anti-CD73 monoclonal dy (mAb), anti-PD-l mAb, and anti-CTLA4 mAb showed a significant chemotherapeutic effect (Young 2014, Antonioli 2013).

In some embodiments, the combination therapy comprises conjoint administration of a compound of the invention, such as a compound of Formula (I), with anti-PD-l therapy. In certain embodiments, the combination therapy comprises conjoint stration of a compound of the invention, such as a nd of Formula (I), with oxaliplatin. In other embodiments, the combination therapy comprises conjoint administration of a compound of the invention, such as a compound of Formula (I), with bicin.

In certain embodiments, a nd of the invention may be ntly administered with non-chemical methods of cancer treatment. In certain embodiments, a compound of the invention may be conjointly administered with radiation therapy. In n embodiments, a compound of the invention may be conjointly administered with surgery, with thermoablation, with focused ultrasound therapy, with cryotherapy, or with any ation of these.

In certain embodiments, compounds of the invention may be conjointly administered with one or more other compounds of the invention. Moreover, such combinations may be conjointly stered with other therapeutic agents, such as other agents le for the treatment of cancer, immunological or neurological diseases, such as the agents fied above. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents with a compound of the invention provides a synergistic effect. In certain embodiments, conjointly administering one or more additional chemotherapeutic agents provides an additive effect.

Pharmaceutical Compositions In certain embodiments, the present ion provides a pharmaceutical preparation suitable for use in a human patient, comprising any of the compounds shown above (e. g., a compound of the invention, such as a compound of formula (I), and one or more pharmaceutically acceptable ents. In certain embodiments, the pharmaceutical preparations may be for use in ng or preventing a condition or disease as described herein. Any of the disclosed compounds may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.

The compositions and methods of the present invention may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non—human . When administered to subject, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. ceutically acceptable carriers are well known in the art and include, for e, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an lial barrier), the aqueous solution is pyrogen—free, or substantially pyrogen—free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical ition can be in dosage unit form such as tablet, capsule ding sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, on, syrup, suppository, injection or the like. The ition can also be present in a transdermal delivery , e. g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to se the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self—emulsifying drug delivery system or a icroemulsifying drug delivery . The pharmaceutical composition (preparation) also can be a liposome or other r matrix, which can have incorporated therein, for example, a nd of the invention. Liposomes, for e, which comprise phospholipids or other lipids, are nontoxic, logically acceptable and metabolizable carriers that are vely simple to make and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, le for use in contact with the tissues of a t without excessive ty, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a ceutically able material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ients of the formulation and not injurious to the subject. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch, (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc, (8) excipients, such as cocoa butter and suppository waxes, (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as ene , (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (l3) agar; (l4) buffering agents, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol, (20) phosphate buffer solutions; and (21) other non—toxic compatible substances employed in pharmaceutical formulations.

A ceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue), absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously, transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or ded in sterile water. Details of appropriate routes of administration and compositions le for same can be found in, for example, US. Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier al to produce a single dosage form will vary depending upon the subject being d, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the nd which produces a therapeutic effect. lly, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most ably from about 10 percent to about 30 percent.

Methods of ing these formulations or compositions include the step of ng into association an active compound, such as a compound of the invention, with the r and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present ion with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral stration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually e and acacia or tragacanth), lyophile, powders, granules, or as a on or a suspension in an aqueous or non-aqueous liquid, or as an oil—in- water or water-in-oil liquid on, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present ion as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, s, granules and the like), the active ingredient is mixed with one or more ceutically acceptable rs, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid, (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia, (3) humectants, such as glycerol, (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) ents, such as kaolin and bentonite clay; (9) ants, such a talc, m stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures f; (10) xing agents, such as, modified and unmodified extrins, and (l l) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), s and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as flllers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert t, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound ned with an inert liquid diluent.

The tablets, and other solid dosage forms of the ceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric gs and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired e profile, other polymer matrices, liposomes and/or microspheres. They may be ized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid itions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, ally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro- encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene , 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert ts, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, ing and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene ol and sorbitan , microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions for , vaginal, or urethral administration may be presented as a itory, which may be prepared by mixing one or more active compounds with one or more le nonirritating ents or carriers comprising, for example, cocoa butter, hylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body ature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. ations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other uminal device. Delivery via such devices may be especially useful for delivery to the r, urethra, , rectum, or intestine.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such rs as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, , lotions, gels, solutions, patches and inhalants. The active compound may be mixed under e ions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and ble fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof Powders and sprays can contain, in addition to an active compound, excipients such as e, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and le unsubstituted arbons, such as butane and propane. ermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in US. Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and US. Patent No. 6,583,124, the contents of which are incorporated herein by reference. If desired, liquid lmic formulations have ties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatible with such fluids. A preferred route of administration is local administration (e.g., topical stration, such as eye drops, or administration via an implant).

The phrases "parenteral administration" and istered parenterally" as used herein means modes of administration other than l and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions le for eral administration comprise one or more active compounds in combination with one or more aceutically acceptable sterile isotonic aqueous or eous solutions, dispersions, sions or emulsions, or e powders which may be tituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, s (such as glycerol, propylene glycol, polyethylene , and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be d by the inclusion of various cterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the able pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum earate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from aneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, d absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable rs such as polylactide—polyglycolide. ing on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible With body tissue.

For use in the methods of this invention, active nds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled ry of drugs, ing proteinacious biopharmaceuticals.

A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Actual dosage levels of the active ingredients in the ceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired eutic response for a ular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the ty of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or als used in combination with the particular compound(s) employed, the age, sex, weight, condition, l health and prior medical history of the subject being treated, and like factors well known in the medical arts.

A physician or narian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical ition required For example, the physician or veterinarian could start doses of the pharmaceutical composition or nd at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the ive amount of the compound will vary according to the weight, sex, age, and medical history of the subject.

Other factors which influence the effective amount may include, but are not limited to, the severity of the subject's ion, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by le administrations of the agent.

Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher el al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a eutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

In certain embodiments, the dosing follows a 3+3 . The traditional 3+3 design requires no ng of the dose—toxicity curve beyond the classical assumption for cytotoxic drugs that toxicity ses with dose. This rule-based design proceeds with cohorts of three patients, the first cohort is treated at a starting dose that is considered to be safe based on extrapolation from animal toxicological data, and the subsequent cohorts are treated at increasing dose levels that have been fixed in advance. In some embodiments, the three doses of a compound of formula (I) range from about 100 mg to about 1000 mg , such as about 200 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 100 mg to about 400 mg, such as about 500 mg to about 1000 mg, and further such as about 500 mg to about 600 mg. Dosing can be three times a day when taken with without food, or twice a day when taken with food. In certain embodiments, the three doses of a compound of formula (I) range from about 400 mg to about 800 mg, such as about 400 mg to about 700 mg, such as about 500 mg to about 800 mg, and further such as about 500 mg to about 600 mg twice a day. In n preferred embodiments, a dose of greater than about 600 mg is dosed twice a day.

If none of the three patients in a cohort experiences a dose-limiting toxicity, r three patients will be treated at the next higher dose level. However, if one of the first three patients experiences a dose—limiting toxicity, three more ts will be treated at the same dose level. The dose escalation continues until at least two patients among a cohort of three to six ts experience dose—limiting toxicities (i.e., 2 about 33% of patients with a dose- limiting toxicity at that dose level). The recommended dose for phase II trials is conventionally defined as the dose level just below this toxic dose level.

In certain embodiments, the dosing schedule can be about 40 mg/m2 to about 100 mg/m2, such as about 50 mg/m2 to about 80 mg/m2, and further such as about 70 mg/m2 to about 90 mg/m2 by IV for 3 weeks of a 4 week cycle.

In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used , the phrase “conjoint stration” refers to any form of administration of two or more different eutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the subject, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either itantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one r. Thus, a subject who receives such treatment can benefit from a combined effect of different therapeutic compounds.

WO 46403 In certain ments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved eff1cacy relative to each individual administration of the compound of the invention (e.g., compound of formula I or Ia) or the one or more additional therapeutic s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. In certain embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine, benenthamine, benzathine, betaine, calcium hydroxide, e, deanol, diethanolamine, lamine, 2- ylamino)ethanol, ethanolamine, ethylenediamine, N—methylglucamine, amine, lH-imidazole, lithium, ne, magnesium, 4-(2—hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, hamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent, Wetting agents, emulsifiers and lubricants, such as sodium lauryl e and magnesium stearate, as well as coloring agents, e agents, coating agents, ning, flavoring and perfuming agents, preservatives and antioxidants can also be t in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium sulflte, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), ted hydroxytoluene (BHT), lecithin, propyl gallate, alpha—tocopherol, and the like; and (3) metal—chelating agents, such as citric acid, ethylenediamine cetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The invention now being generally described, it will be more readily understood by reference to the ing examples which are ed merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

General Synthetic Procedures Compound numbers 1-129 as used in the general synthesis section below refer only to genus ures in this section and do not apply to compounds sed elsewhere in this application. nds disclosed herein can be made by methods depicted in the reaction schemes below.

The starting materials and reagents used in ing these compounds are either available from commercial supplier such as Aldrich Chemical Co., Bachem, etc., or can be made by methods well known in the art. The schemes are merely illustrative of some methods by which the compounds disclosed herein can be synthesized and various modifications to these schemes can be made and will be suggested to POSITA having referred to this disclosure. The starting materials and the intermediates and the final products of the reacton may be isolated and purified if desired using convential ques, including but not limited to filtration, distillation, crystallization, chromatography, and the like and may be characterized using conventional means, including physical constants and spectral data.

Unless specified otherwise, the reactions described herein take place at atmospheric re over a temperature range from about -78 0C to about 150 °C. l Schemes Compounds of Formula (I) having the structure: 0 Ru 0 R” 0V0R9 «#2 OR N RV”? N N < "i < "1 R90 R50 N NARV R50 N 0 0 N/ R" N/ V HOS 30H HO‘ OH HO OH ('3) or (lb) of (IC) where Z, R“, RV, RW, RX, R5, and R9 are analogous to variables Z, Ra, Rb, R”, R5, R9 and RK is -CH2P(O)(OR15)2 or -OP(O)(OH)CH2P(O)(OR15)2 as defined in the Summary, can be sized as illustrated and described in Scheme 1: Scheme 1 HO:SDHO P0 P0 PO 0 deprotection 0 protection 0.,ng oxidation ”.0 OH ’OK ' )(RH— " ' o ,0 Ho~‘ :5’03< H6 ’OH A-1 A-2 A-3 A-6 P= TBDPS,orTDMS R" =i-i,a|ky[.aryl,hetercycle N \ u Li (IflZ R R 0 0R9 N N R" N N PO \i \ ion M1 GAO A-8 (I deprotection </ i R90 N2 _. P0 N R' 0 N/ RV H0: 0 ,N N/ RV —AcOI ' IOAc 9 lycosylation X 7 Rh2(OAc)4 RII ll . ’ — ‘ 1 And bAc Acd bAC R9 = alkyl A-7 A-9 A-10 0 Ru 0 R“ o R“ 0Q0R9 N 0Q;0R9 N 0 OH </ I 1 R5-X A-13 (l \Z I deprotection m I NiRV R90 0 R90 wi..N N/ N —, HO </NN o R" R5 0 o N/ RV R5 0 base Rug—J_ / =—.0E . R" Ace“ 'bAc Acd 1’0Ac HO: ’OH A42 A'14 formula (la) Ketone A-3 is prepared from commercially available diol A-1 via selective protecting the y alcohol with a suitable group such as TBDPS, TBDMS, Ac and B2, and followed by oxidizing the secondary alcohol in A-2 where R” is H, alkyl, TMS, or heterocycles.

Stereoselective addition of the corresponding l nucleophile A-4, such as Grignard reagents or Li ts, to ketone A-3 to provide propargylic alcohol A-5. Removal of the acetonide protecting group is accomplished with d aq. acid, such as TFA, HCl, H2SO4, HClO4, PPTS, CSA or other Lewis acids. Acylation of triol A-6 with reagents, such as AczO, acetyl chloride, and BzCl, in the presence of a base, such as ne, and catalytic 4-DMAP to provide tri-ester such as etate A-7. Glycosylation under conditions (N, O- bis(trimethylsilyl)-acetamide and TMSOTf ) or (TfOH and DBU) in solvent (MeCN, dichloroethane or toluene), between donor A-7 and acceptor A-8, such as 2-chloroadenine, 6- aminochloroadenine, 2,6-dichloroadenine, 5,7—dichloro-1H-imidazo[4,5-b]pyridine, 5- chloro-3H—imidazo[4,5-b]pyridine, uracil, thymine, cytosine or guanine, to provide the nucleoside product A-9. In the case when R[1 is NH2, it is protected as N(Boc)2 with BoczO in the presence of TEA and catalytic 4—DMAP. l of the protecting group in A-9, in the case of P is TBDMS or TBDPS group, treatment with TBAF to give the y alcohol A- which then is undergone an insertion on with diazo reagent A-11 in the presence of catalyst such as Rh2(OAc)4 or Cu(OAc)2 to provide A-12. Alkylation with an ophile A- 13 such as alkyl , triflate, tosylate or mesylate in the presence of base such as CszCO3, K2CO3, LiHMDS, DBU or NaH, to provide A-14. The ester groups in A-14 is finally removed by base such as LiOH, NaOH, and KOH in water to provide A-15 in formula (Ia).

Alternatively, the alkynyl group at the 3’-position in intermediate A-5 can be substituted with either alkyl or vinyl groups by using the corresponding alkyl or vinyl lithium and Grignard reagents at Step 3 in Scheme 1.

Scheme 2 o 0 PO : : H0 0 o a A-11 --IO deprotection ”2 ,,,o R90 R";—7 X0 O R" _ . ’ ,Ok Ru ‘ . "'0 P10: bk Rh2(OAC)4 c ” P10 0 3-1 B-2 R5-X A-13 0 OR9 0 0R9 acylation 9 9 deprotection RORso 0 ‘—RORso O <— 0Ac A020 OH 7‘ for P‘ = A0 R" V . R" . .

A05 bAc AC5 ’OH P050 7' 3-6 B-5 Heterocycle B-7 glycosylation o o 0 OR9 0 OH deprotection R90 R5 0 Het —> HO o R5 o Het R” E: S 7 R" E: E 7 AM? ’OAc Ho‘ bH B-8 formula (la) Compounds in formula (Ia) can also be prepared according to Scheme 2. The le protecting group such as P is a silyl group (TBDPS or TBDMS) in precursor B-l can be selectively removed by reagent such as TBAF or HF in THF while the P1 protecting group such as Ac, B2 and MOM group remains. The resulting primary alcohol B-2 can react with diazo reagent A-11 in solvent such as benzene, toluene, DCM and dichloroethane in the WO 46403 presence of metal catalyst such as Rh2(OAc)4 to give intermediate B-3. Alkylation of B-3 with electrophile A-13 such as halide, triflate, mesylate or sulfonate is accomplished in the presence of a base such as K2CO3, CszCO3, LiHMDS, NaH and DBU to give intermediate B- 4. Removing the acetonide protecting group in B-4 is done by an acid treatment such as aq.

TFA, HCl, H2804 or HClO4 in solvent such as DCM, acetone, THF or dioxane to provide diol B-S. Acylation of B-S with t such as AczO or acetyl chloride in the presence of pyridine, TEA or DIPEA and catalytic 4-DMAP to give tri-acetate B-6 (for P1 = OAc) as a glycosylation donor. This intermediate B-6 is reacted with a glycosylation acceptor heterocycle B-7 such as 2-chloroadenine, 6-aminochloroadenine, 2,6-dichloroadenine, 5,7- dichloro- lH-imidazo[4,5-b]pyn'dine, 5-chloro-3H—imidazo[4,5-b]pyridine, uracil, thymine, cytosine and guanine under the influence of conditions such as [N, 0-bis(trimethylsilyl)— acetamide and TMSOTf ] or (TfOH and DBU) in t (MeCN, dichloroethane or DME) to provide nucleoside intermediate B-8. Finally removal of the ester protecting groups in B—8 with the treatment of aq. LiOH, NaOH, and KOH in t such as THF, dioxane, MeOH or EtOH to provide the desired final product in the formula (Ia).

Scheme 3 0 Cl 0 Ru 0W0}?9 9 </N \N philic I OQOR (N \N displacement I R 0 R59 0 N / —> 9 mg, R 0 R5 0 N / o N/kCI o N/kCI C-2 WEZQ.

AGO: ~ ’ bAC x I AcO OAc ‘34 C-3 Suzuki ng H)2 C-4 in"? fiupllnfin Ru—SNRQ C-5 deprotection egs coup g RU—ZnX C-6 0 Ru 0 Ru 0 0R9 /N o OH < \N I A deprotectlon. </N \N R" : R“ : ‘. ,, ‘. ,, Acd bAc Hd bH C-7 formula (la) Compounds in formula (Ia) can also be prepared according to Scheme 3. 2,6- Dichloroadenine C-l prepared according to Scheme 1 can proceed into several tic transformations. Selective nucleophilic displacement of the 6-chloro group in precursor 1 with nucleophile Ru—H (C-2) such as amines, alkoxides or thiolates in solvent such as DMF, THF, dioxane, alcohols or NMP to provide intermediate C—3. Precursor C-1 also can undergo a ng reaction such as Suzuki, Stille or Negishi reaction with the corresponding reagent such as c acids (C-4), boronic , Tin reagents (C-S) or Zinc reagents (C-6) to provide intermediate C-7, respectively. Treatment of both intermediates C-3 and C-7 with aq. LiOH, NaOH, KOH, NaOMe, NaOEt or KOEt in solvent such as THF, dioxane, MeOH or EtOH to provide the desired final products in the formula (Ia).

Scheme 4 Cl CI CI N \ D-1 N N N \N \N P0; ’ | N/J\Cl <’ l NACI < l N PO N deprotection HO N 0 0 NACI : —> Acd bAc glycosylation R" ,’ _ v, Acd bAc Acd bAc A-7 D-2 D-3 0 RW c)4 R9OHN D-4 RlN R8 Cl CI 0 Rw 0 RW N 0 RW H <N/ 1N1 \ / N / 0'5 H H R90 R5 0 <N I A :0 'N R90 0 R90 0 CI HNR7RB R5 0 N Cl base,R5»X o:< 'Nim ‘— <— R" amine R" R" : a : -, A-13 : -, Acd ’OAc dlsplacement Acd ’OAC A05 ,0Ac D-7 C-1 D-S i deprotectlonRLWR8 0 RW N H < :1 HO R5 0wgs,, N o N Cl Ho‘ ’OH formula (Ia) Compounds in formula (Ia) can also be prepared via C-1 according to Scheme 4. In this method, treatment of A-7 with 2,6-dichloropurine, TMSOTf and MO- bis(trimethylsilyl)acetamide via the Vorbruggen reaction gives protected nucleoside D-2.

Selective removal of the tert-butyldiphenylsilyl moiety from the 5’-hydoxy1 group gives alcohol D-3. Coupling with a desired substituted acyldiazo-reagent D-4 gives substituted nucleoside D-5. A wide variety of diazo reagents can be used in this reaction. Some examples include those where RW is C02R9, SOR9, S02R9, P(O)(OR9)2, and CN and R9 is defined as in the Summary. If an alkyl substituent R5 is desired, it can be iently introduced using an tion reaction where a phile such as RS-X (X = halide, OTf, OMS or OTs) is used with a base like cesium carbonate in a polar aprotic solvent like THF or DMF to give key intermediate C-l. A substituent such as an amine can be added to the purine base by displacing the chlorine at the 6-position to give intermediate D-7 with variety of amines D-6 in a solvent such as EtOH, THF or dioxane. Final deprotection of D-7 by using an aqueous hydrolysis with a base such as lithium hydroxide gives target compound in the structure of formula (1).

Scheme 5 \ / BOH( )2 Pd catalyst acylation deprotection ‘— ‘— Ac20 for P' = Ac N glycosylalion R\N/R7 a R\N,R7 s \ - \ </ l N deprotectlon </ l N —> NACI formula (Ia) Compounds in formula (Ia) can also be prepared according to Scheme 5. Alkylation of sor B-3 from Scheme 2 above with an electrophile E-l such as 4—iodobenzyl halide (Br, C1, or I) or the corresponding OTf, OMs or OTs with base such as K2CO3, CS2CO3, NaH or LiHMDS in solvent like DMF or THF leads to ediate E-2 which can couple with s boronic acids such as (2-oxo-l,2-dihydropyridinyl)boronic acid (E-3) illustrated here. The resulting pyridone product E-4 is ted with various alkyl s (A-13) in the presence of base such as K2CO3, CszCO3, NaH or LiHlVIDS in solvent like DMF and THF to give E-S. The acetonide protecting group in E-S is removed with the treatment of aq. TFA, HCl, H2804 or AcOH in a solvent such as DCM, acetone, e or THF to give diol E-6 which is acetylated with AczO or acetyl chloride with a catalytic amount of 4-DMAP and a base such as pyridine, TEA or DIPEA in solvent like DCM to provide an anomeric mixture E-7 as a glycosylation donor. Intermediate E-7 can either react With heterocyclic acceptor 2,6-dichloroadenine (D-l) or N—substituted ochloroadenine (E-9) which is formed from displacing the 6-chloro group in D-1 with the suitable amines (D-7). Both glycosylation can be done under the activation conditions such as [(N, O-bis(trimethylsilyl)-acetamide and TMSOTf ] or (TfOH and DBU) in solvent (MeCN, roethane or toluene), between donor E-7 and acceptors D-1 or E-9 to provide the corresponding nucleoside products, E-8 or E-10 respectively. Nucleoside E-8 is converted into E-10 via a nucleophilic displacement with s amines (D-7). Finally, desired compounds in formula (Ia) is produced from E- via the deprotection of all its ester groups with treatment of aq. LiOH, NaOH, and KOH in a t such as THF, dioxane, MeOH or EtOH.

Scheme 6 OTBDMS OH Br 0TBDMS 1 . 3—cNoropropy IsocyanaeI. t TEA 1, Rs—X, base 2, NaH or NaOH 2. TBAF, THF 03% PPha, DCM 0 o 0 N4 N4 N4 NHz < NH < N—R5 < N—R5 F 1 F 2 F-3 F 4 glycosylation R7\N,R5 9?:’CI,N \N F-11 Q formula (Ia) Compounds in formula (Ia) can also be prepared according to Scheme 6. Alkylation with benzyl halide F-4 with various alkyl side chains (R5) and precursor B-3 in the presence of base such as K2CO3, CszCO3, LiHMDS or NaH in suitable solvent like DMF or THF leads to intermediate F-S. Triacetate F-7 is formed via a two-step transformation from F—S via a deprotection (aq. TFA in DCM) and acylation (AczO or acetyl chloride in pyridine) as described aforementioned schemes. Glycosylation between F-7 and various acceptors such as 2,6-dichloroadenine (D-l) under an activation conditions [(N, 0-bis(trimethylsilyl)—acetamide and TMSOTf ] or (TfOH and DBU) in solvent (MeCN, dichloroethane or toluene) to provide nucleoside F-8 which is converted to amino analogs F-10 with various amines (F—9) in the presence of base such as pyridine, TEA or DIPEA in appropriate solvent like dioxane, DMF, or THF. Finally, desired molecules in formula (1) is obtained from F-10 with the treatment of aq. LiOH, NaOH, and KOH in a solvent such as THF, dioxane, MeOH or EtOH.

Alternatively, intermediate F-10 can also directly produced from glycosylation between donor F-7 and other acceptors such as N—substituted 6-aminochloroadenines (F—11).

The required benzyl s F-4 is prepared from 4-(((tert-butyldimethylsilyl)oxy)- methyl)aniline (F-l) via a five-step transformation. The cyclic urea ring is initially formed from aniline F-l reacting with 3-chloropropyl nate and followed by ation under the influence of a base such as NaH, NaOH or LiHMDS in solvent like DMF or THF to generate F-2. Intermediate F-2 is then led to F-3 by removal of the TBDMS group with TBAF and proceeds to the final t by converting the primary alcohol to the bromide with CBr4 and PPh3 in solvent such as DCM or THF.

Alternatively, key ediate F-5 is also prepared from precursor B-3 ing to Scheme 7. Alkylation of sor B-3 with halides such as obenzyl bromide in the presence of base such K2CO3 or Cs2CO3 in DMF to provide the nitro intermediate which is then reduced to the aniline with Fe in aq. NH4Cl, Cyclic urea formation is carried out from aniline with 3-chloropropyl isocyanate in the presence of base such as TEA in THF and followed by olecular ring closure with the treatment of base such as NaH or LiHMDS Introduction of the N—alkyl side chains is accomplished with electrophile such as A-13 to provide key intermediate F-S.

Scheme 7 1. 3-chloropropyl isocyanate TEA, THF R 0 O 0 1. base, DMF 2. NaH or NaOH -Ilo —> R" 2. Fe, aq. NH4C| R; X»: Formula (1b) can be prepared ing to Scheme 8. The required diazo reagent G—2 which RW is an aryl or heteroaryl group, can be prepared from ester G—l with the suitable sulfonyl azide reagent, such as midobenzenesulfonyl azide in the presence of a base, such as Et3N and DBU, in MeCN or dioxane. Coupling of diazo reagent G—2 and alcohol A- 9 from Scheme 1 via the insertion reaction catalyzed by Rh or Cu catalyst such as Rh2(OAc)4, in a solvent such as toluene, DCM or dichloroethane to give t G—3. Alkylation of G—3 with an electrophile A-13 such as alkyl halide, triflate, tosylate or mesylate in the presence of base such as CszCO3, K2CO3, LiHMDS, DBU or NaH, to provide G—4. The ester groups in G—4 is finally d by an aq. base such as LiOH, NaOH, and KOH to provide the desired product in formula (Ib).

Scheme 8 o Ru \ 0R9 N o o </ j i Rw </ \z RVKORQ diazoformation RW HO N + O N/ Rh2(OAC)4 mi?— Rv E—O N 0R9 O NARV \. ., R" S 2 A05 IOAC Acd bAc 6-2 A-9 9-3 O R“ O Ru “7?;0R9 N \ N l NARV2 RW ’ Z RS'X A43 72~OH l A deprotection —> R5 O O —> R5 O (N 0 v R" _ . . R" AcO aOAc H6 ’OH G-4 formula (lb) WO 46403 Compounds in formula (Ib) can also be prepared ing to Scheme 9. The y alcohol B-2 can react with diazo reagent G—2 from Scheme 8 in the presence of a metal catalyst such as Rh2(OAc)4 in a solvent such as benzene, toluene, DCM or dichloroethane to give ediate H-1. Alkylation of H-1 with an electrophile A-13 such as halide, triflate, mesylate or sulfonate is accomplished in the presence of base such as K2CO3, CszCO3, LiHMDS, NaH and DBU to give intermediate H-2. Removing the acetonide protecting group in H-2 is done by acid treatment such as aq. TFA, HCl, H2804, HClO4 or CSA in solvent such as DCM, e, THF or dioxane to provide diol H-3. Acylation of H-3 with a reagent such as AczO or acetyl chloride in the presence of pyridine, TEA or DIPEA and catalytic 4-DMAP to give tri-acetate H-4 as a glycosylation donor. This intermediate H-4 is reacted with a glycosylation or heterocycle B-7 such as 2-chloroadenine, 6-amino chloroadenine, 2,6-dichloroadenine, 5,7-dichloro—1H—imidazo[4,5-b]pyridine, 5-chloro-3H— imidazo[4,5-b]pyridine, uracil, thymine, cytosine and guanine under the conditions such as [N, O-bis(trimethylsilyl)—acetamide and TMSOTf ] or (TfOH and DBU) in a solvent (MeCN, dichloroethane or DME) to provide nucleoside intermediate H-5. Finally removal of the ester protecting groups in H—S with the treatment of aq. LiOH, NaOH, and KOH in a solvent such as THF, dioxane, MeOH or EtOH to provide the desired final product in the formula (Ib).

Scheme 9 4%; 0HO O N . ..lo 2 ‘ ' Rv-QQ—.O O 0 0 ection R” " IO II IO ‘_ .’ base .. k R;« ., k ¢ I ¢ I P10 0 P10 0 B 2 H-1 H-2 O o 0 0R9 0R9 3—7 0R9 OH R‘” RW Heterocycle R‘” acylatlon' glycosylation Het R5 O O Het RR5 O 0 O R5 0 0 O OH OAc deprotection —’ —>5R Ac O l / R” _=— 3 l R“ E— S R” __S f Pa_A P10‘ bH °' ‘ c Aco‘ OAc Ac0‘ ’OAc Riv$lcAcO OA H-3 H-4 H-5 formula (lb) Compounds in formula (Ic) can also be ed according to Scheme 10. Tertiary alcohol I-2 where R1 is methyl (prepared according to the procedure reported by Franchetti, P. et al. J. Med. Chem. 2005, 48, 4983—4989) or other alkyl groups; ethynyl (prepared according to the procedure by Hulpia, F. et al. . Med. Chem. Lett. 2016, 26, 197O— 1972) or other l groups, and vinyl groups, was converted into L4 either directly by treatment of acetylation reagent such as AczO and catalytic amount of H2804 in AcOH or vai a 2-step process involving deprotetion of the acetonide group with treatment of aq. TFA or other acid in DCM first and followed by acetylation of the resulting diol 1-3 with a reagent such as AczO or acetyl chloride. Glycosylation of 1-4 with a heteroaromatic glycosyl acceptor such as heterocycle B-7 described in Scheme 2 where R11 is H, Cl, NH2, N—alkyl group such as 2-chloroadenine, 6-aminochloroadenine, 2,6-dichloroadenine, 5,7-dichloro- lH-imidazo[4,5-b]pyridine, 5-chloro-3H—imidazo[4,5-b]pyridine, uracil, thymine, cytosine and guanine under the conditions such as [N, trimethylsilyl)—acetamide and TMSOTf ] or (TfOH and DBU) in a solvent (MeCN, dichloroethane or DME) to e nucleoside intermediate [-5. Removal of the silyl protecting group in 1-5 with a source of fluoride such as TBAF in THF to give primary alcohol 1-6 which was r converted into triol 1-7 with aq. LiOH or NaOH in solvent such as THF, MeOH or EtOH. Finally, ent of 1-7 with methylenebis(phosphonic dichloride) and trimethylphosphate before it is ed by triethylammonium carbonate to provide the desired final product in the formula (1c).

Scheme 10 O o o TBDPSO ...o R1-M TBDPSO mo aq.TFA,DCM TBDPso’mWOH X _’ R1 ’ ; X R1 _. ., 0 0 H6 0 Ac?) OH H H2804 (cat) l-3 A020, AcOH R” R” pyridine N N 4-DMAP <’ \N l A </ \N HO N N TBDPSO N 0 N o 0 CI CI OAc _ TBDPSO TBAF THF glycosylatlon R1 <—’ <— R1 . . R1 _ . a, Acé éAc Aco bAc AcO l-6 l-5 |.4 aq.LiOH,THF (NIKN R” CI—(IP? (lg—CI N \ N N A CI/ V \CI 9 9 HO <’ l o N CI HO—P P\ —> I \/ A | O N O N HO 7’ CI R1 P(O)(OMe)3, TEAB .' .1 1 X H5 OH RHd bH l-7 formula (Ic) nds in formula (Ic) can be prepared according to Scheme 11. Primary l I-6 (where R“ = Cl) is alkylated with ophile J-l such as (diethoxyphosphoryl)methyl trifluoromethanesulfonate or diethyl (iodomethyl)phosphonate in the presence of a base, such as TEA, DIPEA, NaH and CszCO3 in a solvent such as THF, DMF, dioxane or NMP to give intermediate J—2. Installation of the amino group in J-4 via nucleophilic displacement of the chloro group in J-2 with R7R8NH (J—3) where R7 and R8 are H or alkyl , in the presence of a base such as TEA or DIPEA in solvent such as dioxane, THF, or DMF. A two- step deprotection sequence (TMSBr and aq. LiOH or NaOH) is required to convert J-4 to the desired product in formula (Ic).

Scheme 11 gig,“ EtO-PVX AC. EtO J" ”A MA R7JR8NH base THF OEt Egg,“ DIEA,dioxane ACO OAc AcO OAc I-G J-2 NR7R8 NR7R8 \ N N \ 0| </ l 1. TMSBF, MeCN </ l N / 2. esterh drol sis EtO-PA010,“ NJ\C| —.yy H0_'FI',/\o N o “(km OEt S 7 R1 OH R1 . .

ACO OAC AC5 6A0 formula (lc) Those having skill in the art will recognize that the starting als and reaction ions may be varied, the sequence of the reactions altered, and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In l, the need for such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to enced organic chemists. The sures of all articles and references ned in this application, including patents, are incorporated herein by reference.

The ation of the compounds of the present invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures and compounds described in them.

Synthetic Examples Example 1 Synthesis of 2—(((2R, 3S, 4R, 5R)—5-(6-amino-2—chloro-9H—purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)benzylmalonic acid TBDPSO o _ TBDPSO TBDPSO TBDPSO — M Br9 0 ... 0 A020 0A5 THF . .

¢ ~‘ ’ O ”OK HO 0,0)(D HO AcO OAc N \ TMSOTf <’ f): DBU n N c. MeCN N(Boc)2 NH2 N(Boc)2 N \ N \ </NN TBAF,THF </ l 1 N 80620 </ I I N10 <— TBDPSO X j,No N/ l<— TBDPSO N C o MAI X 3/ C HO—;‘»N-,I Eli/i: DMAP Ach GOAc Ach “OAc A06 OAc 0>—2_QB toluene, 95 00 are N2 0 2 o N(Boc)2 o NH2 0 OEt {/NN BnBr K2003 0 CE 0 QB ] N1 DMF I N;\;. TFA DCM E10 —>EtO (’NN 0:0 —A:OO:OIGO E10 0 CI 0<1|NiN10| Acd bAc ACOC 90Ac o NH2 0 NH2 0 OH OEt / lNHB,NMeOH i Nlm / LiOH (N 1% HO O <: N 0N7 EtOH HO: ’OH 0—H; Z‘OH Example 1 Step 1: To a e of (3aR, 5R, 6aS)—5-(((terz‘-butyldiphenylsilyl)oxy)methyl)—2,2- yldihydrofuro[2,3-d][1,3]dioxol-6(3aH)—one (10 g, 23.44 mmol, 1 eq) in THF (100 mL) was added ethynylmagnesium bromide (0.5 M, 328.19 mL, 7 eq) at 15 0C under N2 atmosphere. The mixture was stirred for 16 h before additional ethynylmagnesium bromide (0.5 M, 125mL, 3 eq) was added. The mixture was stirred further for 3 h before it was diluted with saturated aq. NH4C1 (250 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layer was washed with brine (250 mL), dried over NazSO4, filtered and amwmmwdmdwmw.Hmambmmhdwwpmmaflwflwhwmaghman chromatography (petroleum ether: EtOAc = 1:0—4: 1) to provide (3aR, 5R, 6R, 6aR)(((tert— butyldiphenylsilyl)oxy)methyl)ethynyl-2,2-dimethy1-tetrahydrofuro[2, 3 -d][1,3]dioxol—6-ol (19.47 g, 92% yield) as a yellow solid.

Step 2: To a solution of (3aR, 5R, 6R, 6aR)—5-(((lert—butyldiphenylsilyl)oxy)methyl) l-2,2—dimethyltetrahydrofuro[2,3-d][1,3]dioxolol (9.47 g, 20.92 mmol, 1 eq) in DCM (100 mL) was added H20 (10 mL) and TFA (100 mL) at 0 OC. The mixture was stirred at 25 °C for l h before it was quenched with saturated aq. NaHCO3 to pH 7 and then extracted with DCM (2 X 300 mL). The combined organic layer was washed with brine (200 mL), dried over NazSO4, filtered and concentrated to dryness. The crude product was Imfimflbyflwhmhwgdcdmmumflmmwgqmy@amkwnemmflflOAc=10—Od)w provide (3R, 4S, 5R)-5 -(((tert—butyldiphenyl silyl)oxy)methyl)ethynyltetrahydro—furan-2,3 ,4- fim6wwbwawmmgmn Step 3: To a solution of (3R, 4S, 5R)—5—(((tert—butyldiphenylsilyl)oxy)methyl)—4-ethynyltetra— hydrofuran-2,3,4-triol (5.17 g, 12.53 mmol, 1 eq) in pyridine (50 mL) at 15 °C was added 4- DMAP (4.59 g, 37.60 mmol, 3 eq) and AczO (11.74 mL, 125.32 mmol, 10 eq). The mixture was stirred at 15 0C for 16 h before H20 (500 mL) was added to the mixture. The reaction emmmdmmEKMch2mnm)TMcmmmwogmmmWHW%WMMd with brine (200 mL), dried over Na2S04, filtered and concentrated to dryness. The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 1:1) to provide (3R, 4R, 5R)—5-(((lert-butyldiphenylsilyl)oxy)methyl)—4—ethynyltetra- mmfiMma3¢mflUMHmd7Dg7%flwwflwmflbwgm.

Step 4: To a solution of (3R, 4R, (((lerz‘-butyldiphenylsilyl)oxy)methyl)—4-ethynyltetra- hydrofuran—2,3,4-triyl tate (6.89 g, 12.79 mmol, 1 eq) in MeCN (5 mL) at 0 0C was added 2-chloroadenine (2.39 g, 14.07 mmol, 1.1 eq), DBU (5.78 mL, 38.37 mmol, 3 eq) and TBASOTf(11561nL,63961nnufl,5eq) Thennxuueumssfinedat0°Clbr05liandthen stirred at 65 °C for 1 h before it was diluted with saturated aq. NaHCO3 solution (500 mL).

The aqueous phase was extracted with EtOAc (2 x 350 mL). The combined organic layer was washed with brine (350 mL), dried over NazSO4, filtered and concentrated to dryness.

The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 0:1) to provide (2R, 3R, 4R, 5R)(6—amino—2-chloro—9H-purin-9—yl)(((tert— butyldiphenylsilyl)oxy)methyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (4.52 g, 44% ymM)%aydbwde.

Step 5: To a solution of (2R, 3R, 4R,5R)—5-(6-amino—2-chloro-9H—purinyl)(((ier2‘- iphenylsilyl)oxy)methyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (45 g, 6.94 mmol, 1 eq) in DMF (50 mL) at 20 0C was added TEA (4.83 mL, 34.71 mmol, 5 eq), 4- DMAP (254 mg, 2.08 mmol, 0.3 eq) and BOC2O (7.58 g, 34.71 mmol, 5 eq). The mixture was stirred at 20 0C for 1 h before H20 (250 mL) was added to the mixture. The reaction mixture was ted with EtOAc (3 x 230 mL). The combined organic layer was washed with brine (250 mL), dried over , filtered and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 1:1) to provide (2R, 3R, 4R, 5R)-5 -(6—(bi s-(terl—butoxycarbonyl)amino)chloro-9H-purin—9-yl)-2— (((tert—butyldiphenylsilyl)oxy)methyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (3 .26 g, 46% yield) as a yellow foam.

Step 6: To a solution of (2R,3R,4R,5R)—5-(6-(bis-(tert-butoxycarbonyl)amino)chloro-9H- purinyl)—2-(((lert—butyldiphenylsilyl)oxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (3.24 g, 3.82 mmol, 1 eq) in THF (35 mL) at 0 °C was added TBAF (1 M, 5.73 mL, 1.5 eq). The on mixture was stirred at 0 0C for 1 h before it was diluted with H20 (150 mL). The reaction mixture was ted with EtOAc (3 x 130 mL). The combined organic layer was washed with brine (150 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 1:2) to provide (2R, 3R, 4R, (6-N,N’ (tert-butoxycarbonyl)amino) chloro-9H-purinyl)—3 -ethynyl(hydroxymethyl)tetrahydrofuran-3 ,4-diyl diacetate (1 .5 1 g, 54% yield) as a yellow foam.

Step 7: To a solution of (2R, 3R, —5-(6-N,N’ —(bis-(Zert—butoxycarbonyl)amino)chloro- 9H-purinyl)ethynyl-2—(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (1.48 g, 2.43 mmol, 1 eq) in toluene (10 mL) at 20 0C under N2 atmosphere was added Rh2(OAc)4 (214 mg, 485.24 umol, 0.2 eq) and diethyl diazomalonate (903 mg, 4.85 mmol, 2 eq) in toluene (3 mL). The mixture was stirred at 95 0C for 2 h to give a green suspension before it was cooled to room temperature and concentrated to dryness. The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 3: 1) to provide diethyl 2- (((2R, 3R, 4R, 5R)-3 ,4-diacetoxy-5 -(6-N,N’ —(bi s-(tert—butoxycarbonyl)amino)chloro-9H— purin—9-yl)-3—ethynyltetrahydrofuranyl)methoxy)malonate (517 mg, 20% yield) as a yellow foam.

Step 8: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ —(bis-(terl—butoxy- carbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (497.00 mg, 647.00 umol, 1 eq) in DMF (5 mL) at 25°C was added K2CO3 (178.84 mg, 1.29 mmol, 2 eq). The reaction mixture was stirred for 30 min and followed by addition of benzyl bromide (221.32 mg, 1.29 mmol, 153.69 uL, 2 eq). The mixture was stirred at 25°C for 15.5 h before additional K2CO3 (100 mg) and BnBr (100 uL) were added to the mixture. The resulting mixture was stirred at 25°C for 24 h before H20 (50 mL) was added to the reaction.

The reaction mixture was extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over NazSO4, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether: EtOAc = 1:0 — 3: 1) to provide diethyl 2-benzyl(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-(bis-(z‘erl— butoxycarbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)- te (266 mg, 37% yield) as a yellow foam.

Step 9: To a solution of diethyl 2-benzyl—2-(((2R, 3R, 4R, 5R)-3,4—diacetoxy(6—(bis-(tert- butoxycarbonyl)amino)—2-chloro-9H-purin—9-yl)ethynyltetrahydrofuranyl)methoxy)- malonate (266 mg, 309.92 umol, 1 eq) in DCM (3 mL) was added TFA (0.45 mL) at 0 °C.

The mixture was d at 25°C for 16 h before it was treated with saturated aq. NaHCO3 solution to pH 7. The reaction mixture was extracted with DCM (2 x 50 mL). The combined c layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to provide crude l 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-aminochloro-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (195 mg) as a yellow foam.

Step 10: The mixture of crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino- 2-chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (195 mg, 296.33 umol, 1 eq) in saturated NH3 in MeOH (3 mL) was stirred at 10 °C for 16 h before it was concentrated to dryness directly. The crude product was purified by preparative TLC (EtOAc) to provide l R, 3S, 4R, 5R)(6—aminochloro-9H-purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)benzylmalonate (91.7 mg, 49% yield) as a yellow foam.

Step 11: To a solution of diethyl 2-(((2R, 3S, 4R, (6-aminochloro-9H—purin—9—yl)-3— ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)benzylmalonate (81 mg, 141.12 umol, 1 eq) in EtOH (2 mL) was added zO (30 mg, 705.60 umol, 5 eq) in H20 (02 mL) at 10°C. The mixture was stirred at 50°C for 4 h before it was concentrated to dryness.

The residue was dissolved in H20 (50 m1) and extracted with EtOAc (2 x 50 mL). The organic layers were discarded and the aqueous phase was acidified to pH ~25 with 1N aq.

HCl solution. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to provide the title compound (55.4 mg, 74% yield) as a white solid. 1H NMR (400 MHz, DMSO-ds) 8 ppm 8.39 (s, 1H), 7.79 (br s, 2H), 7.20 (br d, J=7.03 Hz, 2H), 7.01 - 7.12 (m, 3H), 5.82 (d, J=7.53 Hz, 1H), 4.87 (d, J=7.78 Hz, 1H), 4.16 (dd, J=5.27, 2.51 Hz, 1H), 3.99 - 4.07 (m, 2H), 3.83 (br d, J=8.03 Hz, 1H), 3.56 (s, 1H), 3.25 (dd, J=6.78 Hz, 2H), LC/MS [M + H] = 518.0.

Example 2 sis of 2-(((ZS, 3R, 4R, 5R)(6-aminochloro-9H-purinyl)ethynyl ytetrahydrofuranyl)methoxy)benzylmalonic acid N(Boc)2 NHBoc NHBoc NHBoc \ \ N \ N \ N / N NH3, MeOH <,N TCDI </N (n-Bu)38nH /N TBDPSO N N’ TBDPSO N o N/ DMAP O N o CI Cl o N/ CI 133er TBDPSO N o N/ X 7’ X 7 CI DCM X 7’ X 7’ mi ”OAc Hcf ’OH 6Tb 6H N 800 N Bee 0 05' NH: ( )2 ( )2 o N(Boc)2 TFA B0020, TEA TBAF DCM /N \ DMAP, DMF /N \ N THF /N \ N ao 0 QB I AN I A I A ' <IN l A N TBDPSO <N HO <N TBDPSO; Rh (0A6) o N CI ; 0 N CI ; o N on tozluene‘: E10 0; N o N CI 10H bBoc 68°C 90809 0 N(Boc)2 o NH2 0 NH2 C 0 CB N 0 QB N O OH \ \ N \ <’ l i TFA,DCM </ | i aq.LiOH,THF </ l i —> EtO o N o N/ —> EC 0 N HO 0 N CI o N/ CI o N/ Cl K2803,DMF r’OBoc "OH ’IOH Examplez Step 1: To a solution of (2R, 3R, 4R,5R)(6—(bis-(terl-butoxycarbonyl)amino)chloro-9H— purinyl)—2-(((lert—butyldiphenylsilyl)oxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (5 g, 5.89 mmol, 1 eq) was added 2M NH3 in MeOH (50 mL) at 0 °C. The reaction mixture was stirred at 25 0C for 16 h before it was concentrated. The crude was purified by flash silica gel column chromatography (0—50% EtOAc in petroleum ether) to provide tert— butyl (9-((2R, 3R, 4S, 5R)(((lerZ-butyldiphenylsilyl)oxy)methyl)ethynyl-3 ydroxy- tetrahydrofuran-Z-yl)ch1oro-9H-purinyl)carbamate (3.78 g, 90% yield) as a yellow foam.

Step 2: To a solution of utyl (9—((2R, 3R, 4S, 5R)—5-(((terl—butyldiphenylsilyl)oxy)- methyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)chloro-9H-purinyl)carbamate (3.78 g, 5.29 mmol, 1 eq) in DCM (40 mL) at 0 °C under N2 atmosphere was added 4-DMAP (258.63 mg, 2.12 mmol, 0.4 eq) and TCDI (4.72 g, 26.46 mmol, 5 eq). The on mixture was stirred at 25 CC for 16 h before it was concentrated. The crude was purified by flash silica gel column chromatography (0—33% EtOAc in petroleum ether) to provide terl-butyl (9-((3aR, 4R, 6R, 6aR)(((terZ-butyldiphenylsilyl)oxy)methyl)-6a—ethynyl—2-thioxotetra- hydrofuro[3,4-d][1,3]dioxol—4-yl)chloro—9H—purinyl)carbamate (1.4 g, 37% yield) as a yellow foam.

Step 3: To a solution of lert—butyl (9—((3aR, 4R, 6R, 6aR)—6-(((Zerl-butyldiphenylsilyl)oxy)- methyl)-6a-ethynylthioxotetrahydrofuro[3 1,3]dioxolyl)chloro-9H—purin yl)carbamate (500 mg, 707.93 umol, 1 eq) in toluene (5 mL) was added AIBN (11.62 mg, 70.79 umol, 0.1 eq) at 20—25°C. The reaction mixture was then heated to 60 oC and followed by addition of (n-Bu)3SnH (561.96 uL, 2.12 mmol, 3 eq). The reaction mixture was stirred at 60 °C for 1.5 h before it was concentrated. The crude was purified by flash silica gel column chromatography (0—33% EtOAc in petroleum ether) to e tert—butyl (9-((2R, 3R, 4R, 5S)- -(((l‘erl—butyldiphenylsilyl)oxy)methyl)ethynyl—3 -hydroxytetrahydro-furanyl) chloro-9H-purinyl)carbamate (220 mg, 47% yield) as a white foam.

Step 4: To a solution of lert-butyl (9-((2R, 3R, 4R, (((terZ-butyldiphenylsilyl)oxy)- methyl)ethynylhydroxytetrahydrofuranyl)chloro-9H-purinyl)carbamate (220 mg, 339.39 umol, 1 eq) in DCM (1.4 mL) at 0 CC was added TFA (0.7 mL, 9.45 mmol, 28 eq). The reaction mixture was d at 25 CC for l h before it was diluted with saturated aq. NaHCO3 solution (15 mL) and extracted with DCM (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2S04, filtered and concentrated to WO 46403 2019/038245 provide crude (2R, 3R, 4R, 5.5)—2-(6-amino-2—chloro—9H—purin—9-yl)—5—(((tert—butyldiphenyl— silyl)oxy)methyl)ethynyltetrahydrofuranol (260 mg) as a yellow foam.

Step 5: To a solution of (2R, 3R, 4R,5S)(6-amino—2-chloro-9H—purinyl)—5-(((lert— butyldiphenylsilyl)oxy)methyl)-4—ethynyltetrahydrofuranol (260 mg, 474.36 umol, 1 eq, crude) in DMF (2.5 mL) was added BOC2O (931.75 mg, 4.27 mmol, 9 eq), TEA (660.25 uL, 4.74 mmol, 10 eq) and 4-DMAP (5.80 mg, 47.44 umol, 0.1 eq) at 0 oC. The reaction mixture was stirred at 25 °C for 1.5 h before it was diluted with H20 (20 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated to provide crude (2R, 3R, 4S, 5S)(6-(N,N’ -bis-((tert- butoxycarbonyl)amino)chloro-9H-purin—9-yl)-5—(((lert—butyldiphenylsilyl)oxy)methyl)—4- ethynyltetrahydrofuranyl utyl carbonate (560 mg) as an orange gum.

Step 6: To a solution of crude (2R, SR, 45, 5S)—2-(6-(N,N’ -bis-((lert-butoxycarbonyl)amino) chloro-9H-purinyl)(((terl—butyldiphenylsilyl)oxy)methyl)ethynyltetrahydrofuran—3 -yl lert—butyl carbonate (560 mg, 660.02 umol, 1 eq, crude) in THF (6 mL) at 0 0C was added TBAF in THF (1 M, 1 mL, 1.52 eq). The reaction mixture was stirred at 0 °C for l h. The on mixture was diluted with H20 (10 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and trated. The crude was d by preparative TLC leum ether : EtOAc = 2: 1) to provide (2R, SR, 45, 5S)(6—(N,N’ —bis-((lert—butoxycarbonyl)amino)chloro-9H—purinyl)— 4-ethynyl-5—(hydroxymethyl)tetrahydrofuranyl terZ-butyl carbonate (93 mg, 45% yield over 3 steps) as a yellow foam.

Step 7: To a solution of (2R, 3R, 4S, 5S)—2-(6-(N,N’ -bis-((Zert—butoxycarbonyl)amino)chloro- 9H-purinyl)ethynyl(hydroxymethyl)tetrahydrofuran-3 -yl tert—butyl carbonate (93 mg, 152.45 umol, 1 eq) in toluene (1 mL) at 25 0C under N2 atmosphere was added Rh2(OAc)4 (6.74 mg, 15.24 umol, 0.1 eq). The reaction mixture was heated to 90 oC and followed by addition of diethyl 2-diazomalonate (85.14 mg, 457,34 umol, 3 eq) in toluene (1 mL). The reaction mixture was stirred at 90°C for 3 h before it was concentrated. The crude residue was purified by flash column tography on silica gel to provide diethyl 2- (((2S, 3S, 4R, 5R)—5-(6-(N,N’ -bis-((Zerz‘-butoxy-carbonyl)amino)chloro-9H-purinyl) WO 46403 ((tert—butoxycarbonyl)oxy)—3—ethynyltetrahydro-furanyl)methoxy)malonate (180 mg) as a Step 8: To a solution of crude diethyl S, 3S, 4R, 5R)(6-(N,N’ -bis-((terl—butoxy- carbonyl)amino)—2—chloro—9H—purinyl)((2‘ert—butoxycarbonyl)oxy)ethynyltetrahydrofuranyl )methoxy)malonate (117.11 mg, 152.45 umol, 1 eq) in DMF (3 mL) was added K2C03 (421.39 mg, 3.05 mmol, 20 eq) at 20—25 °C. The reaction mixture was stirred for 0.5 h and followed by addition of benzyl bromide (271.61 uL, 2.29 mmol, 15 eq). The on was then stirred further for 16 h before it was d with H20 (20 mL) and extracted with EmAd3xmmD.wamMmdmymdwflW%W%Mdmmbmw05mmgmwowr hhfiOgmwmdmdamWmed7meambwupmmaflwflwhwmagflwbmn chromatography (petroleum ether : EtOAc = 1:0 — 2:1 gradient) to provide diethyl 2- (((2S, 3S, 4R, 5R)(6-(N,N’ —bis-((tert—butoxycarbonyl)amino)chloro-9H—purinyl) ((lert—butoxycarbonyl)oxy)—3-ethynyltetrahydrofuranyl)methoxy)benzylmalonate (90 rng)asanofl?whfiegunr Step 9: To a solution of diethyl 2-(((ZS,3S,4R,5R)—5-(6-(N,N’ -bis-((tert-butoxycarbonyl)- amino)—2-chloro-9H-purinyl)((ZerZ-butoxycarbonyl)oxy)ethynyltetrahydrofuran-Z- yl)methoxy)benzylmalonate (90 mg, 104.86 umol, 1 eq) in DCM (0.6 mL) at 0 CC was added TFA (0.3 mL, 4.05 mmol, 39 eq). The reaction mixture was stirred at 25 °C for l h before it was diluted with saturated aq. NaHC03 solution (5 mL) and extracted with DCM (3 x 3 mL). The combined c layer was washed with brine (5 mL), dried over Na2SO4, wmmmmw.HmammmmmwwwmmfiwbymwMMWEHLXmmdwm ether : EtOAc = 1:1) to provide diethyl 2-(((ZS, 3R, 4R, 5R)-5—(6-aminochloro-9H—purin-9— yl)ethynylhydroxytetrahydrofuranyl)methoxy)benzylmalonate (19 mg, 13% yield for 3 steps) as a yellow gum.

Step 10: To a solution of diethyl 2-(((ZS, 3R, 4R, 5R)(6-aminochloro-9H-purinyl) ethynylhydroxytetrahydrofuranyl)methoxy)-2—benzylmalonate (19 mg, 3405 umol, 1 eq) in THF (0.2 mL) was added LiOH'H20 (7.14 mg, 170.26 umol, 5 eq) in H20 (70 uL) at °C. The on mixture was stirred for 5.5 h before it was diluted with H20 (5 mL) and then acidified to pH 2—3 with 1N aq. HCl. The mixture was extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous NazSO4, filtered, and concentrated. The crude e was dissolved in a mixture of H20 (3 mL) and MeCN (2 mL) and then lyophilized to provide the title compound as a white solid. 1H NMR (400 MHz, CD30D) 6 ppm 8.30 (s, 1H) 7.27 (br d, J=5.27 Hz, 2H) 7.17 — 7.24 (m, 1H) 7.15 (br d, J=6.78 Hz, 2H) 5.87 — 5.96 (m, 1H) 4.94 (br s, 1H) 4.68 (br s, 1H) 3.96 — 4.11 (m, 2H) 3.34 = 5020. — 3.40 (m, 2H) 2.57 (d, J=2.51 Hz, 1H) 2.32 (s, 1H); LC/MS [M + H] Example 3 Synthesis of 2-(((2R, SS, 4R, 5R)(6-aminochloro-9H-purinyl)-3,4-dihydroxy(prop- l-yn— l -yl)tetrahydrofuranyl)methoxy)-2—benzylmalonic acid 4DMAP TBDPSO3—7.40—_—MgBr $§fTBDPSO TBDPSO o pyridine $gk TBAF AcOH Qj 0 "0k THF 40°C 0 o —N>Eio 3—3.“:03 OWOEO BnBrCsQCOE NH2 O NH 0 ””2 2 ACQO o OEt 4DMAF (HN’N10</ O OH I 0 CE N [\N </ 1*\N _'d' aq'LiOH mm Ine EtO o 0 THF HO O N _, OAc BO 0 N o N/ o NAG—p oi BSA,TMSOTf . .

C 9 MeCN Q1, . .

AcO OAc : 3/ : 'r AC6 OH OAc HO Examples Step 1: To a solution of (3aR,5R,6aS)(((terZ-butyldiphenylsilyl)oxy)methyl)-2,2—dimethyl- dihydrofuro[2,3-d][l,3]dioxol-6(3ahO-one (10 g, 23.44 mmol, 1 eq) in THF (100 mL) at 20 °C under N2 atmosphere was added (prop-l-ynyl)magnesium bromide (0.5 M, 93.77 mL, 2 eq). The mixture was stirred at 40 °C for 2 h before it was diluted with saturated aq. NH4Cl on (250 mL). The aqueous phase was ted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (200 mL), dried over , filtered and W0 20191246403 concentrated to give crude (3aR,5R,6R,6aR)—5-(((tert—butyldiphenylsilyl)oxy)methyl)—2,2- dimethyl(propynyl)tetrahydrofuro[2,3-d][1,3]dioxolol (11.81 g) as a yellow gum.

Step 2: To a on of crude (3aR, 5R, 6R, 6aR)(((Zert—butyldiphenylsilyl)oxy)-methyl)— 2,2-dimethyl(propyn—1-yl)tetrahydrofuro[2,3-d][1,3]dioxolol (12.2 g, 26.14 mmol, 1 eq) in pyridine (120 mL) at 20 CC was added 4-DMAP (3.51 g, 28.76 mmol, 1.1 eq) and AC2O (4.90 mL, 5229 mmol, 2 eq), The mixture was d at 20 0C for 16 h before it was diluted with H20 (200 mL) and extracted with EtOAc (3 X 100 mL). The ed organic layer was washed with brine (250 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give crude (3aR,5R,6R,6aR)—5-(((tert-butyldiphenylsily1)oxy)methyl)-2,2- dimethyl(propynyl)tetrahydrofuro[2,3-d][1,3]dioxolyl acetate (15 g) as a yellow Step 3: To a solution of crude (3aR, 5R, 6R, 6aR)(((ZerZ-butyldiphenylsilyl)oxy)-methyl)— 2,2—dimethyl(prop-l-yn—l-yl)tetrahydrofuro[2,3-d][l,3]dioxol—6-yl acetate (15 g, 29.49 mmol, 1 eq) in THF (300 mL) at 0 °C under N2 here was added a mixture of TBAF (1 M, 44.23 mL, 1.5 eq) and AcOH (1.26 mL, 22.12 mmol, 0.75 eq). The mixture was stirred at °C for 7 h before it was diluted with saturated aq. NH4Cl solution (300 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel column chromatography leum ether : EtOAc=1 :0—1 : 1) to provide (3aR, 5R, 6R, 6aR)(hydroxymethyl)—2,2-dimethyl(prop—1-ynyl)tetrahydrofuro[2, 3 -d] [ l ,3 ] dioxolyl acetate (5.78 g, 72.5% yield) as a white solid.

Step 4: To a solution of (361R, 5R, 6R, 6aR)-5—(hydroxymethyl)-2,2-dimethyl—6-(prop—1-yn-l— yl)tetrahydrofuro[2,3-d][1,3]dioxolyl acetate (5.78 g, 21.39 mmol, 1 eq) in dichloroethane (60 mL) at 15 °C under N2 atmosphere was added Rh2(OAc)4 (945.21 mg, 2.14 mmol, 0.1 eq) and diethyl diazomalonate (7.96 g, 42.77 mmol, 2 eq). The mixture was stirred at 40 °C for 7 h before it was concentrated to dryness. The crude product was d by flash silica gel column chromatography (0—25% EtOAc in petroleum ether) to provide diethyl 2- W0 20191246403 (((3aR,5R, 6R, 6aR)-6—acetoxy—2,2-dimethyl—6—(prop—1-yn-1—yl)tetrahydrofuro[2,3 -d] [1 , 3 ]- yl)methoxy)malonate as a yellow gum.

Step 5: To a on of diethyl 2-(((3aR,5R, 6R, 6aR)acetoxy-2,2—dimethyl(propyn—1- yl)tetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (7.28 g, 16.99 mmol, 1 eq) in DMF (70 mL) at 20 0C was added CS2CO3 (11.07 g, 33.98 mmol, 2 eq) and BnBr (3.03 mL, .49 mmol, 1.5 eq). The e was stirred at 20 0C for 2 h before it was diluted with H20 (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel gel column chromatography (petroleum ether : EtOAc = l:0—3:l) to provide diethyl 2—(((3aR, 5R, 6R, 6aR)acetoxy-2,2-dimethyl-6—(prop- 1 —yn yl)tetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)benzylmalonate (7.67 g, 87% yield) as a yellow gum.

Step 6: To a solution of l 2-(((3aR,5R, 6R, 6aR)acetoxy-2,2-dimethyl(propyn-l- yl)tetrahydrofuro[2,3-d][1,3]dioxol—5-yl)methoxy)—2-benzylmalonate (7.67 g, 14.79 mmol, 1 eq) in TFA (80 mL) at 20 °C was added H2O (6.97 mL, 387.05 mmol, 26 eq). The e was stirred at 20 °C for 8 h before it was quenched with saturated aq. NaHCOs solution to pH 7 and partitioned with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SO4 and filtered. The e was concentrated to dryness to provide crude diethyl 2-benzyl(((2R,3S,4R)-3,4,5-trihydroxy-3 -(prop-1—ynyl)tetra- hydrofuranyl)methoxy)malonate (5.95 g) as a yellow gum.

Step 7: To a solution of crude diethyl 2-benzyl(((2R, 3S, 4R)-3,4,5-trihydroxy(propyn- 1-yl)tetrahydrofuranyl)methoxy)malonate (5.95 g, 13.63 mmol, 1 eq) in pyridine (60 mL) at 20 0C was added 4-DMAP (5.00 g, 40.90 mmol, 3 eq) and A020 (6.38 mL, 68.16 mmol, 5 eq). The mixture was stirred at 20 0C for 16 h tbefore it was diluted with H20 (300 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with brine (300 mL), dried over Na2SO4, d and concentrated. The crude product was purified by flash silica gel column chromatography (petroleum ether : EtOAc = 1:0—3 : 1) to provide diethyl 2-benzyl(((2R, 3R, 4R)-3,4,5-triacetoxy-3—(prop-1—yn-1 -yl)tetrahydrofuran- 2-yl)methoxy)malonate (5.76 g, 66% yield) as a yellow gum.

Step 8: To a solution of diethyl 2-benzyl(((2R, 3R, 4R)-3,4,5-triacetoxy-3—(propyn rahydrofuranyl)methoxy)malonate (1 g, 1.78 mmol, 1 eq) in MeCN (10 mL) at 20 0C was added N,O-bis(trimethylsilyl)acetamide (BSA) (1.32 mL, 5.33 mmol, 3 eq) and 2-chloro- adenine (301.43 mg, 1.78 mmol, 1 eq). The mixture was d at 65 CC for 30 min before it was cooled to 0 °C and followed by addition of TMSOTf (642 uL, 3.56 mmol, 2 eq) dropwise. The mixture was stirred at 0 0C for 10 min and then at 65 0C for 2 h before it was ed with saturated aq. NaHCO3 (100 mL) and extracted with EtOAc (2 x 60 mL). The combined organic layer was washed with brine (100 mL) and dried over Na2S04, filtered and concentrated. The crude product was purified by flash silica gel column chromatography (0— 33% EtOAc in petroleum ether) to provide diethyl 2-benzyl—2-(((2R, 3R, 4R, 5R)-3,4— diacetoxy(6-aminochloro-9H—purinyl)-3 ynyl)tetrahydrofuran yl)methoxy)malonate (218 mg, 18% yield) as a yellow foam.

Step 9: To a solution of diethyl 2-benzyl-2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino chloro—9H-purinyl)—3-(propyn—1-yl)tetrahydrofuran-2—yl)methoxy)malonate (218 mg, 324.37 umol, 1 eq) in THF (2 mL) was added LiOH‘HzO (136.12 mg, 3.24 mmol, 10 eq) in H20 (2 mL) at 20 °C. The mixture was heated at 45°C for 2 h before it was diluted with H20 (10 mL) and extracted with EtOAc (10 mL). The c layer was discarded and the aqueous phase was acidified with 2 N aq. HCl to pH 2—3. Then the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined c layer was washed with brine (30 mL), dried over NazSO4, filtered and concentrated. The crude product was purified by preparative HPLC to provide the title compound (39.8 mg, 23% yield) as a white solid. 1H NMR (011480—016, 400 MHz) 5 ppm 412 (m, 2H), 8.37 (s, 1H), 7.80 (br s, 2H), 7.19 (br d, J=7.03 Hz, 2H), 7.00—7.11 (m, 3H), 5.88—6.03 (m, 2H), 5.81 (d, J=7.53 Hz, 1H), 4.78 (br s, 1H), 4.12 (dd, J=4.52, 3.01 Hz, 1H), 3.95 (br dd, J=9.91, 4.89 Hz, 1H), 3.82 (br d, J=8.53 Hz, 1H), 3.25 (s, 2H), 1.81 (s, 3H), LC/MS [M + H] = 532.0.

Synthesis of 2-(((2R, 3S, 4R, (6-aminochloro-9H-purinyl)(cyclopropylethynyl)- 3,4-dihydroxytetrahydrofuranyl)methoxy)benzylmalonic acid TBDPSO A OHC 3:7“) _\<j— 0 o 0 TBDPSO TBDPSO HO ne THF Bo N2 '0 "'0 —> —> —> Rh2(OAC)4 O "IO)(n-BUL1,THF 0:"0/%—> ACO ’O/k /ACO O BnBr O O A620, 0 OMOE‘ (332003 0 05* 0 0E! 4—DMAP o OEt DMF TFA, DCM pyridine EtO o —>BO 0 EC 0 o o —> o OH—> EC 0 "'0 Ph ...0 Ph OAc _ : .0OK 5 ubk : ., = ’0“ .- .0 A00 AcO A00 Aco‘ OAc (grid NH2 0 30(31):!“N/kCI aq. LiOH THF ”Oh 0< NH2 TMSOTf, BSA Etoh AcO HO Examp|e4 Step 1: To a solution of ethynylcyclopropane (4.96 g, 75.02 mmol, 6.22 mL, 2 eq) in THF (80 mL) at —78°C under N2 atmosphere was added n-BuLi (2.5 M, 3001 mL, 2 eq) dropwise.

The solution was stirred at —78 °C for 0.5 h and followed by addition of a solution of (3aR, 5R, 6aS)—5-(((terZ-butyldiphenylsilyl)oxy)methyl)-2,2—dimethyldihydrofuro[2,3 -d][1,3]— dioxol-6(3aH)-one (16.0 g, 37.51 mmol, 1 eq) in THF (60 mL) dropwise. Then the solution was allowed to warm to 20 °C and stirred for 1 h before it was then cooled to 0 °C and quenched with water (120 mL). The mixture was extracted with EtOAc (2 X 120 mL). The combined organic layer was washed with brine (200 mL), and dried by Na2S04, filtered and concentrated. The crude was purified by Combi-flash on silica gel (0—15% ethyl acetate in petroleum ether) to give (30R, 5R, 6R, 6aR)—5-(((tert—butyldiphenylsilyl)oxy)-methyl) (cyclopropylethynyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolol (15.8 g, 86% yield) as a syrup.

Step 2: To a solution of (301R, 5R, 6R, 6aR)—5-(((lert-butyldiphenylsilyl)oxy)methyl)(cyclo- propylethynyl)—2,2—dimethyltetrahydrofuro[2,3-d][l,3]dioxolol (15.8 g, 32.07 mmol, 1 eq) in pyridine (160 mL) at 20 °C was added 4—DMAP (4.70 g, 38.48 mmol, 1.2 eq) and A020 (9.01 mL, 9621 mmol, 3 eq). The solution was stirred for 3 h before it was diluted with water (200 mL) and extracted with ethyl acetate (2 X 200 mL). The combined organic layer w&wwkdmmbmwmmmmlmmeNmQMJmflwaMcM%MmmlTMcm® residue was purified by Combi-flash on silica gel ethyl acetate in petroleum ether) to give (3aR, 5R, 6R, 6aR)—5-(((tert—butyldiphenylsilyl)oxy)methyl)-6—(cyclopropylethynyl)—2,2- dimethyltetrahydrofuro[2,3—d][1,3]dioxol-6—yl acetate (14.7 g, 86% yield) as a clear syrup.

Step 3: To a solution of (361R, 5R, 6R, 6aR)-5—(((Zert—butyldiphenylsilyl)oxy)methyl)—6- (cyclopropylethynyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolyl acetate (14.7 g, 27.49 mmol, 1 eq) in THF (150 mL) at 0 °C was added a solution of TBAF (1 M, 41.24 mL, 1.5 eq) and AcOH (1.18 mL, 20.62 mmol, 0.75 eq). The solution was stirred at 20 °C for 16 h before it was diluted with water (300 mL) and extracted with ethyl acetate (2 X 200 mL). The combined organic layer was washed with water (400 mL), brine (400 mL), dried bflMMMmmmemwmmdmeMwwwfifiMfimfiflMmmme (20—60%ethyl acetate in petroleum ether) to give (3aR, 5R, 6R, 6aR)—6-(cyclopropylethynyl)—5- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolyl e (8.15 g, 100% yield) as a white solid.

Step 4: To a solution of (3aR,5R,6R,6aR)—6-(cyclopropylethynyl)(hydroxymethyl)-2,2— dimethyltetrahydrofuro[2,3-01][1,3]dioxol-6—yl acetate (8.15 g, 27 .50 mmol, 1 eq) in dichloroethane (80 mL) at 20 °C under N2 atmosphere was added Rh2(OAc)4 (1.00 g, 2.26 mmol, 0.08 eq) and a on of diethyl diazomalonate (10.24 g, 55.01 mmol, 2 eq) in mdewmmeaomD.flwgmmmdenwwsmmdbrMhbfiMefiwmammewd The crude was purified by Combi-flash on silica gel (15—50% ethyl acetate in petroleum ether) to give diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxy(cyclopropylethynyl)-2,2-dimethyl- tetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (9.52 g, 76% yield) as a yellow oil.

Step 5: To a solution of l 2-(((3aR, 5R, 6R, 6aR)acetoxy-6—(cyclopropylethynyl)-2,2- yltetrahydrofuro[2,3—d][1,3]dioxol-5—yl)methoxy)malonate (4.50 g, 9.90 mmol, 1 eq) in DMF (50 mL) at 20 0C was added CszCO3 (9.68 g, 29.71 mmol, 3 eq) and benzyl bromide (1%anM85mde5eQ.finamwmbnwwstdfirMhbfimefiwmeWd with water (80 mL) and extracted with ethyl e (3 x 80 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried by Na2SO4, d and concentrated. The crude was purified by Combi-fiash on silica gel (15—50% ethyl acetate in petroleum ether) to give diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxy(cyclo-propylethynyl)—2,2- dimethyltetrahydrofuro[2,3—d][l,3]dioxolyl)methoxy)-2—benzyl—malonate (4.10 g, 76% yield) as a colorless syrup.

Step 6: To a solution of diethyl aR, 5R, 6R, 6aR)acetoxy-6—(cyclopropylethynyl)-2,2- dimethyltetrahydrofuro[2,3—d][1,3]dioxol-5—yl)methoxy)-2—benzylmalonate (4.10 g, 7.53 mmol, 1 eq) in DCM (50 mL) at 0 °C was added H20 (10 mL) and TFA (50 mL). The solution was stirred at 20 °C for 2 h before it was quenched with saturated aq. NaHCO3 (80 mL) to pH ~7. The on mixture was exacted with DCM (100 mL). The organic layer was washed with brine (10 mL), dried by NazSO4, filtered and concentrated to give crude diethyl 2-(((2R, 3S, 4R)-3 -acetoxy-3 —(cyclopropylethynyl)-4, 5 -dihydroxytetrahydrofuran-2— hoxy)benzylmalonate (3.80 g) as a yellow gum.

Step 7: To a solution of crude l diethyl 2-(((2R,3S,4R)acetoxy-3 opropyl- ethynyl)-4,5-dihydroxytetrahydrofuranyl)methoxy)benzylmalonate (3.80 g, 7.53 mmol, 1 eq) in pyridine (40 mL) at 20 CC was added 4-DMAP (2.76 g, 22.60 mmol, 3 eq) and AczO (5.64 mL, 60.25 mmol, 8 eq). The solution was d for 16 h before it was diluted with water (80 mL) and extracted with ethyl acetate (2 x 80 mL). The combined organic layer was washed with water (150 mL), brine (150 mL), dried by Na2SO4, filtered and concentrated.

The crude was d by Combi-flash on silica gel (10—50% ethyl acetate in petroleum ether) to give diethyl 2-benzyl(((2R, 3R, 4R)-3,4,5-triacetoxy(cyclopropylethynyl)— tetrahydro-furanyl)methoxy)malonate (2.91 g, 66% yield) as a yellow gum.

Step 8: To a solution of diethyl 2-benzyl(((2R, 3R, 4R)-3,4,5-triacetoxy (cyclopropylethynyl)tetrahydrofuranyl)methoxy)malonate (980 mg, 1.66 mmol, 1 eq) in MeCN (24 mL) at 25 °C was added 2-chloroadenine (338.80 mg, 2.00 mmol, 1.2 eq) and BSA (987,71 uL, 4.00 mmol, 2.4 eq). The suspension was stirred at 65 °C for 0.5 h as it turned clear. The resulting solution was cooled down to 0°C and followed by addition of TMSOTf (444.06 mg, 200 mmol, 361.03 uL, 1.2 eq) dropwise. The reaction mixture was stirred at 40 0C for 4 h before it was allowed to cool to room temperature. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The ed organic layer was washed with brine (50 mL), dried by NazSO4, filtered and concentrated. The crude was purified by Combi-flash on silica gel (30—80% ethyl acetate in petroleum ether) to give diethyl 2-benzyl-2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino chloro-9H—purin-9—yl)(cyclopropylethynyl)tetrahydrofuran-Z-y1)methoxy)malonate (270 mg, 23% yield) as a yellow gum.

Step 9: To a solution of diethyl 2-benzyl-2—(((2R, 3R, 4R, 5R)—3,4-diacetoxy—5-(6-amino chloro-9H—purinyl)(cyclopropylethynyl)tetrahydrofuranyl)-methoxy)malonate (270 mg, 386.75 umol, 1 eq) in THF (8 mL) was added aq. LiOH solution (1 M, 5.80 mL, 15 eq).

The mixture was stirred at 20 0C for 16 h before it was treated with 1N HCl to adjust the pH to 5. The mixture was trated. The crude residue was purified by preparative HPLC to give the title compound (23 mg, 11% yield) as a white solid. 1H1\H\1R (400 MHz, CD30D) 5 ppm 8.04 (s, 1H) 7.14 — 7.27 (m, 2H) 7.01 — 7.08 (m, 3H) .92 (d, J=6.63 Hz, 1H) 4.70 — 4.83 (m, 1H) 4.24 (t, J=3.50 Hz, 1H) 4.02 (t, J=3.31 Hz, 2H) 3.31— 3.45 (m, 2H) 1.25 — 1.33 (m, 1H) 0.72 — 0.79 (m, 2H) 0.63 — 0.71 (m, 2H), LC/MS [M + H] = 559.0.

Example 5 sis of 2—(((2R, 3S, 4R, (6-amino-2—chloro—9H—purinyl)—3 yl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)((2—chloropyridinyl)methyl)malonic acid 0 N<Boc>2 o N(Boc)2 c1 0E1 0 QB N N 016) </r </ I A 5‘0 N o TFA DCM BO 0 N o N/ \ K2003 DMF \ A00: GOAC o NH2 0 2 O 0E1 N CH <’ ‘” l aq.LIOH,THF~ </N 1N1 E10 A ,N N ”0 \ 0; o CI \ N / ~‘ '9 / Aco‘ OAc 0H;:0;OH,N Example 5 Proceeding as described in Example 1 above by substituting BnBr with 2-chloro (chloromethyl)py1idine provided the title compound as a white solid. 1H NMR (CD3OD, 400 MHz) 5 ppm 8.40 (s, 1H), 8.00 (d, J=5. 13 Hz, 1H), 7.36 (s, 1H), 7.23 (d, J=5.13 Hz, 1H), 6.01 (d, J=7.63 Hz, 1H), 5.08 (d, J=7.63 Hz, 1H), 4.39 (dd, J=4.88, 2.75 Hz, 1H), 4.16 (dd, J=10.07, 5.19 Hz, 1H), 4.05 (dd, J=10.01, 2.63 Hz, 1H), 3.47 (s, 2H), 3.05 (s, 1H); LC/MS [M + H] = 553.1.

Example 6 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid TBDPSO HO O OH 0 0 Rh2(OAc)4 "'0 "'0 0* TBAF, THF DCE, 25 °c : —> : E10 0 .~ .,I 1- .,l 0 Ho‘ Ho‘ 0* S 7"'0 —Ho- (K JCSZCOS, BnBr 0 CE OEt Ac20,4-DMAP O: 0 OAc pyridine, DCM O: 0 mo Acd ’OAc —HO¢- ”OX </_<NH, BSA, TMSOTf, MeCN aq. LiOH, MeOH Step 1: To a mixture of (3aR, 5R, 6R, 6aR)-5—(((Zert-butyldiphenylsilyl)oxy)methyl)—6-ethynyl- 2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxolyl acetate (27.4 g, 55.39 mmol, 1 eq) in THF (250 mL) at 0 °C was added AcOH (2.38 mL, 41.54 mmol, 0.75 eq) in TBAF (1 M, 83.09 mL, 1.5 eq). The mixture was d at 15 CC for 15 h before it was partitioned between water (800 mL) and EtOAc (300 mL). The s phase was r extracted with EtOAc (3 x 200 mL). The combined organic layer was washed with brine (300 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on Si02 (1 1—33% EtOAc in petroleum ether) to give (3aR, 5R, 6R, 6aR)ethynyl-5—(hydroxymethyl)—2,2-dimethyltetrahydrofuro— [2,3-d][1,3]dioxolyl acetate (15.2 g, 91% yield) as a light yellow solid.

Step 2: To a mixture of (3aR, 5R, 6R, 6aR)-6—ethynyl(hydroxymethyl)—2,2-dimethyltetra— hydrofuro[2,3-d][1,3]dioxolyl acetate (15.2 g, 59.32 mmol, 1 eq) in dichloroethane (150 mL) at 0 0C was added Rh2(OAc)4 (1.31 g, 2.97 mmol, 0.05 eq) and diethyl diazomalonate (13.25 g, 71.18 mmol, 1.2 eq) in dichloroethane (30 mL). The mixture was stirred at 15 0C under N2 atmosphere for 15 h before additional amount of diethyl diazomalonate (6 g) in dichloroethane (15 mL) was added. The mixture was stirred further at 15°C for 2 h before it was concentrated under d pressure. The e was d by column chromatography on silica gel (11—33% EtOAc in petroleum ether) to give diethyl 2- (((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra—hydrofuro-[2,3—d] [ 1 ,3 ]dioxol yl)methoxy)malonate (15 g, 61% yield) as a white solid.

Step 3: To a mixture of diethyl 2-(((3aR, 5R, 6R, -acetoxyethynyl—2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (14 g, 33.78 mmol, 1 eq) in DMF (140 mL) at 25 °C was added CS2CO3 (22.01 g, 67.57 mmol, 2 eq) and BnBr (6.02 mL, 50.68 mmol, 1.5 eq). The mixture was stirred at 25 0C for 3 h before it was d and the filter cake was washed with EtOAc (50 mL). The filtrate was diluted with water (400 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layer was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and trated under reduced pressure.

The residue was purified by flash silica gel column chromatography (O—33% EtOAc in petroleum ether) to give l 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3—d][1,3]dioxol—S—yl)methoxy)—2—benzylmalonate (13.3 g, 78% yield) as a colorless oil.

Step 4: To a mixture of diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl)methoxy)benzylmalonate (13.20 g, 26.16 mmol, 1 eq) in DCM (100 mL) and H20 (20 mL, 111 mol, 42 eq) was added TFA (100 mL, 1.35 mol, 52 eq). The mixture was stirred at 15 0C for 12 h before water (200 mL) was added.

The aqueous phase was extracted with DCM (2 x 100 mL). The combined organic extract was washed with saturated aq. NaHCO3 (2 x 100 mL), brine (100 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced re. The residue was purified by flash column chromatography (SiOz, eum ether : Ethyl acetate = 10:1 to 1:3) to give l 2-benzyl(((2R, SS, 4R)-3 -ethynyl-3 ,4, 5 -trihydroxytetrahydrofuran-Z-yl)methoxy)malonate (7.8 g, 71% yield) as a ess oil.

Step 5: To a mixture of diethyl 2-benzyl(((2R, 3S, 4R)—3-ethynyl—3,4,5-trihydroxytetra- hydrofuran—2-yl)methoxy)malonate (7.8 g, 18.46 mmol, 1 eq) in pyridine (70 mL) at 15 °C was added 4—DMAP (6.77 g, 5539 mmol, 3 eq) and AczO (17.29 mL, 184.65 mmol, 10 eq).

The mixture was stirred for 15 h before water (400 mL) was added. The mixture was ted with EtOAc (3 x 200 mL). The combined organic layer was washed with 1N aq.

HCl (2 x 200 mL), saturated aq. NaHCO3 (300 mL), brine (300 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column tography (petroleum ether : Ethyl acetate = 1:0 to 2: 1) to give the desired product (7 g). This product was triturated with EtOH (10 mL) and d to give diethyl 2-benzyl(((2R, 3R, 4R)-3 ,4, 5 -t1iacetoxy-3 —ethynyltetrahydrofuran—2-yl)methoxy)— malonate (3.79 g, 37% yield) as a white solid. The filtrate was concentrated under reduced pressure to give slightly impure additional product (3 g).

Step 6: To a solution of diethyl 2-benzyl-2—(((2R, 3R, 4R)-3,4,5-triacetoxy—3-ethynyltetra- hydrofuran-2—yl)methoxy)malonate (116 mg, 0.21 mmol, 1.0 eq) in MeCN (3 mL) at 25 0C was added uracil (28 mg, 0.25 mmol, 1.2 eq) and followed by N,O-bis(trimethylsilyl)— acetamide (BSA) (124 uL, 0.51 mmol, 2.4 eq). The resulting suspension was heated at 65 °C for 30 min as it became clear. The reaction mixture was cooled to 0 0C and followed by dropwise addition of TMSOTf (46 uL, 0.25 mmol, 1.2 eq). The reaction mixture was allowed to warm up and heated at 65 0C for 3 h as all of the starting material was consumed.

The reaction was quenched with cold ted aq. NaHCO3 solution (3 mL) and diluted with EtOAc (15 mL). The organic layer was separated, washed with H20 (2 x 10 mL), brine, dried (MgSO4), filtered and concentrated. The crude residue was purified by flash silica gel column chromatography (0—75% EtOAc in hexanes) to provide the product l 2-benzyl- 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2,4-dioxo-3 ,4-dihydro—pyrimidin- 1 (2]10-yl)ethynyl- tetrahydrofuran-2—yl)methoxy)malonate (104 mg, 82% yield).

Step 7: To a solution of diethyl 2-benzyl-2—(((2R, 3R, 4R, 5R)—3,4-diacetoxy—5—(2,4-dioxo-3,4— dihydropyrimidin- 1 (2]10-yl)-3 yltetrahydrofuranyl)methoxy)-malonate (100 mg, 0.166 umol, 1 eq) in a mixture of THF (1 mL) and MeOH (2 mL) was added aq. LiOH solution (1 M, 3 mL). The mixture was stirred at 40 0C for 24 h before the organic volatile was removed under reduced pressure. The residue was diluted with water (2 mL) and treated with 1N HCl to adjust the pH to 4. The mixture was extracted with EtOAc (3 x 10 mL), The combined c layer was washed with brine, dried (MgSO4), filtered and concentrated to provide the title compound (67 mg) as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.09 (bs, 1H), 7.86 (d, J=8 Hz, 1H), 733—7. 16 (m, 5H), 6.01 (d, J=7 Hz, 1H), 5.07 (d, J=8 Hz, 1H), 4.45 (d, J=7 Hz, 1H), 4.22 (bs, 1H), 4.11—3.94 (m, 2H), 3.55—3.31 (m, 2H), 2.95 (s, 1H), , LC/MS [M + H] = 461.0.

Example 7 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)-3 yl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)(pyridinylmethyl)malonic acid 0 Cl 0 O A020 OWOB Q) 0 TFA O 4—DMAP N / DCM 10% H20 pyridine EtO O —> EtO —2> ...o 052CO3 :10 El\O Q DMF. 20°C . 5 Acd IO O NH2 (LN, 0 CE N EtO </ [A aq.LiOH,THF f @om <N E10 0 N 0 o N Acn BSA TMSOTf \\ \ MeCN \ N / 5 .9 AcO OAC Example7 Step 1: To a e of diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxol—5-yl)methoxy)malonate (1.2 g, 2.90 mmol, 1 eq) in DMF (20 mL) at 20 °C was added CS2CO3 (6.60 g, 20.27 mmol, 7 eq) and oromethyl) pyridine hydrochlon'de (1.90 g, 11.58 mmol, 4 eq). The mixture was stirred for 2 h before it was filtered and the filter cake was washed with EtOAc (20 mL). The filtrate was diluted with water (60 mL) and extracted with EtOAc (3 x 50 mL). The combined extract was washed with water (2 x 50 mL), saturated aq. NH4Cl (50 mL), brine (50 mL), dried over anhydrous W0 20191246403 NazSO4, filtered and concentrated under reduced pressure. The residue was purified by column tography on SiO2 (14—33% EtOAc in petroleum ether) to give diethyl 2- (((3Q‘R, 5R, 6R, 6aR)—6-acetoxyethynyl—2,2-dimethyltetrahydrofuro[2,3 —d][1,3]—dioxol—5- yl)methoxy)—2-(pyridinylmethyl)malonate (900 mg, 61% yield) as a yellow oil.

Step 2: To a mixture of diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl)methoxy)(pyridinylmethyl)-malonate (900 mg, 1.78 mmol, 1 eq) in DCM (5 mL) and H20 (1 mL, 55.51 mmol, 31.18 eq) was added TFA (5 mL, 67.53 mmol, 37.93 eq). The mixture was stirred at 20 0C for 12 h before it was concentrated under reduced pressure. The crude residue was azeotroped with DCM (3 x 10 mL) under d pressure to provide crude diethyl 2-(((2R,3S,4R)ethynyl-3,4,5-trihydroxytetra- hydrofuranyl)methoxy)(pyridinylmethyl)malonate (1.1 g) as a brown oil.

Step 3: To a mixture of crude diethyl R,3S,4R)ethynyl-3,4,5-trihydroxy-tetrahydro- furan—2-yl)methoxy)—2-(pyridinylmethyl)malonate (1.1 g, 2.60 mmol, 1 eq) in pyridinie (8 mL) at 20 °C was added 4-DMAP (952.17 mg, 7.79 mmol, 3 eq) and A020 (2.43 mL, 25.98 mmol, 10 eq). The mixture was stirred for 12 h before it was partitioned between water (30 mL) and EtOAc (20 mL). The s phase was further ted with EtOAc (2 x 20 mL). The combined t was washed with water (20 mL), 0.5 N aq. HCl (2 x 10 mL), and brine (20 mL), dried over anhydrous Na2804, filtered and concentrated under reduced pressure. The e was purified by flash column tography on SiO2 (25— 50% EtOAc in petroleum ether) to give diethyl 2-(pyridinylmethyl)(((2R,3R,4R)—3,4,5- triacetoxyethynyl-tetrahydrofuranyl)methoxy)malonate (640 mg, 45% yield) as a brown syrup.

Step 4: To a mixture of diethyl 2-(pyridin—4-ylmethyl)-2—(((2R, 3R, 4R)—3,4,5-triacetoxy—3- ethynyltetrahydrofuranyl)methoxy)malonate (40 mg, 72.79 umol, 1 eq) and 2-chloro- adenine (13.58 mg, 80.07 umol, 1.1 eq) in MeCN (1.5 mL) was added BSA (44.98 uL, 181.98 umol, 2.5 eq) at 25 °C under N2 atmosphere. The mixture was stirred at 65 0C for 0.5 h before it was cooled to 0 OC and followed by dropwise addition of TMSOTf (26.31 uL, 145.58 umol, 2 eq). The mixture was stirred at 0 °C for 0.5 h and then at 65 °C for 2 h. The reaction mixture was cooled to room temperature and quenched with saturated aq.

NaHC03 (6 mL). The mixture was extracted with EtOAc (3 x 8 mL). The ed organic layer was washed with brine (5 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to provide diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy-S—(6-aminochloro-9H—purin-9—yl)-3 - ethynyltetrahydrofuran-Z-yl)methoxy)(pyridinylmethyl)-malonate (13 mg, 26% yield) was obtained as a yellow gum.

Step 5: To a mixture of diethyl R, 3R, 4R, 4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(pyridinylmethyl)—malonate (50 mg, 75.87 umol, 1 eq) in THF (1 mL) was added 1N aq. LiOH (1 mL). The mixture was stirred at 50 0C for 1 h before it was cooled to room temperature and adjusted the pH 6—7 with 2N aq. HCl solution. The mixture was concentrated under reduced pressure and the residue was purified by ative reverse—phase HPLC to provide the title nd (34 mg) as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.50 (bs, 1H), 8.32 (d, J=4 Hz, 2H), 7.50 (d, J=5 Hz, 2H), 6.01 (d, J=7 Hz, 1H), 4.80 (d, J=6 Hz, 1H), 4.38 (q, J=3 Hz, 1H), 4.10—3.95 (m, 2H), 3.45 (bs, 2H), 3.06 (s, 1H), LC/MS [M + H] = 519.0.

Example 8 Synthesis of 2-(((2R, SS, 4R, 5R)(6—amino—2-chloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran—2-yl)methoxy)—2-(furanylmethyl)malonic acid 510%?0Q O o OEt Q/OH—’PPh3 CBr4 0 TFA H20 \\ EC 0 B o ’ 0“ 052003 DMF / \ —AcO 0 Ho: OH 0 gig”: o NH2 0 NH2 0 DE! <’ 0 OEt ,N 0 OH km N \N \N A020.4—DMAP < l X LIOH I X EtO o H—C> / _ o BO 0 N o N/ HO 0 N OAc Cl 0 N ' - 0| ”mime / \ BSA, TMSOTf / H20,THF \ / \ _ MeCN : = ,5 O : a, O ‘1 ,, AcO OAc Aco‘ OAc Ho‘ ’OH Example8 -lOO- Step 1: To a mixture of PPh3 (4.28 g, 16.31 mmol, 1.6 eq) and CBr4 (4.06 g, 12.23 mmol, 1.2 eq) in DCM (20 mL) at 0 °C under N2 atmosphere was added furanylmethanol (1 g, 10.19 mmol, 1 eq) in DCM (5 mL) dropwise. The mixture was stirred at 20 0C for 2 h before it was quenched with saturated aq. NaHCO3 (30 mL) and then extracted with EtOAc (2 x 15 mL).

The combined c layer was washed with brine (30 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to provide crude 3-(bromomethyl)furan (2.9 g) as yellow gum which was used in the next step directly t further purification.

Step 2: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][l,3]dioxolyl)methoxy)malonate (l g, 2.41 mmol, 1 eq) in DMF (5 mL) at 20 °C was added CszCO3 (2.36 g, 7.24 mmol, 3 eq) and crude 3-(bromomethyl)furan (2.9 g) in DMF (6 mL). The mixture was stirred for 2 h before it was partitioned between water (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (3 x 15mL).

The combined organic extract was washed with water (20 mL), saturated aq. NH4Cl (2 x 20 mL), brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under d pressure. The residue was purified by column chromatography on Si02(10—25% EtOAc in petroleum ether) to give diethyl 2-(((3aR, 5R, 6R, -acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][l,3]dioxolyl)methoxy)(furanylmethyl)malonate (375 mg, 31% yield) as a light yellow oil, Step 3: To a mixture of diethyl aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetra- uro[2,3-d][1,3]dioxolyl)methoxy)(furanylmethyl)-malonate (375 mg, 758.36 umol, 1 eq) in DCM (2 mL) and H20 (0.4 mL, 2220 mmol, 29 eq) was added TFA (2 mL, 27.01 mmol, 36 eq). The mixture was stirred at 20 0C for 12 h before it was concentrated under reduced pressure to provide crude diethyl 2-(((2R,SS, 4R)ethynyl-3,4,5-trihydroxy- ydrofuranyl)methoxy)(furanylmethyl)malonate (420 mg) as an oil which was used in next step without further purification.

Step 4: To a mixture of crude diethyl 2-(((2R, 3S, 4R)ethynyl-3,4,5-trihydroxytetrahydro— furan—2-yl)methoxy)—2-(furan—3-ylmethyl)malonate (420 mg, 1.02 mmol, 1 eq) in pyridine (4 mL) at 20 °C was added AczO (954 uL, 10.18 mmol, 10 eq) and 4-DMAP (373 mg, 3.06 WO 46403 mmol, 3 eq). The mixture was stirred for 12 h before it was partitioned between water (15 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (2 X 20 mL). The combined organic extract was washed with water (10 mL), 0.5N aq. HCl (2 x 5 mL), brine (10 mL), dried over anhydrous NazSO4, filtered and concentrated, The e was purified by preparative TLC (petroleum ether : EtOAc =3: 1) to give diethyl 2-(furan-3 -ylmethyl) (((2R, 3R, 4R)—3,4,5-triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (95 mg, 17% yield) as a yellow oil.

Step 5: To a mixture of diethyl 2-(furanylmethyl)(((2R, 3R, 4R)—3,4,5-triacetoxy ethynyltetrahydrofuranyl)methoxy)rnalonate (50 mg, 92.85 umol, 1 eq) and 2-chloro- addenine (17.32 mg, 102.14 umol, 1.1 eq) in MeCN (1.2 mL) was added BSA (57.38 uL, 232.13 umol, 2.5 eq) at 25 CC under N2 atmosphere. The mixture was stirred at 65 CC for 0.5 h before it was cooled to 0 °C and followed by dropwise addition of TMSOTf (33.56 uL, 185.70 umol, 2 eq). The mixture was d at 0 °C for 0.5 h and then at 65 0C for 2 h before it was cooled to room temperature and quenched with saturated aq. NaHCO3 solution (2 mL).

The mixture was extracted with EtOAc (3 x 2 mL). The combined organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, filtered and concentrated under d re. The residue was purified by preparative TLC (petroleum ether : EtOAc = 1:1) to provide diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy—5-(6-aminochloro-9H—purin—9-yl)—3— ltetrahydrofuranyl)methoxy)(furanylmethyl)malonate (17 mg, 29% yield) as a yellow gum.

Step 6: To a mixture of diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3 -ethynyltetrahydrofuranyl)methoxy)(furan-3 -ylmethyl)-malonate (3 3 mg, 50.92 umol, 1 eq) in THF (1 mL) was added 1N aq. LiOH (1 mL). The mixture was stirred at °C for 3 h before it was extracted with EtOAc (2 mL). The organic layer was ded.

The aqueous phase was adjusted the pH 2—3 with 2N aq, HCl before it was extracted with EtOAc (4 x 5 mL). The combined organic extract was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The e was dissolved in a mixture of MeCN (1 mL) and H20 (1 mL) and then dried by lyophilization to provide the title compound (10.0 mg, 37% yield) as a white solid. -lO2- 1H NMR (400 MHz, DMSO—dd) 6 ppm 8.48 (s, 1H) 7.81 (br s, 2H) 7.35 (s, 2H) 6.29 (s, 1H) 6.22 (br s, 1H) 6.02 (br d, J=6.50 Hz, 1H) 5.83 (d, J=7.50 Hz, 1H) 4.75 — 4.90 (m, 1H) 4.16 (dd, J=4.75, 2.75 Hz, 1H) 3.92 (br dd, J=10.07, 5.07 Hz, 1H) 3.77 (br d, J=8.00 Hz, 1H) 3.48 (s, 1H) 3.08 (s, 2H); LC/MS [M + H] = 507.9.

Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro—9H—purinyl)—3-ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)(4—(2-oxotetrahydropyrimidin- 1 (2H)- yl)benzyl)malonic acid NHBoc NHBoc o 2 0 o oWOE 0 GE 0 GE N <N<Nf\N OZrN/Qj </N IN:J\Cl_>Fe,NH4C| </ l 1 N/cCI E10 0 N EtO O N / CIMN‘C9O E10 0 o o o N CI K24303 DMF EtOH, H20 DCM Acd bAc ACG bAC OZN HzN o NHBoc o NHBoc o NH2 OEt <N OH 0 OH ’ 1 N10 <N’ 1 N10 (N/ \N o NaH THF N 0 TFA DCM HO 0 N o NAG “Ow )LN Ho‘ )LN Ho‘ ’OH HNQ HN\J Examples Step 1: To a solution of l 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-N,N’ -(bis-(ter2‘- butoxycarbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuran—2-y1)methoxy- )malonate (7.26 g, 4.92 mmol, 1 eq) in DMF (80 mL) at 25°C was added K2CO3 (13.60 g, 98.40 mmol, 20 eq). The reaction mixture was stirred for 0.5 h and followed by addition of 1-(bromomethyl)nitro-benzene (15.94 g, 73.80 mmol, 15 eq). The reaction e was stirred for 24 h before it was diluted with H20 (3 00 mL) and extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with brine (100 mL), dried over Na2S04, filtered and concentrated. The crude residue was purified by flash silica gel column chromatography (petroleum ether : EtOAc = 10: 1—2: 1) to provide diethyl R, 3R, 4R, 5R)- 3,4-diacetoxy(6-((z‘erl—butoxycarbonyl)amino)chloro-9H-purinyl)—3-ethynyltetra— hydrofuranyl)methoxy)(4-nitrobenzyl)malonate (2.36 g) was obtained as a brown gum.

Step 2: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-((tert—butoxycarbonyl)- amino)—2-chloro-9H-purinyl)—3-ethynyltetra-hydrofuran—2-yl)methoxy)—2-(4-nitrobenzyl)- W0 20191246403 malonate (2.26 g, 2.81 mmol, 1 eq) in EtOH (23 mL) at 0 °C was added Fe (786 mg, 14.07 mmol, 5 eq) and NH4C1 (151 mg, 2.81 mmol, 1 eq) in H20 (8.5 mL). The reaction mixture was stirred at 50 °C for 4 h before it was filtered and the filtrate was concentrated. The crude residue was purified by flash silica gel column chromatography (petroleum ether : EtOAc = 1:0 — 1:1) to provide diethyl 2-(4-aminobenzyl)-2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-((tert— butoxycarbonyl)-amino)chloro-9H-purin—9-yl)-3—ethynyltetra-hydrofuranyl)methoxy)- malonate (280 mg) as a yellow foam.

Step 3: To a solution of diethyl 2-(4-aminobenzyl)—2-(((2R, 3R, 4R,5R)—3,4-diacetoxy(6— ((tert—butoxycarbonyl)amino)chloro-9H-purinyl)—3-ethynyltetrahydrofuran—2-yl)- methoxy)malonate (280 mg, 362.14 umol, 1 eq) in DCM (3 mL) at 0 0C was added 1-chloro- 3-isocyanatopropane (86.59 mg, 724.28 umol, 2 eq). The reaction mixture was stirred at °C for 16 h before it was trated. The crude residue was purified by preparative TLC (petroleum ether : EtOAc = 1:0—1 : 1) to provide diethyl 2-(4-(3 -(3-chloropropy1)ureido)- )—2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy—5-(6-((tert-butoxycarbonyl)amino)-2—chloro—9H— purinyl)—3-ethynyltetrahydrofurany1)methoxy)ma1onate (120 mg, 33% yield) as a foam.

Step 4: To a on of diethyl 2-(4—(3 -(3 -ch1oropropyl)ureido)benzyl)—2-(((2R, 3R, 4R, 5R)— acetoxy(6—((lerl—butoxycarbonyl)amino)ch1oro-9H—purinyl)—3-ethynyltetra— uran-2—yl)methoxy)malonate (120 mg, 134.42 umol, 1 eq) in THF (1.2 mL) at 0 °C was added NaH (11 mg, 268.84 umol, 60% in mineral oil, 2 eq). The reaction mixture was stirred at 25 °C for 2 h before it was quenched with H20 (0.2 mL) at 0 °C. The reaction mixture was then stirred at 25 0C for 16 h. The reaction mixture was ed to pH 3—4 with 1N aq. HCl solution and then extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2S04, filtered and concentrated to provide crude 2-(((2R, 3S, 4R, 5R)(6-((tert—butoxycarbonyl)amino) chloro-9H-purinyl)ethyny1-3,4—dihydroxytetrahydrofuran-Z-yl)methoxy)(4-(2-oxo— tetrahydropyrimidin-1(2hO-yl)benzyl)malonic acid (77 mg, 73% yield) as a white solid.

Step 5: To a solution of crude 2-(((2R, 3S, 4R, 5R)(6-((lert—butoxycarbonyl)amino)chloro- 9H—pu1in-9—yl)ethyny1—3,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetra— hydropyrimidin-1(2110-y1)benzyl)malonic acid (76 mg, 106.13 umol, 1 eq) in DCM (0.5 mL) —104— W0 20191246403 ) at 0 °C was added TFA (0.25 mL, 338 mmol, 32 eq). The reaction mixture was stirred at °C for 2 h before it was concentrated. The residue was re-dissolved with saturated aq.

NaHCO3 solution (5 mL) and extracted EtOAc (3 x 5 mL). The combined c layer was washed with brine (15 mL), dried over anhydrous NazSO4, filtered and concentrated.

The crude residue was purified by ative reversed-phase HPLC to provide the title compound (8.6 mg, 12% yield) as a white solid. 1H NMR (CD3OD, 300 MHz) 6 8,28 (s, 1H), 7.11 (d, J=8.52 Hz, 2H), 7.02 (d, J=8.52 Hz, 2H), 5.99 (d, J=7.44 Hz, 1H), 4.79 (d, J=7.41 Hz, 1H), 4.29 (t, J=2.76 Hz, 1H), 4.01—3.91 (m, 2H), 3.54—3.41 (m, 4H), .32 (m, 2H), 3.05 (s, 1H), 2,03—1.94 (m, 2H); LC/MS [M + H] = 616.2.

Example 10 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofurany1)methoxy)(4—(2-oxopiperidin— 1 -yl)benzyl)malonic acid NHBoc O o o NHBoc O NHB°° o 0E1 0 OH 0 CB N \N / \N @ </N I <N INA NaH THF 0' v E10 0 N NAG —> HO o «Mfr:N o o NAG ‘0 O 0 0| TEA, DCM, 25°C o 0 _ : ., .- a _ X 7 a, Acd bAc H6 ”OH N N AcO OAc H2N H Step 1: To a solution of crude diethyl 2-(4-aminobenzyl)-2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy—5- (6-((terZ-butoxycarbonyl)amino)-2—chloro-9H—purinyl)ethynyltetrahydrofuranyl)- methoxy)malonate (140 mg, 160 umol, 1 eq) in DCM (2 mL) at 25°C was added TEA (107 mg, 1.06 mmol, 147 uL, 6.59 eq) and followed by 5-chloropentanoyl chloride (24.9 uL, 192 umol, 1.2 eq). The mixture was stirred for 1 h before it was partitioned between DCM (20 mL) and H20 (20 mL). The organic phase was washed with H20 (10 mL), dried over NazSO4, filtered and concentrated under reduced pressure. The residue was d by ative TLC (petroleum ether : EtOAc = 1:1) to give l 2—(4-(5-chloropentanamido)— benzyl)(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-((lert—butoxycarbonyl)amino)chloro-9H— purin—9-yl)-3—ethynyltetrahydrofuran—2-yl)methoxy)malonate (130 mg, 69% yield) as a yellow gum.

Step 2: To a solution of diethyl 2-(4-(5-chloropentanamido)-benzy1)—2-(((2R, 3R, 4R, 5R)-3,4- diacetoxy(6-((tert—butoxycarbonyl)amino)chloro-9H—purin—9-yl)—3—ethynyltetrahydrofuranyl )methoxy)malonate (104 mg, 105 umol, 1 eq) in THF (2 mL) at 25 °C was added NaH (25.2 mg, 630 umol, 60% in mineral oil, 6 eq). The mixture was d for 4 h before it was quenched with H20 (1 mL), The reaction mixture was stirred at 20 °C for 14 before it was partitioned between EtOAc (10 mL) and water (20 mL). The aqueous phase was acidified to pH 5—6 with 2N aq. HCl solution before it was partitioned between EtOAc (20 mL) and brine (10 mL), dried over anhydrous NazSO4, d and concentrated under reduced pressure to give crude 2-(((2R,3S,4R,5R)(6-((tert—butoxycarbonyl)amino) -9H—purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2- oxopiperidin-l-yl)benzyl)malonic acid (58 mg) as a ess gum.

Step 3: To a mixture of crude 2-(((2R, 3S, 4R, 5R)-5—(6-((lert—butoxycarbonyl)amino)chloro- 9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxopiperidin- 1-yl)benzyl)malonic acid (58 mg, , 1 eq) in DCM (500 uL) was added TFA (400 uL, .40 mmol, 67 eq). The mixture was stirred at 20 CC for 2 h before it was quenched with 2N aq. LiOH (500 uL). The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was adjusted to pH 5—6 with 2M aq. HCl solution. The aqueous phase was partitioned between EtOAc (2 x 20 mL) and brine (5 mL), dried over anhydrous NazSO4, d and concentrated under reduced pressure. The crude product was purified by preparative HPLC and lyophilized to give the title compound (6.9 mg, 14% yield) as a white solid. 1H NMR (400 MHz, DMSO-dé) 5 ppm 8.32 (s, 1H) 7.33 (d, J=8.53 Hz, 2H) 6.98 (d, J=8.28 Hz, 2H) 5.98 (d, J=7.53 Hz, 1H) 4.79 (m, 1H) 4.28 (t, J=2.76 Hz, 1H) 4.04 (br s, 2H) 3.39 - 3.54 (m, 4H) 3.05 (s, 1H) 2.43 (m, 2H) 1.88 (br t, J=2.89 Hz, 4H); LC/MS [M + H] = 615.3.

Example 11 Synthesis of R, 3S, 4R, 5R)(6-aminochloro-9H-purinyl)ethynyl-3,4- oxytetrahydrofuranyl)methoxy)(4-(1 —(methoxymethy1)oxo— 1 ,2- dihydropyridinyl)benzyl)malonic acid 0 N030C)2 O O :dB’OfiOH arkINAm Br Boy? 0 Br MOMVCI,K2003 Br 0 —, —> C—>Br4Pphs HN \ acetone \0/\N \ Pd(dppf)C|2, K2003 DCM ’0 \ \ \ dioxane, H20 \0 \ K2003 DMF N OEt N OH N \ \ </ l N l </ I N 0 N o NAG 0 TFA,DCM O</N NJ\CI O N aq.LiOH o NACI _ . _ _ _ .

“ ’OAc Aco¢ ’OAc HO\‘ ”OH \o/‘N \OPN Example 11 Step 1: To a solution of 3-bromopyridin-2(1110-one (2.25 g, 12.93 mmol, 1 eq) in acetone (40 mL) at 25 0C was added K2CO3 (4.47 g, 32.33 mmol, 2.5 eq). The suspension was stirred for 0.5 h and followed by addition of MOM-Cl (2.79 mL, 36.76 mmol, 2.84 eq) dropwise. The mixture was stirred at 25 °C for 15 h before it was diluted with water (40 mL) and extracted with ethyl acetate (2 X 30 mL). The combined organic layer was washed with brine (50 mL), dried by Na2SO4, filtered and trated. The crude residue was purified by flash on silica gel (20—60% ethyl acetate in petroleum ether) to e 3-bromo(methoxy- methyl)-pyridin-2(1}D-one (1.22 g, 43% yield) as a clear oil.

Step 2: To a solution of 3-bromo(methoxymethyl)pyridin-2(11-D—one (1.38 g, 6.33 mmol, 1 eq) and (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)phenyl)methanol (1.06 g, 6.96 mmol, 1.1 eq) in dioxane (12 mL) was added K2CO3 (2.62 g, 18.99 mmol, 3 eq), Pd(dppf)Cl2 (463 mg, 632.89 umol, 0.1 eq) and H20 (4 mL). The mixture was de-gassed with N2 for 10 min before it was then heated at 80 °C for 16 h under N2 atmosphere. The reaction was d with water (10 mL) and extracted with ethyl acetate (3 x 10 mL). The ed organic layer was washed with brine (25 mL), dried by Na2SO4, filtered and concentrated. The crude residue was purified by Combi-flash on silica gel (SO—100% ethyl acetate in petroleum ether) to provide 3—(4-(hydroxymethyl)phenyl)—1—(methoxymethyl)py1idin—2(MED—one (1.30 g, 84% yield) as a yellow gum.

Step 3: To a solution ofPPh3 (8.34 g, 31.80 mmol, 6 eq) in DCM (50 mL) at —25 °C was added CBr4 (10.55 g, 31.80 mmol, 6 eq) . The yellow suspension was stirred at —25 °C for 1 h and followed by addition of a solution of 3-(4-(hydroxymethyl)phenyl)—1- (methoxymethyl)-pyridin-2(MED-one (1.30 g, 5.30 mmol, 1 eq) in DCM (10 mL) dropwise.

The yellow suspension was stirred at —25 °C for 0.5 h before it was diluted with MTBE (180 mL). The precipitate was filtered off and the e was concentrated to give crude (2.8 g) as a yellow gum. The crude residue was purified by Combi-flash on silica gel (30—100% ethyl acetate in petroleum ether) to provide 3-(4-(bromomethyl)phenyl)—1-(methoxymethyl)- pyridin-2(1H)—one (760 mg, 46% yield) as a white solid.

Step 4: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-N,N’ -(bis-(ter2‘- butoxycarbonyl)amino)—2-chloro-9H—pu1inyl)ethynyltetrahydrofuran—2-yl)-methoxy)— malonate (100 mg, 130.18 umol, 1 eq) in DMF (1.5 mL) at 20 °C was added K2CO3 (53.97 mg, 390.54 umol, 3 eq). The suspension was stirred for 0.5 h and followed by addition of 3- (4-(bromomethyl)phenyl)(methoxymethyl)pyridin-2(1H)-one (44.13 mg, 143.20 umol, 1.1 eq). The sion was stirred at 20 °C for 16 h before it was diluted with water (2 mL) and extracted with ethyl acetate (3 X 2 mL). The combined organic layer was dried by Na2S04, filtered and concentrated. The crude residue was d by preparative TLC (petroleum ether : ethyl acetate = 1:1) to e diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-(N,N’ — bis-(terZ-butoxy-carbonyl)amino)chloro—9H—purinyl)—3-ethynyltetrahydro-furan yl)methoxy)—2—(4-(1—(methoxymethyl)—2-oxo—1,2-dihydropyridin-3—yl)benzyl)-malonate (71 mg, 55% yield) as a clear syrup.

Step 5: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-(N,N’ -bis-(terZ-butoxy- yl)amino)—2—chloro—9H-purinyl)ethynyltetrahydrofuranyl)—methoxy)—2-(4—( l - (methoxymethyl)-2—oxo-1,2—dihydropyridin—3-yl)benzyl)-malonate (68 mg, 68.31 umol, 1 eq) in DCM (1.7 mL) at 0 CC was added TFA (0.3 mL, 4.05 mmol, 59 eq). The mixture was stirred at 20 0C for 2 h before it was quenched with ted aq. NaHCO3 on to adjust the pH to 9. The mixture was extracted with ethyl acetate (3 x 8 mL). The combined organic layer was concentrated to give crude (98 mg) as a yellow gum. The crude residue was purified by preparative TLC (ethyl acetate) to provide l 2-(((2R, 3R, 4R, 4- diacetoxy—5—(6-aminochloro-9H-purin—9-yl)ethynyltetrahydrofuranyl)-methoxy) (4-(1-(methoxymethyl)—2-oxo-1,2-dihydropyridin-3 -yl)benzyl)-malonate (21 mg, 38% yield) as a colorless syrup.

Step 6: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-aminochloro-9H— purin—9-yl)—3 —ethynyltetrahydrofuran—2-yl)methoxy)—2-(4-( l —(methoxy-methyl)-2—oxo- 1 ,2— dihydropyridinyl)benzyl)malonate (20 mg, 25.15 umol, 1 eq) in THF (1 mL) was added 1M aq. LiOH (503 uL, 20 eq). The mixture was stirred at 18 °C for 22 h before it was acidified to pH 2 with 1N aq. HCl and concentrated. The crude residue was d by preparative HPLC and the fraction was dried by lyophilization to provide the title compound (2.1 mg, 13% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.45 (br s, 1H), 7.81 (br s, 2H), 7.67 (dd, J=6.75, 1.75 Hz, 1H), 7.51 (br d, J=6.75 Hz, 1H), 7.36 (br d, J=6.88 Hz, 2H), 7.20 (br d, J=7.50 Hz, 2H), 6.33 (t, J=6.75 Hz, 1H), 6.20 (br s, 1H), 6.01 (br d, J=6.88 Hz, 1H), 5.82 (d, J=7.50 Hz, 1H), .28 (s, 2H), 4.65—4.89 (m, 1H), 4.06—4.23 (m, 1H) .06 (m, 1H), 3.67—3.86 (m, 1H), 3.40—3.52 (m, 3H), 3.18—3.30 (m, 2H), LC/MS [M + H] = 655.1.

Example 12 Synthesis of 2—(((2R, 3S, 4R, 5R)—5-(6-amino-2—chloro—9H—purin—9-yl)—3—ethynyl—3,4- dihydroxytetrahydrofuranyl)methoxy)—2-(4-(2-oxo-1,2-dihydropyridin-3 - yl)benzyl)malonic acid o N(Boc)2 O 2 N(Boc)2 OQOB NfN Br (NfN BOH( )2 <:> o 0151 HN </ I l l I E10 0 N E10 0 N o N¢kc1 o Nékm K2003, DMF Pd(dppf)C|2, K2C03 , . dioxane,H20 o N(Boc)2 <’Mfgl N TFA, DOM O : o ,N NAG aq.LiOH,THF —> —> And bAc Exam ple 12 Step 1: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ —(bis-(terl—butoxy- carbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuranyl)-methoxy)-malonate (12.59 g, 16.39 mmol, 1 eq) and 1-(bromomethyl)iodo-benzene (48.67 g, 163.90 mmol, 10 eq) in DMF (120 mL) at 20 °C was added K2CO3 (33.98 g, 245.85 mmol, 15 eq). The solution was stirred for 16 h before it was diluted with water (200 mL) and extracted with ethyl acetate (3 X 200 mL). The ed organic layer was washed with water (400 mL), brine (400 mL), dried by Na2SO4, filtered and concentrated. The crude residue was purified by Combi-flash on silica gel % ethyl acetate in petroleum ether) to give diethyl 2- (((2R, 3R, 4R, 5R)—3 ,4-diacetoxy-5 -(6-N,N’ -(bi t-butoxycarbonyl)-amino)chloro-9H- purinyl)—3-ethynyltetra-hydrofurany1)methoxy)(4-iodobenzyl)—malonate (2.94 g, 18% yield) as a yellow solid.

Step 2: To a solution of diethyl R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ (terZ-butoxy- carbonyl)amino)—2-chloro-9H-purinyl)ethynyltetrahydrofuranyl)—methoxy)(4— iodobenzyl)malonate (1.10 g, 1.12 mmol, 1 eq) and (2-oxo—1,2-dihydropyridinyl)boronic acid (310.53 mg, 2.24 mmol, 2 eq) in dioxane (12 mL) was added K2CO3 (463.41 mg, 3.35 mmol, 3 eq), Pd(dppf)Cl2 (81.78 mg, 111.77 umol, 0.1 eq) and H20 (4 mL). The mixture was degassed with N2 for 10 min and then stirred at 80 0C for 1 h under N2 atmosphere. The dark mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 10 mL).

The combined organic layer was washed with brine (30 mL), dried by Na2804, filtered and concentrated. The crude residue was purified by Combi-flash on silica gel (40—100%ethyl acetate in petroleum ether) to give diethyl 2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy—5-(6-N,N’ -(bis— (Zert-butoxy-carbonyl)amino)chloro-9H-purinyl)—3-ethynyltetrahydrofuranyl)- methoxy)-2—(4—(2-oxo—1,2-dihydropyridin-3—yl)benzyl)malonate (220 mg, 21% yield) as a yellow gum.

Step 3: To a solution of diethyl R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ -(bis-(terZ-butoxy- carbonyl)amino)—2—chloro—9H-purinyl)—3-ethynyltetrahydrofuranyl)—methoxy)—2-(4—(2- oxo—1,2-dihydropyridinyl)benzyl)malonate (180 mg, 189.20 umol, 1 eq) in DCM (2.4 mL) was added TFA (0.6 mL, 8.10 mmol, 43 eq). The yellow solution was stirred at 20 0C for 2.5 h before it was quenched with saturated aq. NaHCO3 (5 mL) and extracted with ethyl acetate (3 x 4 mL). The combined c layer was concentrated to give crude (108 mg) as a yellow gum. The crude residue was purified by preparative TLC (ethyl acetate) to give diethyl 2-(((2R, 3R, 4R, 5R)—3 ,4-diacetoxy(6-aminochloro-9H-purinyl)-3 yltetra- hydrofuranyl)methoxy)—2-(4-(2—oxo-1,2—dihydropyridin-3 -yl)benzyl)—malonate (23 mg, 16% yield) as a yellow solid.

Step 4: To a solution of diethyl R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(4-(2-oxo-1,2-dihydropyridin yl)benzyl)malonate (23 mg, 30.62 umol, 1 eq) in THF (2.5 mL) was added 1M aq. LiOH (0.6 mL, 20 eq). The reaction mixture was stirred at 20 °C for 4 h before it was acidified to pH 6 with 1N aq. HCl and trated to give crude (32 mg) as a yellow gum. The crude residue was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um, Mobile phase: [water (O.225%FA)—CAN]; B%: 15%-3 5%, 10min). The product was dried by lyophilization to give the title compound (21 mg, 11% yield) as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.24 (s, 1H), 7.46 (dd, J=6.88, 1.63 Hz, 1H), 7.28—7.34 (m, 5H), 6.39 (t, J=6.75 Hz, 1H), 5.96 (d, J=7.38 Hz, 1H), 4.77—4.84 (m, 1H), 4.29 (t, J=2.88 Hz, 1H), 4.03 (d, J=2.75 Hz, 2H), 3.38—3.51 (m, 2H), 3.04 (s, 1H); LC/MS [M + H] = 611.0.

Example 13 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro-9H—purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-((2-carboxy-[ 1 , 1'-biphenyl]yl)methyl)malonic N(Boc)2 1 NAG TFA, DCM Example 13 Step 1: To a mixture of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ —(bis-(ierl— butoxycarbonyl)amino)chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)- malonate (99.87 mg, 130.01 umol, 1 eq) in DMF (0.5 mL) was added K2CO3 (53.90 mg, 390.03 umol, 3 eq). The mixture was stirred at 40 °C for 0.5 h and followed by on of methyl 4-(bromomethyl)—[1,l'-biphenyl]carboxylate (79.35 mg, 260.02 umol, 2 eq) which was prepared according to the reported procedure by D. Stoermer et al (J. ofMed. Chem. 2012, 55, 5922-5932). The mixture was stirred at 40 0C for 15.5 h before it was diluted with water (4 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was washed with water (2 x 5 mL) and brine (5mL), dried over anhydrous NazSO4, d and concentrated. The crude residue was d by preparative TLC (petroleum ether : EtOAc = 1:1) to give diethyl 2-(((2R, 3R, 4R, 4-diacetoxy(6-N,N’ -(bis-(ZerZ-butoxycarbonyl)- amino)—2-chloro-9H—purinyl)-3 —ethynyltetrahydrofuranyl)methoxy)((2-(methoxy- carbonyl)-[1,1'-biphenyl]yl)methyl)malonate (70 mg, 53% yield) as a colorless syrup.

Step 2: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-N,N’ -(bis-(2‘erl- butoxycarbonyl)amino)chloro-9H-purin—9-yl)ethynyltetrahydrofuranyl)methoxy) ((2—(methoxycarbonyl)—[1,1'-biphenyl]—4—yl)methyl)malonate (70 mg, 7053 umol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL, 6.75 mmol, 96 eq). The mixture was stirred at 20 °C for 2 h before it was quenched with saturated aq. NaHCO3 to pH 7—8 and extracted with EtOAc (3 x 10 mL). The combined organic layer was washed with water (2 x 8 mL) and brine (8 mL), dried over anhydrous NazSO4, filtered and trated. The crude residue was purified by preparative TLC (petroleum ether : EtOAc = 1:1) to give diethyl 2— (((2R, 3R, 4R, 5R)-3 ,4-diacetoxy-5 -(6-amino—2-chloro-9H—purinyl)-3 -ethynyltetrahydro- furanyl)-methoxy)((2-(methoxycarbonyl)-[1,l'-biphenyl]yl)methyl)malonate (40 mg, 71% yield) as a colorless syrup.

Step 3: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3 -ethynyltetrahydrofuranyl)methoxy)((2-(methoxy-carbonyl)-[1, 1 '- yl]-4—yl)methyl)malonate (30 mg, 3787 umol, 1 eq) in THF (1 mL) was added 1M aq.

LiOH (568 uL, 15 eq). The mixture was stirred at 25 0C for 20 h before it was diluted with water (1 mL) and extracted with EtOAc (3 x 2 mL). The organic layer was discarded. The pH of the water phase was adjusted to 2 with 2N aq. HCl to produce a precipitate. The -ll2- precipitate was collected by filtration to give desired product (28 mg) as the first crop. The aq. phase was further extracted with EtOAc (4 X 2 mL). The combined organic layer was dried over anhydrous NazSO4, filtered and concentrated to provide the second crop (10 mg) as a white solid. These two crops were ed and d by preparative HPLC and the fraction was lyophilized to give the title compound (8.0 mg, 33% yield) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.21 (s, 1H), 7.66 (s, 1H), 7.46 (br d, J=7.6 Hz, 1H), 7.24—7.32 (m, 3H), 7.12 (dd, J=7. 1, 2.3 Hz, 2H), 7.07 (d, J=7.9 Hz, 1H), 5.99 (d, J=7.4 Hz, 1H), 4.84 (br s, 1H), 4.33 (br s, 1H), .16 (m, 2H), 3.43—3.60 (m, 2H), 3.03 (s, 1H); LC/MS [M + H] = 638.2.

Example 14 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chlorophenyl-9H-purin—9-yl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)malonic acid O‘B(OH)2 0 Cl 0 OH 1>d(0Ac)2 052003 / £11 P(05H4SO3Na)3 (N I A (N m—>MeCN::H20(21) HO 0 ONNC| H6 ”OH Example 14 Step 1: To a on of 2,6—dichloroadenine (0.8 g, 4.23 mmol, 1 eq) in H20 (10 mL) and MeCN (5 mL) was added phenylboronic acid (464.49 mg, 3.81 mmol, 0.9 eq), CS2CO3 (3.45 g, 10.58 mmol, 2.5 eq), Pd(OAc)2 (47.51 mg, 211.64 umol, 0.05 eq) and trisodium;3-bis(3— sulfonatophenyl)phosphanylbenzenesulfonate (601.50 mg, 1.06 mmol, 0.25 eq) at 20 0C under N2 atmosphere. The mixture was stirred at 110 °C for 2 h before it was allowed to cool and diluted with H20 (50 mL). The on mixture was extracted with EtOAc (5 x 50 mL).

The combined organic layer was washed with brine (50 mL), dried over NazSO4, filtered and concentrated. The crude product was triturated with a mixture of petroleum ether (9 mL) and EtOAc (3 mL) to provide 2-chloro—6-phenyl-9H—purine (140 mg, 14% yield) as a yellow solid.

Step 2: To a solution of 2-chlorophenyl—9H-purine (321.05 mg, 585.30 umol, 1 eq) in MeCN (0.5 mL) was added diethyl 2-benzyl(((2R, 3R, 4R)-3,4,5—triacetoxyethynyltetra- -ll3- W0 20191246403 hydrofuran-2—yl)methoxy)malonate (135 mg, 585.30 umol, 1 eq) and BSA (347 uL, 1.40 mmol, 2.4 eq) at 15°C. The mixture was stirred at 65°C for 30 min as it became clear. The mixture was cooled to 0 °C and followed by dropwise addition of TMSOTf (126.91 uL, 702.35 umol, 1.2 eq) . The e was stirred for 0 °C 10 min and then at 65 °C for 3 h before it was cooled and quenched with saturated aq. NaHCO3 (40 mL). The reaction mixture was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (40 mL) and dried over Na2SO4, filtered and concentrated. The crude t was purified by flash silica gel column chromatography (petroleum : EtOAc = 1:0 — 1:1) first and then by preparative TLC (petroleum : EtOAc = 1:1) to provide diethyl 2-benzyl (((2R,3R,4R,5R)—3,4-diacetoxy(2-chloropheny1-9H-purinyl) ethynyltetrahydrofuranyl)methoxy)malonate (135 mg) as a yellow gum.

Step 3: To a solution of diethyl 2-benzyl(((2R, 3R, 4R, 5R)—3,4-diacetoxy—5-(2-chloro phenyl-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (135 mg, 187.73 umol, 1 eq) in THF (2 mL) was added LiOH'H2O (78.77 mg, 1.88 mmol, 10 eq) in H2O (0.2 mL) at 20 °C. The mixture was stirred at 45°C for 2 h before it was diluted with H20 (10 mL) and with EtOAc (2 mL). The organic layer was ded and the aqueous phase was acidified with 2N aq. HCl to pH 2—3. Then the aqueous phase was extracted with EtOAc (3 x mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered and concentrated. The crude product was purified by ative HPLC to provide the title compound (27.6 mg, 24% yield) as a white solid. 1H NMR (400 MHz, e) 5 ppm 9.23 (s, 1H), 8.75 - 8.81 (m, 2H), 7.61 — 7.68 (m, 3H), 7.07 — 7.22 (m, 5H), 6.03 (d, J=6.53 Hz, 1H), 4.62 (d, J=6.53 Hz, 1H), 4.20 (dd, J=6.90, 2.64 Hz, 1H), 3.72 (br dd, J=9.91, 7.15 Hz, 2H), 3.55 (s, 1H), 3.03 (br d, J=1.51 Hz, 2H); LC/MS [M +H] = 579.1.

Example 15 Synthesis of 2-allyl(((2R, 3S, 4R, 5R)—5—(6-aminochloro-9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)malonic acid —114— 0 allyl bromide O 0 ACZO 0 CE! 052co3 O TFA O 4DMAP DMF 20°C DCM 10% H20 pyridine E10 0Q10 —> EtO —>EtO O A) A) of , AcO AcO\ 0 (IHNfN:N O NH2 0 CB *C' 0 0H 0 QB N N (x l aq.LiOH </ i 1 E10 0 —> HO / $4.0M Eto O N :Nk 0 N 0 N BSA TMSOTf O N/ CI THF \ \ MeCN \ _ _ . \ _ Acd ”OAc Ho‘ OH Step 1: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl—2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (600 mg, 1.45 mmol, 1 eq) in DMF (1 mL) was added allyl bromide (263 mg, 2.17 mmol, 15 eq) and CszCOs (943 mg, 2.90 mmol, 2 eq). The mixture was stirred at 20 0C for 2 h before it was diluted with water (15 mL) and extracted with EtOAc (4 X 10 mL). The combined organic phase was washed with water (10 mL), brine (10 mL), dried over anhydrous Na2S04, filtered and concentrated to provide crude diethyl aR, 5R, 6R, 6aR)—6-acetoxy-6—ethynyl—2,2-dimethyltetrahydro-furo[2,3 -d] [1 3 ]- dioxolyl)methoxy)—2-allylmalonate (685 mg) as a colorless gum.

Step 2: To a solution of crude diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2- dimethyltetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)—2-allylmalonate (685 mg, 1.51 mmol, 1 eq) in DCM (5 mL) was added TFA (5 mL, 6753 mmol, 45 eq) and H20 (1 mL, 55.51 mmol, 37 eq). The mixture was stirred at 20 0C for 16 h before it was diluted with water (15 mL) and adjusted the pH to 7—8 with solid NaHCO3. The reaction mixture was extracted with a mixture of DCM and MeOH (4 x 12 mL, 10: l/Vzv). The combined extract was washed with saturated aq. NaHCO3 (8 mL), brine (8 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure to give crude l 2-(((2R,3S,4R) yethynyl-4,5-dihydroxytetrahydrofuranyl)methoxy)allylmalonate (580 mg) as a yellow gum.

Step 3: To a solution of crude diethyl 2-(((2R,SS,4R)—3-acetoxyethyny1-4,5-dihydroxytetra- hydrofuranyl)methoxy)allylmalonate (580 mg, 1.40 mmol, 1 eq) in ne (5 mL) was added A020 (1.31 mL, 14.00 mmol, 10 eq) and 4—DMAP (513 mg, 4.20 mmol, 3 eq). The mixture was stirred at 20 °C for 15 before it was d with water (15 mL) and extracted with EtOAc (3 x 10 mL). The combined extract was washed with 0.5 N aq. HCl (2 X 8 mL), NaHCO3 (2 x 8 mL), brine (8 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether : EtOAc = 5:1 — 2:1) to give (420 mg, 60% yield) as a colorless gum.

Step 4: To a mixture of diethyl 2-allyl(((2R, 3R, 4R)—3,4,5-triacetoxyethynyltetra- hydrofuran-2—yl)methoxy)malonate (360 mg, 722.20 umol, 1 eq) and 2-chloro-9H—purin-6— amine (135 mg, 794.42 umol, l.l eq) in MeCN (5 mL) was added BSA (446.28 uL, 1.81 mmol, 2.5 eq) at 25 °C under N2 atmosphere. The mixture was d at 65 °C for 0.5 h.

The reaction mixture was cooled to O 0C and followed by dropwise addition of TMSOTf (261.00 uL, 1.44 mmol, 2 eq) in MeCN (1 mL). The e was stirred at 65 CC for 3 h before it was allowed to cooled and quenched with saturated aq. NaHCO3 solution (15 mL).

Then the mixture was extracted with EtOAc (4 x 10 mL), washed with saturated brine (8 mL), dried over ous , filtrated and concentrated. The crude product was d by Combi-flash on silica gel (20—40% EtOAc in petroleum ether) to give diethyl 2- allyl(((2R,3R,4R,5R)-3,4-diacetoxy(6-aminochloro-9H-pu1inyl)ethynyltetra- hydrofuranyl)methoxy)malonate (190 mg) as a colorless gum.

Step 5: To a solution of diethyl 2-allyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-amino chloro-9H—purin-9—yl)ethynyltetrahydrofuranyl)methoxy)malonate (100 mg, 164.47 umol, 1 eq) in THF (0.5 mL) was added LiOH'HzO (6.90 mg, 164.47 umol, 1 eq). The mixture was stirred at 50 °C for l h before it was diluted with water (6 mL) and extracted with EtOAc (3 x 4 mL). The organic layer was discarded. The pH of the aq. phase was adjusted to 2 with 2N aq. HCl solution. The aq. phase was then extracted with EtOAc (4 x 6 mL). The combined organic phases was washed with brine (6 mL), dried over ous Na2SO4, filtered and concentrated to provide a solid. The solid was dissolved in a e of MeCN (1 mL) and water (1 mL) and then lyophilizied directly to give the title compound (65.2 mg, 83% yield) as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.83 (s, 1H) 6.05 (d, J=7.5 Hz, 1H) 5.84 (br dd, J=17.2, .2 Hz, 1H) 5.15 (dd, J=17.2, 1.6 Hz, 1H) 4.99 - 5.05 (m, 2H) 4.27 (t, J=2.5 Hz, 1H) 4.00 -ll6- (dd, J=10.2, 2.6 Hz, 1H) 3.79 (dd, J=10.3, 2.8 Hz, 1H) 3.06 (s, 1H) 2.88 (d, J=7.3 Hz, 2H), LC/MS [M + H] = 467.9.

Example 16 Synthesis of 2-(((2R, 35, 4R, 5R)(6-amino-Z-chloro-9H-purin-9—yl)-3 -ethyny1-3 ,4- oxytetrahydrofuran-Z-yl)methoxy)-2—ethy1malonic acid 0 NH2 3%:0 OH O 'NACI H6 ’OH Example 16 Proceeding as described in Example 15 above but substituting allyl bromide with EtBr provided the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 6 ppm 8.53 — 8.83 (m, 1H) 7.81 (br s, 2H) 5.91 — 6.40 (m, 2H) 5.83 (d, J=7.88 Hz, 1H) 4.91 (d, J=7.75 Hz, 1H) 4.14 (t, J=2.88 Hz, 1H) 3.75 (dd, J=10.26, 3.25 Hz, 1H) 3.56 (s, 1H) 3.47 — 3.51 (m, 1H) 1.93 — 2.04 (m, 2H) 0.76 (t, J=7.38 Hz, 3H), LC/MS [M + H] = 4559.

Example 17 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-aminoch1oro-9H—purin-9—yl)-3 -ethyny1-3 ,4- oxytetrahydrofurany1)methoxy)methylmalonic acid 0 NH2 0>7?OH N <’ fN HO 0: N o NAG —Ho‘: ”0H Example 17 Proceeding as described in Example 15 above but substituting allyl bromide with methyl bromide provided the title compound as a white solid. 1HWR (400 MHz, DMSO-d6) 5 ppm 13.38 (br s, 2H) 8.69 (s, 1H) 7.82 (br s, 2H) 6.17 (br s, 1H) 5.98 (br d, J=7.25 Hz, 1H) 5.82 (d, J=7.63 Hz, 1H) 4.85 (br t, J=6.94 Hz, 1H) 4.15 (t, J=2.75 Hz, 1H) 3.83 (dd, J=10.13, 3.25 Hz, 1H) 3.53 — 3.65 (m, 2H) 1.52 (s, 3H); LC/MS [M + H] = 441.8.

W0 20191246403 Example 18 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(thiophenyl)-9H—purinyl) ethyny1-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid \S _S_ 0?: 0 CE N \N —AcO ’o </ l l A BC 0 N o NACI N Cl Pd(OAc)2. 052003 DBU TMSOTf MeCN P(C6H4803Na)3 : ‘. .9 MeCN H20 AcO OAc aq. LiOH, THFi _ O OH N </ :1 HO O N O N/ Cl H6 "0H Step 1: To a mixture of 2-chloroadenine (800 mg, 4.23 mmol, 1 eq) in MeCN (5 mL) and H20 (10 mL) at 20 °C under N2 atmosphere was added 4,4,5,5-tetramethyl(thiophenyl)- 1,3,2-dioxaborolane (800.37 mg, 3.81 mmol, 0.9 eq), Pd(OAc)2 (47.51 mg, 211.64 umol, 0.05 eq), CS2CO3 (3.45 g, 10.58 mmol, 2.5 eq) and triphenylphosphine-3,3’-3”-trisulfonic acid ium salt (601.50 mg, 1.06 mmol, 0.25 eq). The mixture was stirred at 110 CC for 3 h before it was allowed to cool and partitioned between EtOAc (3 x 20 mL) and H20 (10 mL). The combined organic phase was washed with H20 (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was triturated with leum ether : EtOAc = 3: 1) and left standing for for 14 h. The precipitate was collected by suction filtration and dried to provide 2-chloro(thiophenyl)-9H—purine (190 mg, 19% yield) as a yellow solid.

Step 2: To a e of 2-chloro(thiophenyl)-9H-purine (140 mg, 591.51 umol, 1 eq) and diethyl 2-benzyl(((2R, 3R, 4R)—3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuran yl)methoxy)malonate (324.47 mg, 591.51 umol, 1 eq) in MeCN (3 mL) at 0° C was added DBU (267 uL, 1.77 mmol, 3 eq). The e was stirred at 0°C for 10 min and followed by dropwise addition of TMSOTf (481 uL, 2.66 mmol, 4.5 eq). The mixture was stirred at 0 0C -ll8- for 30 min and then at 65 °C under N2 atmosphere for 14 h. The reaction mixture was d to cool and partitioned between EtOAc (3 X 20 mL) and saturated aq. NaHCO3 (2 x mL). The combined organic phase was washed with brine (2 X 20 mL), dried over NazSO4, d and concentrated. The crude product was purified by preparative TLC leum ether : EtOAc = 2:1) to provide diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4- diacetoxy-5—(2-chloro(thiophenyl)-9H—purinyl)—3-ethynyltetrahydrofuran—2- yl)methoxy)-malonate (150 mg, 31% yield) as a white solid.

Step 3: To a mixture of diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-chloro (thiophenyl)—9H-purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (150 mg, 206.85 umol, 1 eq) in THF (2 mL) was added LiOH'H2O (2 M, 2 mL, 19.34 eq). The mixture was stirred at 25 CC for 2 h before it was partitioned between EtOAc (10 mL) and water (10 mL). The aqueous phase was adjusted to pH ~2 with 2M aq. HCl solution. The aqueous phase was partitioned between EtOAc (40 mL) and brine (20 mL), dried over anhydrous NazSO4, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um, mobile phase: [water(0.225%FA)-ACN];B%: 43%-63%, 10min) and lyophilized to provide the title compound (31.6 mg, 26% yield) as a white solid. 1H NMR (400 MHz, DMSO-dd) 5 ppm 8.87 (s, 1H) 8.60 (dd, J=3.76, 1.25 Hz, 1H) 8.02 (dd, J=5.02, 1.00 Hz, 1H) 7.36 (dd, J=4.89, 3.89 Hz, 1H) 7.16 — 7.28 (m, 2H) 6.93 — 7.10 (m, 3H) 6.31 (br s, 1H) 6.11 (br d, J=6.02 Hz, 1H) 5.99 (d, J=7.53 Hz, 1H) 4.88 — 4.97 (m, 1H) 4.23 (dd, , 2.76 Hz, 1H) 3.99 (br dd, J=10.42, 4.39 Hz, 1H) 3.84 (br d, J=8.53 Hz, 1H) 3.56 (s, 1H) 3.26 (s, 2H); LC/MS [M + H] = 585.0.

Example 19 Synthesis of 2-(((2R, 3S, 4R, (6-aminochloro-9H—purinyl)-3 yl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxo- l l- l ,2-dihydropyridin-3 - yl)benzyl)malonic acid -ll9- N(Boc)2 o OEt N /\/rB A O o OH Br 9000qu HN5BI' K2C03,K|, Br HO L. acetone, 20 °C \PNb \OBWH); O CBr4. PPha 0 A05 IOAC —> —> —> —> \ \ Pd(dppf)Cl2, K2C03 \PN dioxane, H20, so °c \ \ \/\N\ \ 535583132": Step 1: To a solution of 3-bromopyridin-2(1110-one (3 g, 17.24 mmol, 1 eq) in acetone (100 mL) was added K2CO3 (11.91 g, 86.21 mmol, 5 eq). The suspension was d at 20 0C for 0.5 h and followed by addition of 1—bromopropane (4.71 mL, 51.73 mmol, 3 eq) and K1 (859 7rnnufl,03eq) Thenfixunenmssfinedat20OCfor16lL.Admfionalmnountofl- bromopropane (1.0 g) was added to the reaction mixture and the mixture was stirred further at °C for 3 h. The on was d with water (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine (100 mL), and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by Combi—Flash (silica gel, 20—60% EtOAc in petroleum ether) to provide 3-bromopropylpyridin-2(1H)— one (123 g, 33% yield) as a clear oil.

Step 2: To a solution of 3-bromopropy1pyridin-2(1H)—one (1.79 g, 8.28 mmol, 1 eq) and (4-(hydroxymethyl)phenyl)boronic acid (1.38 g, 9.11 mmol, 1.1 eq) in dioxane (18 mL) was added K2CO3 (3.43 g, 24.84 mmol, 3 eq), Pd(dppf)Cl2 (606 mg, 828.00 umol, 0.1 eq) and H20 (6 mL). The mixture was ed with N2 for 10 min and then stirred at 80°C for 16 h under N2 atmosphere. The reaction mixture was cooled and filtered. The filtrate was wmmmmw.UmmfiflwwwpmfiuflowflfiHwhfimwgd30flfithOAMn petroleum ether) to provide 3-(4-(hydroxymethyl)phenyl)—1-propy1pyridin-2(1hO-one (1.84 g, 91% yield) as a brown solid.

Step 3: To a solution of PPh3 (1.94 g, 7.40 mmol, 6 eq) in DCM (15 mL) was added CBr4 (245g,740nnnd,6eq)M—25°C.Theydhnysdufionumssfinaim—QS°Clbr1hand followed by addition of 3-(4-(hydroxymethyl)phenyl)propylpyridin-2(lhO-one (300 mg, -l20- 1.23 mmol, 1 eq) in DCM (3 mL) dropwise. The yellow suspension was stirred at —25 °C for 0.5 h to e a yellow suspension. The reaction mixture was diluted with MTBE (50 mL) to produce more itate. The precipitate was d off and the filtrate was concentrated. The residue was purified by CombiFlash a gel column, 10—100 % of EtOAc in petroleum ether) to provide 3-(4-(bromomethy1)pheny1)—1-propylpyridin-2(1H)—one (243 mg, 64% yield) as a clear oil.

Step 4: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ —(bis-(terl— carbonyl)amino)—2-chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)- malonate (554 mg, 721.20 umol, 1 eq) in DMF (5 mL) was added K2CO3 (299.03 mg, 2.16 mmol, 3 eq). The mixture was stirred at 20 0C for 0.5 h and followed by addition of 3-(4- (bromomethyl)phenyl)—1-propylpyridin-2(1H)—one (242.91 mg, 793.32 umol, 1.1 eq). The mixture was stirred at 20 °C for 16 h before it was diluted with water (30 mL) and extracted by EtOAc (4 x 20 mL). The combined organic layer was washed with water (100 mL), dried over anhydrous NazSO4, filtered and concentrated. The residue was purified by Combi Flash (silica gel, 20—30% of EtOAc in petroleum ether to provide l 2-(((2R, 3R, 4R,5R)—3,4- diacetoxy(6-N,N’ -(bis-(terl-butoxycarbonyl)amino)chloro-9H-purinyl)-3 -ethynyl- tetrahydrofuranyl)methoxy)(4-(2-oxo— l -propyl- l ,2-dihydropyridinyl)benzyl)- malonate (209 mg) as a colorless gum.

Step 5: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-N,N’ -(bis-(terl‘-butoxy- carbonyl)amino)—2-chloro-9H-pu1in—9-yl)-3—ethynyltetrahydrofuranyl)methoxy)—2-(4-(2— oxo—1-propyl-1,2-dihydropyridinyl)benzyl)malonate (209 mg, 210.38 umol, 1 eq) in DCM (2 mL) at 0 0C was added TFA (0.7 mL, 9.45 mmol, 44.94 eq). The solution was d at 20 0C for 2 h before it was quenched by ted aq. NaHCO3 (5 mL) and extracted with EtOAc (4 x 10 mL). The combined organic layer was dried over anhydrous NazSO4, filtered and trated. The residue was purified by Combi Flash (silica gel, 30—70% of EtOAc in petroleum ether) to provide diethyl 2-(((2R,3R,4R,5R)—3,4-diacetoxy(6-aminochloro- 9H-purinyl)—3-ethynyltetrahydrofuran-2—yl)methoxy)-2—(4-(2-oxo-l-propyl-1,2—dihydropyridinyl )benzyl)malonate (91 mg, 55% yield) as a white solid.

Step 6: -l2l- To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-S—(6-aminochloro-9H— purinyl)—3 -ethynyltetrahydrofuranyl)methoxy)(4-(2-oxopropyl-1,2-dihydro- pyridin-3—y1)benzy1)malonate (91 mg, 114.72 umol, 1 eq) in THF (1 mL) was added 1N aq.

LiOH (1 mL). The mixture was stirred at 20 0C for 2.5 h before it was diluted with water (5 mL) and the ing on was washed with EtOAc (2 x 10 mL). The c extract was discarded. The aqueous layer acidified to pH 2 with 2N aq. HCl and then extracted with EtOAc (4 x 8 mL). The combined organic layer was dried over anhydrous NazSO4, filtered and concentrated. The residue was dissolved in a mixture ofMeOH (5 mL) and water (20 mL) and was dried by lyophilization to provide thet title compound (51 mg, 67% yield) as a white solid. 1HWR (400 MHz, CD30D) 5 ppm 8.08 (s, 1H), 7.53 (dd, J=6.80, 2.0 Hz, 1H), 7.28—7.39 (m, 5H), 6.34 (t, J=6.9 Hz, 1H) ,5.96 (d, J=7.6 Hz, 1H), 4.77 (d, J=7.6 Hz, 1H), 4.28 (s, 1H), 4.07—4.15 (m, 1H), 4.01 (dd, J=10.3, 2.8 Hz, 1H), 3.92 (t, J=7.4 Hz, 2H), 3.39—3.58 (m, 2H), 3.06 (s, 1H), 1.65—1.80 (m, 2H), 0.94 (t, J=7.4 Hz, 3H), LC/MS [M + H] = 653.1.

Example 20 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro-9H—purinyl)—3 yl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(4-(1 -ethyloxo-1 ,2-dihydropyridin-3 - yl)benzyl)malonic acid N(Boc2) 0%?—0E!Off \,Br Eloy—2— I Br K2C03 Kl Br HO o HN\5—.acetone 20 °C G B(OH)2 O /‘N\ CBr4 PPhs AcO OAc Pd(dppf)CI2 K2003 dioxane H20, 80 ”C /\N\§éCCO31,éD;V|: o NH2 0 NH; 0 CE N CH </ ‘N - </ I TFA DCM A aq. LIOH,THF Y—b O I‘- ,0. 'N N CI —> NACI — O Acd bAC Example 20 Proceeding as described in Example 19 above but substituting propyl bromide with ethyl bromide provided the ttitle compound as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.15 (s, 1H), 7.53 (dd, J=6.6, 1.3 Hz, 1H), 7.25—7.38 (m, 5H), 6.32 (t, J=6.9 Hz, 1H), 5.96 (d, J=7.6 Hz, 1H), 4.78 (d, J=7.5 Hz, 1H), 4.30 (s, 1H), -l22- WO 46403 4.09—4.15 (m, 1H), 3.95—4.04 (m, 3H), 3.39—3.58 (m, 2H), 3.06 (s, 1H), 1.28—1.32 (m, 3H); LC/MS [M + H] = 639.1.

Example 21 sis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—ch1oro-9H-purinyl)—3 -ethyny1-3 ,4- dihydroxytetrahydrofurany1)methoxy)(4-(1-(2-hydroxyethy1)oxo-1,2- dihydropyridin-3—y1)benzy1)malonic acid 0 /\,Br 0 O HO OH Br 3’ Br TBDPSCI HN \ K2C03. acetone TBDPSOfN \ Imldazoli DMF TBDPSOJ‘N \ L©_B(OH)Z —> —.

\ \ \ Pd(dppf)C|2, K2003 TBDPSO\/\N \ dioxane, H20 \ 0 (HA _i\l.o N CI 0 Br Accf ’OAc CBC“ PPh3 TFA, DCM —’ — ¢ 9 —> TBDPSO AGO OAC DCM \/\N l K2003, DMF TBDPSO\/\N 0 “Hz OEt N 0 NH2 0 NH2 </ i AN o 0E1 /N OH \N /N \N o N o N 0| < l A < 1 A TBAF,THF o ,N N CI aq.LiOH,THF ,N N c: A06 bAC 0; 1:0 : ‘4, 5 '3 TBDPSO\/\N H6 OH HO OH Exampiem Step 1: To a mixture of 3-bromopyridin-2(lhO-one (3 g, 17.24 mmol, 1 eq) in e (100 mL) at 20 °C was added KI (859 mg, 5.17 mmol, 03 eq), K2CO3 (5.96 g, 43.10 mmol, 25 eq) and 2-bromoethanol (4.90 mL, 68.97 mmol, 4 eq). The mixture was d for 4 before it was filtered and the filter cake was washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel column chromatography (petroleum ether : EtOAc = 5:1 to 0:1) to provide 3- bromo(2-hydroxyethyl)pyridin-2(lib-one (2.2 g, 59% yield) as a yellow gum.

Step 2: To a mixture of 3-bromo(2-hydroxyethyl)pyridin-2(1H)-one (2.2 g, 10.09 mmol, 1 eq) in DMF (15 mL) at 20 °C was added imidazole (1.72 g, 25.22 mmol, 2.5 eq) and TBDPSCl (5.18 mL, 20.18 mmol, 2 eq). The mixture was stirred for 2 h before it was diluted with H20 (60 mL) and extracted with EtOAc (3 x 30 mL). The combined extract was washed with saturated aq. NH4C1 (2 x 30 mL), brine (30 mL), dried over anhydrous Na2S04, WO 46403 filtered and concentrated under reduced pressure. The residue was d by flash silica gel column chromatography (petroleum ether : EtOAc = 1:0 to 6: 1) to provide 3-bromo(2- ((tert-butyldiphenylsilyl)oxy)ethyl)-pyridin-2(1H)-one (3.75 g, 79% yield) as a light yellow Steps 3 — 8: Proceeding as described in Example 19 above but substituting 3-(4—(bromomethyl)— phenyl)propylpy1idin-2(lhO-one with 3—bromo(2-((terz‘-butyldiphenylsilyl)oxy)ethyl)- pyridin-2(1H)—one provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.33 (s, 1H), 7.50—7.57 (m, 1H), 7.41—7.47 (m, 1H), 7.39 (d, J=8.13 Hz, 2H), 7.29 (br d, J=8.13 Hz, 2H), 6.35 (t, J=6.88 Hz, 1H), 5.98 (d, J=7.13 Hz, 1H), 4.71 (d, J=7.00 Hz, 1H), 4.30 (br s, 1H), 3.93—4.16 (m, 4H), 3.83 (m, 2H), 3.36— 3.50 (m, 2H), 3.05 (s, 1H), LC/MS [M + H] = 655.1.

Example 22 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)-3 yl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)(4-(2-methoxypyridin-3 -yl)benzyl)malonic acid o N(Boc)2 0 0E! B(OH)2 <N \N N \ / I | E10 0 N o NAG Pd(dppf)C|2, K2C03 _ ~ . e,H20 I AC6 bAC TFA,DCM NAG aq.LiOH,THF —> —> Example 22 Step 1: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-N,N’ —(bis-(terZ-butoxy- carbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuran-Z-yl)—methoxy)—2-(4— iodobenzyl)malonate (900 mg, 914.47 umol, 1 eq) and (2-methoxypy1idyl)boronic acid (168 mg, 1.10 mmol, 1.2 eq) in dioxane (9 mL) 25 0C was added K2CO3 (379 mg, 2.74 —124— mmol, 3 eq), Pd(dppf)C12 (67 mg, 9145 umol, 0.1 eq) and H20 (3 mL). The mixture was degassed with N2 for a while and then heated to 80 0C for 16 h before it was diluted with water (10 mL), and ted with ethyl acetate (2 x 10 mL). The combined organic layer was dried by NazSO4, filtered and concentrated. The crude product was purified by Combi- flash (silica gel, 10—50 % of EtOAc in petroleum ether) to give diethyl R, 3R, 4R, 5R)- 3,4-diacetoxy(6-MN’ -(bis-(Zert—butoxycarbonyl)amino)—2-chloro-9H—purinyl)—3- ethynyltetrahydro-furanyl)-methoxy)-2—(4-(2-methoxypyridinyl)benzyl)malonate (l 17 mg, 13% yield) as a yellow gum.

Step 2: To a solution of diethyl R, 3R, 4R, 4-diacetoxy(6-N,N’{bis-(tert- butoxycarbonyl)amino)chloro-9H-purin—9-yl)-3—ethynyltetrahydrofuranyl)-methoxy) (4-(2-methoxypyridinyl)benzyl)malonate (90 mg, 93.23 umol, 1 eq) in DCM (3 mL) was added TFA (0.4 mL, 5.40 mmol, 58 eq). The solution was stirred at 20 °C for 2 h before it was quenched with saturated aq. NaHCO3 (4 mL) and extracted with EtOAc (3 x 4 mL). The combined organic layer was concentrated to give crude diethyl 2-(((2R, 3R, 4R, 5R)—3,4- diacetoxy(6-aminochloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)(4- (2-methoxypyridiny1)benzy1)-malonate (42 mg) as a yellow gum.

Step 3: To a solution of crude diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-aminochloro- 9H—purin-9—yl)—3-ethynyltetrahydrofuranyl)methoxy)(4-(2-methoxy-pyridin yl)benzyl)malonate (42 mg, 54.89 umol, 1 eq) in THF (2.5 mL) was added 1M aq. LiOH (0.8 mL, 15 eq). The reaction mixture was stirred at 20 0C for 4 h before it was acidified to pH 6 with 1N aq. HCl and concentrated. The crude t was purified by preparative HPLC and the fraction was dried by lyophilization to give the title compound (6 mg, 17% yield) as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.10 (s, 1H), 8.01 (dd, J=4.94, 1.69 Hz, 1H), 7.48 (dd, J=7.25, 1.63 Hz, 1H), 7.24 — 7.35 (m, 4H), 6.93 (dd, J=7.32, 5.07 Hz, 1H), 5.97 (d, J=7.50 Hz, 1H), 4.89 — 4.96 (m, 1H), 4.29 (br s, 1H), 4.05 (br d, J=5.00 Hz, 2H), 3.76 (s, 3H), 3.51 (br d, J=14.76 Hz, 1H), 3.42 (br d, J=14.51 Hz, 1H), 3.01 (s, 1H); LC/MS [M + H] = 625.1.

Example 23 Synthesis of 2-(((2R, 3S, 4R, (6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(3-(trifluoromethoxy)benzyl)malonic acid 0 NH2 0 OH N \ <’ ' i Ho o N o N CI PX 23—7,.., 0 Ho‘ ’OH Example 23 Proceeding as described in Example 1 above but substituting benzyl bromide with 1- (bromomethyl)-4—(trifluoromethoxy)benzene provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 8 8.43 (s, 1H), 7.09—7.25 (m, 3H), 6.95—6.98 (d, J= 8.1 Hz, 1H), .04 (d, J: 7.32 Hz, 1H), 5.00—5.03 (d, J: 7.41 Hz, 1H), .37 (t, J: 3.33 Hz, 1H),4.05—4.15(m,2H),3.38—3.53 (q, J: 15 Hz, 2H), 2.99 (s, 1H); LC/MS [M + H] = 6020.

Example 24 Synthesis of 2—(((2R, 3S, 4R, 5R)—5-(6-amino-2—chloro—9H—purin—9-yl)—3 —ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)(thiophen-3 -ylmethyl)malonic acid Example 24 Proceeding as described in Example 1 above but tuting benzyl bromide with 3— (bromomethyl)thiophene provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.39 (s, 1H), 7.09—7.17 (m, 2H), 6.98—7.00 (d, J: 5.04.0 Hz, 1H), 6.01—6.04 (d, J= 7.47 Hz, 1H), 5.00—5.02 (d, J= 7.29 Hz, 1H), 4.32—4.34 (t, J= 2.76 Hz, 1H), 4.01—4.11 (m, 2H), 3.41—3.54 (q, J: 15 Hz, J: 9.03 Hz, 2H), 2.98 (s, 1H), LC/MS [M + H] = 524.0. -l26- Example 25 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(propynyl)malonic acid 0 NH2 0 OH 0001,,N Ho” : Ho“ OOH Example 25 ding as described in Example 1 above but substituting benzyl bromide with propargyl bromide provided the title nd as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.96 (s, 1H), 6.07—6.09 (d, J= 7.53 Hz, 1H), 5.01—5.04 (d, J = 7.53 Hz, 1H), 4.29—4.30 (m, 1H), 3.92—4.05 (m, 2H), 3.01—3.15 (m, 2H), 2.99 (s, 1H), 2.28—2.30 (t, J: 2.58 Hz, 1H); LC/MS [M + H] = 467.

Example 26 Synthesis of 2—(((2R, SS, 4R, (6-amino-2—chloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofurany1)methoxy)malonic acid 0 o NH2 0 NH2 0M0E1 N 0 CE N - 0 OH N </ :‘N FFADCM ML “323%” M BO 0: N 41*“ N o NAG —> E10 0: N NAc1—’ HO «fN o 0: o Aco bAc Acd bAc H5 bH Example 26 Step 1: A solution of diethyl 2-(((2R,3R,4R,5R)-3,4-diacetoxy(6-MN’ -(bis-(tert-butoxy- carbonyl)amino)—2-chloro-9H—purinyl)ethynyltetrahydrofuran-Z-yl)methoxy)malonate (200 mg, 0.26 mmol) in CH2C12 (1 mL) under argon here at 0 0C was added TFA (0.5 mL). The mixture was d for 5 minutes and allowed to warm up and stirred for l h.

Additional amount of TFA (0.4 mL) was added to the reaction mixture and it was stirred further 1.5 h before it was concentrated. The residue was azeotroped with DCM (5 x 5 mL) under reduced pressure to provide crude diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6- amino-Z-chloro-9H-purinyl)ethynyltetrahydro-furany1)methoxy)malonate which was used in the next step without further purification.

Step 2: To a solution of crude l 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-aminochloro- in—9-yl)—3-ethynyltetrahydrofuran—2-yl)methoxy)malonate (026 mmol) from the previous step in a mixture ofMeOH (8.5 mL) and water (1.5 mL) was added powdered lithium hydroxide monohydrate (86 mg, 2.08 mmol). The resulting mixture was stirred for 16 h before the organic volatile was removed under reduced pressure. The residue was diluted with additional water (11 mL) and ted with EtOAc (12 mL). The organic layer was discarded. The aqueous phase was acidified to pH ~2.5 with 1N aq. HCl on and extracted with EtOAc (3 x 12 mL). The combined organic layer was dried (NazSO4), filtered and concentrated to provide the title compound (45.5 mg) as a light brown solid. 1H NMR (CD3OD, 300 MHz): 5 8.94 (s, 1H), 6.08 (d, J = 7.52 Hz, 1H), 5.05 (d, J = 7.52 Hz, 1H), 4.65 (s, 1H), 4.29 (t, J = 2.40 Hz, 1H), 4.06 (dd, J = 10.7, 2.5 Hz, 1H), 3.93 (dd, J = .64, 2.50 Hz, 1H), 3.12 (s, 1H); LC/MS [M + H] = 428.

Synthesis of 2-(((2R, 3S, 4R, 5R)((1H-pyrazolyl)ethynyl)(6-aminochloro-9H-purin- 9-yl)-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 0 N(BOC)2 O N(BOC)2 OM03 IfiNH Woa o / o «811:1 N ED —. 0 o (NIL/:1 : X 7’ Cl CI 3)ZCI2,Cu| / .- ., TEA,THF / : . .

\ . Aco ’OAc HN‘N Aco‘ ’OAc O NH2 0 NH2 0 0E1 O OH TFA DCM , W (NfiNk aq. L'OH THF QI , —, BO 0 N 0 O N/ HO «NnN CI O N/ CI / / _ _ ’ — s HN '9 ’ — s HN '9 ‘N AGO OAC ‘N HO OH Example 27 Step 1: To a mixture of 3-iodo- lH-pyrazole (407 mg, 2.1 mmol), PdC12(PPh3)2 (82 mg, 0.12 mmol), CuI (22 mg, 0.12 mmol), and Et3N (10 mL) in THF (10 mL) under argon atmosphere was added diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-N,N’ -(bis-(z‘erl—butoxycarbonyl)— amino)chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (l g, 1.2 mmol). The resulting mixture was stirred at 60 0C overnight before it was allowed to cool to -l28- room temperature and the organic volatile was removed under reduced pressure. The resulting crude residue was purified by flash silica gel column chromatography (60—100% EtOAc in hexanes) to provide diethyl 2-(((2R,3R,4R,5R)—3-((lH—pyrazolyl)ethynyl)—3,4- diacetoxy-S—(6-N,N’ -(bis-(terZ-butoxycarbonyl)amino)chloro-9H-purin—9-yl)tetrahydro— furanyl)methoxy)malonate as a solid.

Step 2: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3-(( lH—pyrazol-3 -yl)ethynyl)-3,4- diacetoxy-S—(6-N,N’—(bis-(terl—butoxycarbonyl)amino)chloro-9H—purin—9—yl)tetrahydro— furanyl)methoxy)malonate (100 mg, 0.12 mmol) in a DCM (3 mL) was added TFA (1 mL). The resulting e was stirred at 25 °C for 4 h before it was concentrated to e crude diethyl 2-(((2R, 3R, 4R, 5R)-3 -(( 1H-pyrazolyl)ethynyl)-3 ,4—diacetoxy(6—amino chloro-9H—purinyl)tetrahydrofuranyl)methoxy)malonate which was used in the next step without further purification.

Step 3: To a solution of crude diethyl 2-(((2R, 3R, 4R, 5R)((lH—pyrazol-3—yl)ethynyl)-3,4- oxy-S-(6-aminochloro-9H—purinyl)tetrahydrofuranyl)methoxy)malonate in a e of THF (5 mL) and H20 (2 mL) was added LiOH'H2O (50 mg, 1.2 mmol). The resulting e was stirred at 25 °C for 24 h before it was cooled to O 0C and acidified to pH 6.5 with 1N aq. HCl. The reaction mixture was concentrated. The crude residue was purified by preparative reversed-phase HPLC and dried by lyophilization to e the title compound as a white solid. 1H NMR (CD3OD, 300 MHZ) 5 8.96 (s, 1H), 7.56-7.76 (m, 1H), 6.50-6.57 (m, 1H), 6.12— 6.14 (d, J: 7.14 Hz, 1H),5.13—5.15(d,./= 6.78 Hz, 1H), 4.63-4.70 (m, 1H), 4.38 (s, 1H), 399-4. 13 (m, 2H); LC/MS [M + H] = 495.

Examples 28 & 29 Synthesis of 2-(((2R, 3S, 4R, (6-aminochloro-9H—purinyl)—3-(( l -benzyl- lH- pyrazol-3 -yl)ethynyl)-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 2-(((2R, 3S, 4R, 5R)-5—(6-amino—2-chloro-9H—pu1inyl)-3 -((1-benzyl-lH—pyrazol-5— yl)ethynyl)-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid -l29- o N(Boc)2 o N(Boc)2 N(Boc)z 3L?“ «“fN 052003,DMF >4“ </“ P” $2.o N NACI BO 0 N o o NAG + 38f?<No ’kcn / step1 / \ HNiN/ . : . éstepo4J TFA, DCM| . ~ a Q/ N‘N c o , AcO OAc N‘N A—co‘ OAc step 2 lTFA, DCM o NH2 0 NH2 5334:"El «“ 0 OEt N </ :1 N IN: 50%?0 N o o N Cl ©\/N~N/ | \ : . , N‘N Acd bAc step:Taq.OACLiOH, THF step 5J0aq' LiOH, THF 0 NH2 0 NHZ 0%?“ «N ‘N Ho 0 N «NM o INACI IN: ©VN‘N//$2. . 31—7| Hd ' ’OH N‘N Example 28 @ Example 29 Step 1 : To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3-((1H—pyrazolyl)ethynyl)-3,4- diacetoxy-S-(6-N,N’-(bis-(terl-butoxycarbonyl)amino)chloro-9H-purinyl)tetrahydro- 2-yl)methoxy)malonate (100 mg, 0.12 mmol), in anhydrous DMF (2 mL) under argon atmosphere at O 0C was added oven dried CszCO3 (78 mg, 024 . The mixture was stirred at room ature for 20 minutes followed by addition of benzyl bromide (29 ul, 0.24 mmole). The resulting mixture was stired at room temperature for 2 h before it was diluted with EtOAc (15 mL) and H20 (5 mL). The organic layer was separated, washed with H20 (20 mL), brine, dried over NazSO4 and concentrated. The crude e was purified by flash silica gel column chromatography (0—50% EtOAc in hexanes) to provide diethyl 2- (((2R, 3R, 4R,5R)—3 ,4-diacetoxy-3 -((1 -benzyl- 1H-pyrazolyl)ethynyl)(6-N,N” -(bis-(lerl‘- butoxycarbonyl)amino)—2-chloro-9H—purinyl)tetrahydrofuranyl)methoxy)-ma1onate and l 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy-3 —((1 -benzyl- 1H-pyrazol—5 -yl)ethynyl)(6-N,N’ - (bis-(tert—butoxycarbonyl)amino)—2-chloro-9H—purinyl)tetrahydro-furan hoxy)malonate.

Steps 2 — 3: Proceeding as descnbed in Example 27 above but substituting diethyl 2- (((2R, 3R, 4R,5R)—3 -(( 1H-pyrazol-3 -yl)ethynyl)—3 ,4-diacetoxy(6-N,N’ -(bis-(lert— -l30- butoxycarbonyl)amino)—2-chloro-9H—purinyl)tetrahydrofuran-Z—yl)methoxy)malonate with diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy-3 -((l l- 1H-pyrazol-3 -yl)ethynyl)(6-N,N’ - (bi s-(tert—butoxycarbonyl)amino)—2-chloro—9H-purinyl)tetrahydrofuran-Z-yl)methoxy)— malonate ed the title compound (Example 28) acid as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.95 (s, 1H), 7.685 (s, 1H), .38 (m, 5H), 6.50 (s, 1H), 6.10-6.13 (d, J: 7.05 Hz, 1H), 5.35 (s, 2H), 5.16—518 (d, J: 7.35 Hz, 1H), 4.68—4.76 (m, 1H), 4.38 (s, 1H), 3.96—4.16 (dd, J = 9.84 Hz, J =17 Hz, 2H), LC/MS [M + H] = 585.

Steps 4 — 5: Proceeding as described in Example 27 above but substituting diethyl 2- (((2R, 3R, 4R, 5R)—3 -(( 1H-pyrazol-3 -yl)ethynyl)—3 ,4-diacetoxy-5 -(6-N,N’ -(bi s-(lerZ-butoxycarbonyl )amino)—2-chloro-9H—purinyl)tetrahydrofuran—2-yl)methoxy)malonate with diethyl R, 3R, 4R, 5R)—3,4-diacetoxy-3 —((l -benzyl- 1H-pyrazol—5 -yl)ethynyl)-5—(6-N,N’ - (bis-(terZ-butoxycarbonyl)amino)chloro—9H—purinyl)tetrahydrofuran-Z-yl)methoxy)— malonate provided the title compound (Example 29) as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.88 (s, 1H), 7.53 (s, 1H), 7.23—7.35 (m, 5H), 6.59 (s, 1H), 6.10-6.13 (d, J: 6.09 Hz, 1H), 5.46 (s, 2H), 5.15—5.17 (d, J: 6.9 Hz, 1H), 43541.41 (m, 2H), 3.71—4.01 (dd, J= 10.71, J= 33, 2H); LC/MS [M + H] = 585.

Examples 30 & 31 Synthesis of yl(((2R, 3S, 4R, 5R)(5-chloro(isopropylamino)-3H—imidazo[4,5- b]pyridinyl)ethynyl-3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid 2-benzyl—2-(((2R, 3S, 4R, 5R)-5 -(2-chloro(dimethylamino)-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid -l3l- o N 0 Cl 0 OEt <’ l 0 QB N H N/ CI <’ 1 E10 0 EtO O _ O N O N/ Cl BSA, TMSOTf Z X 7WD“ MeCN I X 7’ c -, .~ ,1 Acd bAc step 1 Acd bAc i—PrNHz, TEA Step 2 I DMF, 75 °c O \N/ O OEt N </ Ii + BO 0 N O N/ CI —Ho“ °OH jan'HNstep3 LiOH, THF Step4i aq. LiOH THF —HO ”OH $740°0H Example 30 Example 31 Step 1: To a solution of l 2-benzy1-2—(((2R, 3R, 4,5-triacetoxy-3—ethyny1tetra- hydrofuranyl)methoxy)malonate (500 mg, 0.91 mmol) in MeCN (6 mL) at 25 0C was added 5,7-dichloro-1H-imidazo[4,5-b]pyridine (223 mg, 1.18 mmol) and followed by N,0- bis(trimethy1silyl)acetamide (BSA) (535 uL, 2.19 mmol). The resulting suspension was heated at 85 0C for 15 min as it became clear. The reaction mixture was allowed to cool to nmmwmmmmmfiflmwdWaMMmufflMMHTQQnng8mmdflhme.Hm mmmmmmmmumHMnmmmwaWS%flm3h%aflfimewmmgmmmdww consumed. The reaction was ed with cold saturated aq. NaHCO3 solution and diluted with EtOAc (15 mL). The organic layer was separated, washed with H20 (20 mL), brine, dried over Na2SO4 and concentrated. The crude residue was purified by flash silica gel column chromatography (O—50% EtOAc in hexanes) to provide diethyl 2-benzy1 (((2R,3R,4R,5R)—3,4-diacetoxy(5,7-dichloro-3H—imidazo[4,5-b]pyridin-3 -y1)—3-ethynyltetrahydrofuranyl )methoxy)malonate as a foam.

Step 2: To a sealed tube containing diethyl 2—benzyl(((2R, 3R, 4R, 5R)-3,4—diacetoxy(5,7- ro-3H—imidazo[4,5-b]pyridinyl)ethynyltetrahydrofuranyl)methoxy)malonate (80 mg, 0.12 mmol) in anhydrous DMF (1 mL) was added isopropyl amine (0.5 mL, 5.9 mmol) and Et3N (1 mL, 7.1 mmol). The reaction mixture was heated at 75 0C for 72 h before it was allowed to cool and diluted with EtOAc (15 mL) and H20 (5 mL). The c layer was separated, washed with H20 (20 mL), brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel column chromatography (0—50% EtOAc in hexanes) to e l 2—benzyl—2-(((2R,3S,4R,5R)(5-chloro—7-(isopropylamino)-3H—imidazo- [4,5-b]pyridin-3 -yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonate and diethyl 2-benzyl(((2R, 3S, 4R, 5R)—5-(5-chloro(dimethylamino)-3H—imidazo[4,5-b]— pyridin-3 -yl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonate as foam.

Step 3: To a solution of diethyl 2-benzyl(((2R,3S,4R,5R)(5-chloro(isopropylamino)— 3H—imidazo[4,5-b]pyridinyl)—3 -ethynyl-3,4-dihydroxytetra-hydrofuranyl)methoxy)- malonate (10 mg, 0.016 mmol) in a e of THF (3 mL) and H20 (1 mL) was added LiOH-H2O (10 mg, 0.24 mmol). The resulting mixture was stirred at 25 °C for 24 h before it was cooled to O 0C and acidified to pH 6.5 with 1N aq. HCl. The crude residue was purified by preparative reversed-phase HPLC and dried by lyophilization to e 2-benzyl (((2R, SS, 4R, 5R)(5 o—7-(isopropylamino)—3H—imidazo[4, 5-b]pyridin—3 -yl)—3 yl- 3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid as a white solid. 1H NMR (CD3OD, 300 MHz) 6 8.25 (s, 1H), 7.25—7.28 (m, 2H), 7.05 (m, 3H), 6.43 (s, 1H), 6.06—6.08 (d, J: 7.17 Hz, 1H), 4.95—4.98 (d, J: 705 Hz, 1H), 4.32 (s, 1H), 4.05—4.11 (m, 2H), 3.89—3.93 (m, 1H), 3.31—3.39 (m, 2H), 2.99 (s, 1H), 1.30—1.33 (m, 6H), LC/MS [M + H] = 560.

Step 4: To a solution of diethyl 2-benzyl(((2R,3,S', 4R,5R)(5-chloro-7—(dimethyl-amino)- 3H—imidazo[4,5-b]pyridin-3—yl)-3 -ethynyl-3,4-dihydroxytetrahydrofuran-2—yl)methoxy)- malonate (21 mg, 0.035 mmol) in a mixture of THF (3 mL) and H20 (1 mL) was added LiOH'H2O (30 mg, 0.71 mmol). The resulting mixture was stirred at 25 0C for 24 h before it was cooled to O 0C and acidified to pH 6.5 with 1N aq. HCl. The reaction mixture was concentrated. The crude residue was purified by preparative reversed-phase HPLC and dried by lyophilization to provide the title compound as a white solid. -l33- 1H NMR (CD3OD, 300 MHz) 5 8.68 (s, 1H), 7.21-7.24 (m, 2H), 6.99-7.03 (m, 3H), 6.49 (s, 1H), 6.15—6.17 (d, J: 7.08 Hz, 1H), 4.99—5.02 (d, .1: 7.17 Hz, 1H), 4.35—4.37 (t, .1: 3.12 Hz, 1H), 4.07-4.08 (m,2H), 3.36-3.50 (m, 8H), 2.99 (s, 1H); LC/MS [M + H] = 546.

Example 32 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(2-ch1oro((2-hydroxyethy1)amino)-9H-pu1iny1) ethyny1-3 ,4-dihydroxytetrahydrofurany1)methoxy)—2—(thiophen-3 -y1methy1)ma1onic acid 0 0 O A020 0 CE 0 QB TFA 0 0E! 4_DMAp 3'(bromomethyl)thiophene DCM, 10% H20 pyridine EtO 03:7 E10 0 —>E10 0 0 0 ...0 CSgCOg Q / DMF,20°C \ Q3—7-0 / \ Q .- -. )V , ., )T . ., A06 0 8 A06 0 3 A06 OH 0' OH 0 0 HN’\/ N 0 CI 0 OEt (I /\/OH 1 A o OEt HzN 0 CE N N \ fl N’ CI TEA,dioxane —> <, <’ l 1 E10 0 —> / 0 BO 0 N \j:/ EtO o N OAc BSA,TMSOTf O N 0 N C' / \ Q MeCN / / \ _ ‘ \ _ .

S Acd l'OAc S 700$ i'OAc S Acd aOAc 0 HN/\/OH 0 0H N \ aq.LiOH,THF </ I i —>HO 0 N 0 N’ Cl / \ _ 3 H6 ”OH Example32 Steps 1 — 3: ding as described in Example 15 above but substituting allyl bromide with 3— methy1)thiophene provided l 2-(thiopheny1methy1)(((2R, 3R, 4R)-3,4,5- triacetoxyethynyltetrahydrofuranyl)methoxy)malonate as a solid.

Step 4: To a solution of chloro-1H—imidazo[4,5-b]pyridine (238 mg, 1.26 mmol) in MeCN (6 mL) at 25 °C was added N,O-bis(trimethy1si1y1)acetamide (B SA) (571 uL, 2.34 mmol). The ing suspension was heated at 85 0C for 15 min as it became clear. The reaction mixture was allowed to cool to room temperature followed by addition of diethyl 2- (thiophen-3 -y1methy1)(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethyny1tetrahydrofurany1)- methoxy)malonate (540 mg, 0.97 mmol) and TMSOTf (228 ul, 1.26 mmol) dropwise. The reaction mixture was then d at 85 °C for 2.5 h as all of the starting material was —134— consumed. The reaction was quenched with cold saturated aq. NaHCO3 solution and diluted with EtOAc (15 mL). The organic layer was separated, washed with H20 (20 mL), brine, dried over Na2SO4 and concentrated. The crude e was purified by flash silica gel column tography (O—50% EtOAc in hexanes) to provide diethyl 2-(((2R, 3R, 4R, 5R)- 3,4—diacetoxy(2,6-dichloro-9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)-2— (thiophenylmethyl)malonate as a foam.

Step 5: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2,6-dichloro-9H—purin yl)ethynyltetrahydrofuranyl)methoxy)(thiophen-3—ylmethyl)malonate (100 mg, 0.146 mmol) in 1,4-dioxane (2 mL) was added TEA (20 uL, 0.146 mmol) followed by ethanolamine (13 ul, 0.219 . The resulting mixture was stirred at 25 0C for 2 h before it was diluted with EtOAc (15 mL) and H20 (5 mL). The organic layer was separated, washed with H20 (20 mL), brine, dried over Na2SO4 and concentrated to provide crude diethyl 2-(((2R, 3R, 4R, 5R)—3 ,4-diacetoxy(2-chloro((2-hydroxyethyl)amino)-9H—purin yl)ethynyltetrahydrofuranyl)methoxy)(thiophenylmethyl)malonate which was used in the next step without further purification.

Step 6: To a solution of crude diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-chloro—6-((2- hydroxyethyl)amino)-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)(thiophen ylmethyl)malonate in a e of THF (4 mL) and H20 (1 mL) was added 2O (80 mg, 1.91 mmol). The resulting mixture was stirred at 25 °C for 24 h before it was cooled to 0 °C and acidified to pH 6.5 with 1N aq. HCl. The reaction mixture was concentrated. The crude residue was purified by preparative reversed—phase HPLC and dried by lyophilization to provide the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.32 (s, 1H), .16 (m, 2H), .99 (m, 1H), 6.00— 6.03 (d, J: 7.41 Hz, 1H), 4.99—5.02 (d, J: 7.38 Hz, 1H), 4.32—4.34 (t, J: 3.03 Hz, 1H), 400—4. 11 (m,2H), 3.65-3.79 (m, 4H), .53 (q, J= 15.42 Hz, J= 5.79 Hz, 2H), 2.98 (s, 1H); LC/MS [M + H] = 568.0.

Example 33 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(2-chloro—6-(isopropylamino)-9H-purin—9-yl)—3—ethynyl— 3 ,4-dihydroxytetrahydrofuranyl)methoxy)(thiophen-3 -ylmethyl)malonic acid -l35- <’ \” HO O N O NAG / \ _ S 7 8 —HO‘ ITOH Proceeding as described in Example 32 above but substituting ethanolamine with i— PrNH2 provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.28 (s, 1H), 7.08-7.16 (m, 2H), 6.97-6.99 (m, 1H), 5.99— 6.02 (d, J: 7.38 Hz, 1H), 5.00—5.02 (d, J: 735 Hz, 1H), 4.31-4.43 (m, 2H), 4.00-4.12 (m,2H), 3.40—3.53 (q, J= 15.63 Hz, J: 5.4 Hz, 2H), 2.98 (s, 1H), 1.27—1.32 (m, 6H), LC/MS [M + H] = 566.0.

Example 34 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((3-hydroxypropyl)amino)-9H—purin- 9-yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 0 I o HNMOH O C O 0E1 (NfN H2N\/\/OH O OEt O OE'E NAG (N N fl I j: TEA,dioxane <’ I 1 EC 0 / 0 E10 0 N / E10 0 N OAc BSA,TMSOTf o N 0 N CI C' Q MeCN _ ~ ‘ AGO bAc 760“ bOAc H6 ”0H aq. LiOH MeOH, THF 0 HN/\/\OH 0 OH ac“N HO 0: N o NAG —H(5: 30H Step 1: To a solution of 2,6-dichloro-9H—purine_(690 mg, 3.65 mmol) in dry CH3CN( 15 mL) was added N,O-bis(trimethylsilyl)acetamide (0.28 mL, 112 mmol) Via syringe. The mixture was heated to 95 °C under argon atmosphere for 5 minutes and then cooled to t. To this mixture was added diethyl yl(((2R, 3R, 4R)-3,4,5-triacetoxy-3—ethynyltetra- hydrofuranyl)methoxy)malonate (2 g, 3.65 mmol) and followed by TMSOTf (0.09 mL, 0.494 mmol). The resultin mixture was heated at 95 °C for 2.5 h before it was cooled to ambient temperature and diluted with water (60 mL) and EtOAc (60 mL). The organic phase -l36- was washed successively with equal volumes of saturated NaHCO3 solution and brine. The aqueous phase was further extracted with EtOAc (2 X 30 mL). The combined organic phase was dried (MgSO4), filtered and concentrated. The crude residue was d by flash silica gel column chromatography (5—60% EtOAc in hexane) to e diethyl 2-benzyl (((2R, 3R, 4R, 5R)-3 cetoxy-5 -(2, 6-dichloro-9H—purinyl)tetrahydrofuran-2—yl)- methoxy)malonate (1.61 g) as an off-white solid.

Step 2: To a solution of diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2,6-dichloro- 9H—purinyl)tetrahydrofuranyl)methoxy)malonate (102 mg, 0.15 mmol) in dry dioxane (1 mL) was added triethylamine (0.02 mL, 0.15 mmol) and 3-aminopropanol (16 mg, 0.212 mmol). The ing mixture was stirred for 1.5 h before it was diluted with water (15 mL) and DCM (15 mL). and the organic phase was collected. The organic layer was washed with brine (15 mL). The aqueous phase were further extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over MgSO4, filtered and concentrated to provide crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3 ,4-diacetoxy(2-chloro((3 -hydroxypropyl)amino)- 9H-purinyl)tetrahydrofuranyl)methoxy)malonate as a clear viscous oil.

Step 3: To a solution of crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)—3,4-diacetoxy(2-chloro- 6-((3 -hydroxypropyl)amino)-9H—purinyl)tetrahydrofuranyl)methoxy)malonate (0. 15 mmol) in H20 (0.2 mL), MeOH(1 mL) and THF (0.28 mL) was added ed LiOH mono-hydrate (43 mg, 1.05 . The e was stirred for 4 h and then sonicated for minutes. Additional LiOH mono—hydrate (7 mg) was added and sonication continued for 1 h before the organic volatile was removed under reduced pressure and the residue was diluted with water (10 mL) and EtOAc (10 mL). The mixture was cooled at 0 °C and acidified to pH ~3 with 1N aq. HCl. The organic phase was collected and the s phase was further extracted with EtOAc (2 x 10 mL). The combined EtOAc phases were dried over MgSO4, filtered and concentrated. The crude residue was purified by preparative reversed- phase HPLC to e the title compound as a off-white solid. 1H NMR (CD3OD, 300 MHz) 5 8.19 (bs, 1H), 7.21—73 (m, 2H), 7.00—7.10 (m, 3H), 6.00 (d, J = 7.36 Hz, 1H), 4.98 (d, J = 7.36 Hz, 1H), 4.33 (t, J = 3.18 Hz, 1H), 4.02—4.15 (m, 2H), 3.68 -l37- (t, J = 6.18 Hz, 2H), 3.59—3.72 (m, 2H), 3.47 (d, J = 14.95 Hz, 1H), 3.38 (d, J =14.95 Hz, 1H), 2.99 (s, 1H), 1.84-1.95 (m, 2H); LC/MS [M + H] = 576.0.

Example 35 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro(((R)—2-hydroxypropyl)amino)-9H— purinyl)ethyny1-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid Example 35 Proceeding as described in Example 34 above but substituting propanolamine with (R)-l-aminopropanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.19 (bs, 1H), 7.22-7.30 (m, 2H), 7.02-7.10 (m, 3H), 6.01 (d, J = 7.38 Hz, 1H), 4.98 (d, J = 7.38 Hz, 1H), 4.33 (t, J = 3.17 Hz, 1H), .13 (m, 3H), .69 (m, 1H), 3.43 (qt, J = 14.64 Hz, 2H), 3.41-3.55 (m, 1H), 2.99 (s, 1H), 1.24 (d, J = 6.30 Hz, 3H); LC/MS [M + H] = 5760.

Example 36 Synthesis of 2-benzyl(((2R, 3S, 4R, (2-chloro-6—(((S)—2-hydroxypropyl)amino)—9H— purinyl)-3—ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid Example 36 Proceeding as described in Example 34 above but tuting propanolamine with (SD-l—aminopropan-Z-ol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.19 (bs, 1H), 7.23—7.29 (m, 2H), 7.03—7.10 (m, 3H), 6.00 (d, J = 7.35 Hz, 1H), 4.96 (d, J = 7.35 Hz, 1H), 4.32 (t, J = 3.30 Hz, 1H), 3.98-4.13 (m, 3H), .68 (m, 1H), 3.35-3.55(m, 3H), 2.99 (s, 1H), 1.25 (d, J = 6.30 Hz, 3H); LC/MS [M + H] = 576.0.

Example 37 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(6-(bis(2-hydroxyethyl)amino)chloro-9H- puriny1)—3-ethyny1-3 ,4-dihydroxytetrahydrofurany1)methoxy)malonic acid 0 \/\N/\/OH 0 OH N HO O: N 0 «KC.

H6 bH Example 37 Proceeding as bed in Example 34 above but substituting propanolamine with diethanolamine and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR , 300 MHz) 5 8.16 (s, 1H), 7.22-7.29 (m, 2H), 6.99-7.09 (m, 3H), 6.02 (d, J = 7.33 Hz, 1H), 4.97 (d, J = 7.33 Hz, 1H), 4.00-4.37 (m, 2H), 4.29—4.34 (m, 2H), 4.03-4.13 (m, 3H), .91 (m, 4H), 3.46 (d, J = 14.92 Hz, 1H), 3.37 (d, J = 14.92 Hz, 1H), 2.98 (s, 1H); LC/MS [M + H] = 606.0.

Example 38 Synthesis of 2-benzy1(((2R, 3S, 4R, 5R)(2-chloro((2-methoxyethyl)amino)-9H-purin- 9-yl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 0 HN/\/OMe O OH N HO 0 «11 : N o N/ Cl HO: ”OH Example 38 Proceeding as described in Example 34 above but substituting propanolamine with 2- methoxyethylamine and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.17 (bs, 1H), 7.22—7.30 (m, 2H), 7.01—7.09 (m, 3H), 6.01 (d, J = 7.33 Hz, 1H), 4.98 (d, J = 7.33 Hz, 1H), 4.33 (t, J = 3.20 Hz, 1H),4.03-4.13 (m, 2H), 3.69-3.79 (m, 2H), 3.62 (t, J = 5.13 Hz, 2H), 3.47 (d, J = 14.89 Hz, 1H), 3.40 (s, 3H), 3.38 (d, J = 14.89 Hz, 1H), 2.99 (s, 1H), LC/MS [M + H] = 576.0. -l39- Example 39 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-ch1oro((2-methoxyethyl)-(methy1)amino)— 9H-purinyl)—3-ethyny1-3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid 0 \N/\/OMe 0 OH /N (N \N HO 0:0 NA01 H6 ’OH Example 39 Proceeding as described in e 34 above but substituting propanolamine with (2- methoxyethyl)methylamine and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.18 (bs, 1H), 7.22—7.29 (m, 2H), 6.99-7.09 (m, 3H), 6.02 (d, J = 721 Hz, 1H), 4.98 (d, J = 7.21 Hz, 1H), 4.32 (t, J = 3.41 Hz, 1H), 4.03—4.14 (m, 2H), 3.68 (t, J = 5.42 Hz, 2H), 3.34—3.49 (m, 7H), 3.36 (s, 3H), 2.99 (s, 1H); LC/MS [M + H] = 5900.

Example 40 Synthesis of 2-benzyl(((2R, SS, 4R, 5R)(2-chloro(((1—hydroxycyclobuty1)- methy1)amino)-9H—purin—9-y1)—3—ethynyl—3,4-dihydroxytetrahydrofuran—Z- hoxy)malonic acid Example 40 Proceeding as described in Example 34 above but tuting olamine with 1- (aminomethy1)cyclobutanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.18 (bs, 1H), 7.23—7.29 (m, 2H), 7.01—7.09 (m, 3H), 6.01 (d, J = 7.36 Hz, 1H), 4.98 (d, J = 7.36 Hz, 1H), 4.32 (t, J = 3.21 Hz, 1H),4.03-4.11 (m, 2H), 3.73—3.79 (m, 2H), 3.36—3.50 (m, 2H), 2.99 (s, 1H),2.03-2.21 (m, 4H), 1.59—1.85 (m, 2H), LC/MS [M + H] = 602.0.

Example 41 Synthesis of 2-benzyl(((2R, 3S, 4R, (2-chloro(3-hydroxyazetidiny1)-9H—purin y1)-3 -ethyny1-3 ,4-dihydroxytetrahydrofurany1)methoxy)ma1onic acid —140— WO 46403 0 OH /[EL/gN HO <N H6 bH Example 41 ding as described in Example 34 above but substituting propanolamine with azetidinol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.29 (bs, 1H), 7.21—7.29 (m, 2H), 6.99-7.11 (m, 3H), 6.01 (d, J = 7.33 Hz, 1H), 5.01 (d, J = 7.33 Hz, 1H), 4.57—4.82 (m, 3H), 4.33 (t, J = 3.39 Hz, 1H), 4.14—4.27 (m, 2H), 4.07 (qd, J = 4.04, 2.92 Hz, 2H), 3.30—3.50 (m, 2H), 2.98 (s, 1H), LC/MS [M +H] = 574.0.

Example 42 Synthesis of yl(((2R, 3S, 4R, 5R)-5—(2-chloro(2-(hydroxymethyl)azetidin-l-yl)—9H— purinyl)—3-ethynyl-3 ydroxytetrahydrofuran-Z-yl)methoxy)malonic acid 0 N O OH N \ </ 1 N HO 0:0 N NAG HO“ "OH Example 42 Proceeding as described in Example 34 above but substituting propanolamine with azetidin-Z-ylmethanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.17-8.29 (m, 1H), 7.22—7.28 (m, 2H), 701—7. 12 (m, 3H), .98—6.03 (m, 1H), 4.98 (d, J=7.30 Hz, 1H), 42741.45 (m, 3H), 4.00—4.13 (m, 3H), 3.83- 3.92 (m, 1H), 3.33—3.50 (m, 3H), 2.99 (s, 0.5H), 2.97 (s, 0.5H), 2.49—2.63 (m, 1H), .64 (m, 1H), LC/MS [M + H] = 588.0.

Example 43 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro((1-(hydroxymethyl)- cyclopropyl)amino)—9H—purinyl)—3-ethynyl-3,4—dihydroxytetrahydrofuran-Z- yl)methoxy)malonic acid —141— Example 43 Proceeding as described in Example 34 above but substituting propanolamine with (1- yclopropyl)methanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 6 8.18 (s, 1H), 7.22—7.32 (m, 2H), .11 (m, 3H), 6.01 (d, J=7.36 Hz, 1H), 4.96 (d, J=7.36 Hz, 1H), 4.32 (t, J=3.24 Hz, 1H),4.02—4.14(m, 2H), 3.76 (bs, 2H), 3.46 (d, J=15.04 Hz, 1H), 3.38 (d, J=15.04 Hz, 1H), 2.99 (s, 1H), 0.88—1.03 (m, 4H); LC/MS [M + H] = 588.0.

Example 44 Synthesis of 2-benzyl—2-(((2R,3S,4R,5R)—5-(2-chloro—6-(((1-hydroxycyclopropyl)- methyl)amino)-9H—purinyl)—3-ethyny1-3,4-dihydroxytetrahydrofuran-Z- yl)methoxy)malonic acid Example 44 ding as described in Example 34 above but substituting propanolamine with 1- (aminomethyl)cyclopropanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.18 (s, 1H), 7.08—7.25 (m, 5H), 5.98—6.02 (d, J=7 Hz, 1H), 4.93—4.97 (m, 2H), 4.30 (bs, 1H), 3.98—4.10(m, 2H), 3.71 (bs, 2H), 3.39—3.51 (m, 2H), 3.00— 3.13 (s 1H), 0.71—0.80 (m, 4H); LC/MS [M + H] = 588.2.

Example 45 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chl oro((cyclobutylmethyl)amino)-9H-pu1in- 9-yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid —142— Proceeding as described in Example 34 above but substituting propanolamine with cyclobutylmethanamine and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CDsOD, 300 MHz) 5 8.19 (s, 1H), 7.24—7.27 (m, 2H), 7.05—7.07 (m, 3H), 5.98- 6.01 (d, J: 8 Hz, 1H), 4.93—4.95 (d, J: 7 Hz, 1H2), 4.31—4.33 (bs, 1H), .10 (m, 2H), 3.58 (s, 2H), 3.39—3.48 (m, 2H), 3.00 (s, 1H), 2.66—2.71 (m, 1H), 2.12—2.15 (m, 2H) 1.84— 1.97 (m, 4H); LC/MS [M + H] = 586.2.

Example 46 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(3-(hydroxymethyl)azetidinyl)-9H- purin—9-yl)ethynyl—3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid NNACI Hcf bH Example 46 Proceeding as described in Example 34 above but substituting propanolamine with azetidinylmethanol and followed by ester hydrolysis with LiOH ed the title compound as a white solid. 1H NMR , 300 MHz) 5 8.09 (s, 1H), 7.05—7.25 (m, 5H), 6.00-6.02 (d, J: 7Hz, 1H), 4.93-4.97 (m, 1H), 4.33 (bs, 1H), 3.96-4.11 (m, 2H), 3.78 (bs, 2H), 3.36—3.40 (m, 6H), 2.99 (bs, 2H); LC/MS [M + H] = 588.2.

Example 47 sis of 2-benzyl-2—(((2R, 3S, 4R, 5R)—5-(2-chloro(3-hydroxy-3 -methy1azetidinyl)- 9H-purinyl)—3 -ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid —143— N \ <N/ N o: O 'N/Am —HO‘: 'l’OH Example 47 Proceeding as described in Example 34 above but substituting olamine with 3- azetidinol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.30 (s, 1H), 5 (m, 5H), .03 (d, J: 7H2, 1H), 4.98-5.01 (m, 1H), 4.33 (bs, 4H), 4.01—4.09 (m, 2H), 3.73 (bs, 1H), 3.35—3.47 (m, 2H), 2.98 (s, 1H), 1.57 (s, 3H); LC/MS [M + H] = 5882.

Example 48 Synthesis of 2-benzyl(((2R, 3S, 4R,5R)—5-(2-chloro((3 -hydroxycyclobutyl)— (methyl)amino)—9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuran-Z- yl)methoxy)malonic acid Example 48 Proceeding as described in Example 34 above but substituting propanolamine with 3- (methylamino)cyclobutanol and followed by ester hydrolysis with LiOH provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.26 (s, 1H), 6.96-7.28 (m, 5H), 6.02-6.04 (d, J: 7H2, 1H), .27 (bs, 1H), 4.98-5.02 (m, 1H), 4.33 (bs,2H), 3.95—4.15(m, 3H),3.36—3.51 (m, 4H), 2,99 (s, 1H), .69 (m, 2H), 2.22—2.25 (m, 2H); LC/MS [M + H] = 602.2.

Examples 49 & 50 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—ch1oro-9H—purinyl)-3 -ethyny1-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)-3 -ethoxyoxo-2—(3-(trifluoromethy1)- benzyl)propanoic acid —144— 2-(((2R, 3S, 4R, 5R)-5 -(6-aminochloro—9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z—yl)methoxy)—2-(3-(trifluoromethyl)benzyl)malonic acid TFA, DCM EtO o S 7 Cszcog, DMF Acd bAc O NH2 0 2 O 2 0 0E1 0 DE N 0 OH N (IN \N aq.LiOH,THF I </ l ‘1 </ l —> + EtO o: N N/ HO O N N :1": HO O o o N/ o N/ Cl on CI _Aco“' ”om Ho‘ ’OH Hcs ”OH CF3 CF3 CF3 e 49 Example 50 Proceeding as described in e 8 above but substituting furan with fluoromethyl )benzene provided the title compounds both as white solid by preparative reversed- phase HPLC purification. 2-(((2R, 3S, 4R, 5R)—5-(6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl )methoxy)—3-ethoxyoxo(3 uoromethyl)—benzyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 5 8.33 (bs, 1H), 7.51—7.54 (d, J=8 Hz, 2H), 7.38-7.40 (d, J=6 Hz, 1H), 7.21—7.26 (t, J=7 Hz, 1H), 6.00—6.04 (m, 1H), .02 (dt, J=4.7, 52 Hz, 1H), 4.36 (bs, 1H), 4.02—4.22 (m, 4H), 3.45—3.58 (m, 2H), 3.02—3.12 (d, J=29 Hz, 1H), 1.18—1.24 (m, 3H), LC/MS [M + H] = 614.2. 2-(((2R, 3S, 4R, 5R)—5-(6-aminochloro-9H—purinyl)-3 —ethynyl-3 ,4-dihydroxytetrahydro- furanyl)methoxy)(3-(trifluoromethyl)benzyl)malonic acid: 1H NMR (CD3OD, 300 MHz) 5 8.30 (s, 1H) 7.52—7.54 (d, J=9 Hz, 2H), 7.37—7.39 (d, J = 7 Hz, 1H), 7.23—7.25 , (t, J=7 Hz, 1H), 6.01-6.03 (d, J=7 Hz, 1H), 4.97—5.00 (d, J=7 Hz, 1H), 4.37 (bs, 1H), 4.12—4.14 (m, 2H), 3.44—3.57 (m, 2H), 3.01 (s, 1H), LC/MS [M + H] = 586.2.

Example 51 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro-9H—purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)(3-chlorobenzyl)malonic acid —145— O NH2 0 OH N HO O: N O N/ CI —H(§ "’OH Example 51 ding as described in Example 8 above but substituting furan with 3-chloro- benzene ed the title compound as a white solid by ative reversed-phase HPLC purification. 1H NMR (CD3OD, 300 MHz) 8 8.42 (s, 1H), 7.27 (bs, 1H), 7.14-7.15 (d, J: 6 Hz, 1H), 7.02—7.06 (m, 2H), .05 (d, J: 8 Hz, 1H), 5.03—5.06 (d, J: 7 Hz, 1H), 4.35—4.39 (m, 2H), 3.39—3.49 (m, 2H), 3.01 (s, 1H), 2.48—2.54 (t, J = 8 Hz, 1H) 2.22—2.32 (m, 1H); LC/MS [M +H] = 552.1.

Example 52 Synthesis of R, 3S, 4R, 5R)—5-(6-amino-2—chloro—9H—purin—9-yl)—3 —ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(3 -methoxybenzyl)malonic acid 0 NH2 0 OH N \ <’ l N HO 0:0 N NAG H6 ’OH Example 52 Proceeding as described in Example 8 above but substituting furan with 3-methoxy- benzene provided the title compound as a white solid by preparative reversed-phase HPLC purification. 1H NMR (CD3OD, 300 MHz) 6 8.40 (s, 1H), 6.96-7.02 (t, J : 8 Hz, 1H), 6.82 (bs, 2H), 6.59- 6.62 (m, 1H), 6.02-6.04 (d, J: 7 Hz, 1H), 5.01—5.04 (d, J: 8 Hz, 1H), 4.35—4.39 (m, 2H), 3.54 (s, 3H), 3.45—3.50 (m, 1H), 2.97 (s, 1H), 2.48-2.54 (t, J : 8 Hz, 1H) 2.22-2.32 (m, 1H), LC/MS [M + H] = 548.1.

Example 53 Synthesis of 2-([1, 1'-biphenyl]ylmethyl)—2-(((2R,3S,4R,5R)(6-aminochloro-9H— purinyl)-3—ethynyl—3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 53 Proceeding as described in Example 8 above but substituting furan with 3-biphenyl provided the title compound as a white solid by preparative reversed-phase HPLC ation. 1H NMR (CD3OD, 300 MHz) 8 8.23 (s, 1H), .43 (m, 9H), 5.99—6.02 (d, J: 7 Hz, 1H), 4.96—4.98 (d, J: 7 Hz, 1H), 4.35 (s, 1H), .15 (m, 2H), 3.41—3.57 (m, 2H), 3.04 (s, 1H): LC/MS [M + H] = 594.2.

Example 54 Synthesis of 2-(((2R, SS, 4R, 5R)(6—aminochloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z—yl)methoxy)-2—((2'—carboxy-[1,l'-biphenyl]-4—yl)methyl)malonic Example 54 Proceeding as described in Example 8 above but substituting furan with 3- methyl [1,1’-biphenyl]carboxylate provided the title compound as a White solid by preparative reversed-phase HPLC purification. 1H NMR (CD3OD, 300 MHz) 6 8.27 (s, 1H), 7.71-7.73 (d, J: 7 Hz, 1H), 7.29-7.48 (m, 4H), 7.14-7.16 (d, J: 8 Hz, 1H), 7.08—7.10(d,J= 8 Hz, 2H), 5.99-6.01 (d, J: 8 Hz, 1H), 4.88— 4.91 (m, 1H), 4.30 (bs, 1H), 4.03—4.12 (m, 2H), 3.39-3.57 (m, 2H), 2.99 (s, 1H); LC/MS [M + H] = 63 8.2.

Example 55 Synthesis of 2-(((2R, 3S, 4R, 5R)(6—aminochloro—9H-purinyl)ethyl-3,4- dihydroxytetrahydrofuran-Z-y1)methoxy)malonic acid —147— O N(Boc)2 0 N(Boc)z oWOEt O QB N Pd/C, H2, EtOAc Q </ f): TFA, DCM EC (NfN 0: N NA —> EtO O N 0 CI : O N , c| Acd i’OAc A06 bAc o NH2 0 NH2 0>2—CE (NIKKI 0 0H N aq.NaOH,THF Q (/ l ED 0: N NACI —> HO 0: N :NK o o N/ Cl Aw“ 'OAc Ho‘ ’OH Example 55 Ddiethyl 2-(((2R, 3R, 4S, 5R)—5—(N6,N6-bis-Bocchloro-9H—pu1in-9—y1)—3 -((lert— butoxycarbonyl)oxy)—4-fluorotetrahydrofurany1)methoxy)ma1onate (100 mg, 0.13 mmol) was dissolved in EtOAc (2 mL). The solution was purged three times with Argon gas and followed by careful addition of ium on carbon (20 mg, 10 wt%). The resulting slurry was purged three times with Argon gas and then placed under H2 (1 atm in a balloon). The reaction was held for 70 h at t temperature. The suspension was filtered through diatomaceous earth, washed with EtOAc (3 X 2 mL). The filtrate was trated to an oil which was then dissolved in DCM (1 mL) and ed by on of TFA (100 uL). The resulting solution was held overnight before it was concentrated. The pale yellow oil residue was dissolved in THF (1 mL) and cooled at 0 °C. To this reaction mixture was added 4M NaOH (100 uL) and the reaction was allowed to warm to ambient temperature over 14 h before it was concentrated. The crude residue was purified by preparative reversed-phase HPLC to provide the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 6 8.90 (s, 1H), 6.09—6.11 (d, J: 7 Hz, 1H), 4.69—4.72 (d, J: 8 Hz, 1H), 4.64 (bs, 1H), 4.19 (s, 1H), 3.83 (bs, 3H), 1.88—1.95 (m, 3H), 1.06—1.11 (t, J: 7 Hz, 3H); LC/MS [M + H] = 432.2.

Example 56 Synthesis of R,3S, 4R, 5R)(6—aminoch1oro—9H—purinyl)ethy1-3,4- dihydroxytetrahydrofuranyl)methoxy)—2-benzylmalonic acid o N “”2 0 QB Pd/C,H2 0 CE (’N l ,l 0 tOAc N 0] BO 0 —> EtO <N % Etc 0 O OAc BSA, TMSOTf Q MeCN _ ' Acd bAc Acd ISOAc aq.LiOH MeOH,THF O NH2 0 OH N HO O ddN O N/ CI H6 "0H Example 56 Step 1: A mixture of diethyl 2-benzyl(((2R,3R,4R)-3,4,5-triacetoxyethynyltetrahydro- furan—2-yl)methoxy)malonate (1.0 mmol, 549 mg) and palladium on carbon (100 mg, 10 wt%) in EtOH (5 mL) and EtOAc (5 mL) under an atmosphere of H2 was stirred for 24 h before it was filtered through diatomaceous earth, rinsed with EtOAc (3 X 5 mL). The filtrate was concentrated and purified via flash silica gel column chromatography to provide diethyl 2-benzyl(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethyltetrahydrofuranyl)methoxy)malonate.

Steps 2 — 3: Proceeding as described in Example 7 above but substituting diethyl 2-(pyridin ylmethy1)(((2R, 3R, 4R)-3 ,4, 5 -tri acetoxy-3 —ethyny1tetrahydrofuran—2-yl)methoxy)malonate with diethyl 2-benzy1(((2R, 3R, 4R)—3 ,4, 5-triacetoxy-3 -ethy1tetrahydrofuranyl)methoxy)- te and followed by ester ysis provided the title compound as a white solid via preparative reversed-phase HPLC purification. 1H NMR (CD3OD, 300 MHz) 5 8.46 (s, 1H), 7.18-7.20 (m, 2H), 7.04—7.09 (m, 3H), 6.01-6.04 (d, J 2 8 Hz, 1H), 4.63—4.66 (d, J: 8 Hz, 1H), 4.21 (bs, 1H), 3.76—3.96 (m, 2H), 3.39—3.52 (m, 2H), 1.76-1.83 (m, 2H), 0.98-1.03 (t, J: 7 Hz, 3H), LC/MS [M + H] = 522.2 Example 57 sis of R, 3S, 4R, 5R)—5-(6-amino-2—chloro—9H—purinyl)-3,4-dihydroxy vinyltetrahydrofuran-Z-yl)methoxy)benzylmalonic acid —149— o \ 0 QB Lindlar catalyst H2 0 (N l i O EtOH EtOAc N EtO o '—> (N 0 BO 0 [N10 Ajwom BSA. TMSOTf \ MeCN ~ .

Acd bAc aq. LiOH MeOH THF Ho HNl/Nki<’ Ho‘ ’OH Example 57 Step 1: A mixture of diethyl 2-benzyl(((2R,3R,4R)-3,4,5-triacetoxyethynyltetra- hydrofuran-Z—yl)methoxy)malonate (525 mg, 0.96 mmol) and Lindlar catalyst , 5 wt%) in EtOH (5 mL) and EtOAc (5 mL) under an atmosphere of Hz was stirred for 24 h before it was d through diatomaceous earth, rinsed with EtOAc (3 X 5 mL). The filtrate was concentrated and d via flash silica gel column tography to e diethyl 2-benzyl(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -viny1tetrahydrofuran-Z-yl)methoxy)malonate.

Steps 2 — 3: Proceeding as described in Example 7 above but substituting diethyl 2-(pyridin ylmethyl)—2-(((2R, 3R, 4R)-3 ,4, 5 -tri acetoxy-3 -ethynyltetrahydrofuran-Z-yl)methoxy)malonate with diethyl 2-benzyl(((2R, 3R, 4R)—3,4,5—triacetoxyvinyltetrahydrofuranyl)methoxy)- malonate and followed by ester hydrolysis provided the title compound as a white solid via preparative reversed—phase HPLC purification. 1H NMR (CD3OD, 300 MHz) 5 8.44 (s, 1H), 7.21—7.22 (m, 2H), 7.06-7.11 (m, 3H), 6.14— 6.23 (m, 1H), 6.08-6.10 (d, J= 8 Hz, 1H), 5.55—5.61 (m, 1H), 5.25—5.29 (m, 1H), 4.81 (s, 1H), 4.14 (bs, 1H), 3.91—3.94 (m, 1H), 3.62-3.65 (d, J: 9 Hz, 1H), 3.50—3.55 (d, J: 15 Hz, 1H), 3.39 (s, 1H); LC/MS [M + H] = 520.1.

Example 58 Synthesis of yl(((2R, 3S, 4R, 5R)—5-(5-chloro-3H—imidazo[4,5-b]pyridin—3-yl)-3— ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid O OE‘ (”ND 0 OH 0 OEt N \ </ \ /N H CI l H,THF. ( EC 0 —> —> l/ $0“ / HO O N ‘0 O N 0 N BSA,TMSOTf o N Cl C] \ DCE _ . , AGO bAC R _Aco‘: L’OAc H6 ’OH R = H, TMS Example 58 Step 1: To a solution of an anomeric mixture of diethyl 2-benzyl-2—(((2R, 3R, 4R)-3,4,5- triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (175 mg, 0.319 mmol) in dry dichloroethane (3.5 mL) was added 5—chloro—3H-imidazo[4,5-b]pyridine (65 mg, 0.422 mmol) and followed by addition bis(trimethylsilyl)acetamide (BSA) (0.28 mL, 1.12 mmol) via syringe. The mixture was heated at 95 °C under argon atmosphere for 1 h before it was cooled to ambient temperature and followed by addition of TMSOTf (0.09 mL, 0.494 mmol) via syringe. The resulting mixture was heated at 95 0C for 5 h before it was allowed to cool and diluted with water (30 mL) and extracted with EtOAc (30 mL). The organic phase was washed successively with equal volumes of saturated NaHCO3 solution and brine.

The aqueous phases was r extracted with EtOAc (2 x 30 mL). The combined organic phase was dried (MgSO4), filtered and concentrated. The crude residue was purification by preparative TLC (55% EtOAc in hexanes) to provide less polar diethyl yl—2- (((2R, 3R, 4R,5R)—3,4-diacetoxy(5-chloro—3H—imidazo[4,5-b]py1idinyl)((trimethyl— silyl)ethynyl)tetrahydrofuranyl)methoxy)malonate (44 mg) as a viscous oil and the desired diethyl 2-benzyl(((2R, 3R, 4R, 5R)—3 ,4-diacetoxy(5-chloro-3H—imidazo[4, 5-b]pyridin—3 - yl)ethynyltetrahydrofuranyl)methoxy)malonate (22 mg) as a viscous oil.

Step 2: To a solution of l yl(((2R, 3R, 4R, 4-diacetoxy(5-chloro-3H- imidazo[4,5—b]pyridinyl)ethynyltetrahydrofuranyl)methoxy)malonate (22 mg, 0.034 mmol) in THF (0.6 mL) was added a solution of 1N aq. LiOH (0.24 mL). Additional 1N aq.

LiOH (0.58 mL) was applied over a period of 2 days with a combination of periodically sonication and stirring. The reaction mixture was concentrated and diluted with water (10 mL) and EtOAc (10 mL), The reaction mixture was cooled at 0 °C and acidified to pH ~3 with 1N aq. HCl. The layers were separated and the aq. layer was r extracted with EtOAc (2 x 10 mL). The combined organic layer was dried over MgSO4, filtered and trated. The crude residue was purified by ative reversed-phase HPLC to provide the title compound as a off-white solid. 1H NMR (CD3OD, 300 MHz): 5 8.63 (bs, 1H), 8.01 (d, J: 8.14 Hz, 1H), 7.34 (d, J: 8.14 Hz, 1H), 7.29-7.23 (m, 2H), 7.07—6.99 (m, 3H), 6.21 (d, J= 7.33 Hz, 1H), 5.04 (d, J= 7.33 Hz, 1H), 4.34 (t, J: 3.02 Hz, 1H), 4.14—4.03 (m, 2H), 3.48 (d, J: 12.53 Hz, 1H), 3.37 (d, J: 12.53 Hz, 1H), 2.99 (s, 1H); LC/MS [M + H] = 5020.

Example 59 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(6-(benzylamino)—2-chloro-9H—purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid “380%.“;OK MOMCI “fig—7,? TBAF THF MOMO MOMO cozAll )J‘cozEt RhZOAc4 ijz'fl A020, AcOH QCLOZB BnBr OAC H so2 4 O COzEt <— .0 CS2003 cog/«u 002A" m~ 002A”*0 : : : : é I"O)(‘— AcO OAc MOMO MOMO (IN ‘N | BnNH2 N N/ COzEt DIPEA COZEl H dioxane NI— BSA,TMSOTf 002A" ”A 002A" (Dy—N MeCN - - AcO OAc AcO OAc NY\N aq LiOH COZH Np THF Step 1: A suspension of sodium hydride (60%, mineral dispersion; 1.91 g, 47.7 mmoL) in anhydrous THF (150 mL) was cooled to 0 OC and treated with a second solution of (3aR, 5R, 6R, 6aR)(((lerl—butyldimethylsilyl)oxy)methyl)—6-ethynyl-2,2-dimethyltetrahydro- furo[2,3-d][l,3]dioxolol (10g, 30.4mmoL) in THF (50 mL) over 15 s. After stirring mins at 0 °C, the mixture was warmed to room temperature and stirred for an additional 1.5 h. The mixture was then cooled back to 0 OC and treated with MOMCl (6.81mL, 80.7 mmoL, 2.6 eq) was added dropwise. Once the addition was complete, the cooling bath was removed and stirring was continued for 2 h at room temperature. The on was quenched by the slow addition of saturated aqueous ammonium chloride (50 mL), washed with water and extracted with ethyl acetate (100 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated. The crude product was purified via silica gel chromatography (30% ethyl acetate in s) to afford utyl-(((3aR, 5R, 6R, 6aR)ethynyl(methoxy- methoxy)—2,2-dimethyltetrahydrofuro[2,3 3]dioxol-5—yl)methoxy)dimethylsilane (9.95 g, 88% yield) as a white solid.

Step 2: A solution of the above alcohol (9.8g, 26.3mmoL) in anhydrous THF (100mL) was cooled to 0 OC and treated with 1N solution of tetrabutylammonium fluoride in THF (3 7mL, 36.8mmoL, 1.4 eq) over 15 minutes. After the addition is complete, the reaction was warmed to room temperature and stirred for 3h. When the reaction was te (3h), the les were concentrated ing a viscous residual oil which was dissolved in dichloromethane (5mL), loaded directly onto a silica gel column (~300cc) and d via silica gel chromatography, eluting with hexanes to 50% Ethyl acetate in hexanes to afford ((3aR, 5R, 6R, 6aR)ethynyl(methoxymethoxy)-2,2-dimethyltetrahydrofuro[2,3 -d][1,3]- dioxolyl)methanol (6.18g, 91% yield) as a white solid.

Step 3: A solution of the above alcohol (175 mg, 0.678 mmoL) in anhydrous benzene (8 mL) and l 3-(propenyl) 2-diazomalonate (188 mg, 0.949 mmoL) was treated with rhodium(II) acetate (5.8 mg, 0.013 mmoL, 0.02 eq) and warmed to 60-65 0C for 2 h. Once complete, the solution is concentrated, dissolved in dichloromethane (1.5 mL) and loaded directly onto a silica gel column (~100cc) and purified via silica gel chromatography, eluting with (0-50% ethyl acetate in hexanes) to afford 1-ethyl 3-propenyl 2- (((3Q‘R, 5R, 6R, 6aR)—6-ethynyl(methoxymethoxy)-2,2-dimethyltetrahydrofuro[2,3 -d] [1 ,3]- yl)methoxy)malonate (252 mg, 87%) (mixture of isomers) as a pale-yellow oil.

Step 4: While under nitrogen, a solution of malonate from the previous step (250 mg, 0.583 mmol) and benzyl e (0.42 mL, 3.5 mmol, 6 eq) in anhydrous DMF (8 mL) was treated with and cesium carbonate (760 mg, 2.33 mmol) and stirred at room temperature for 4 h.

Once complete, the reaction was filtered through a celite pad, washed with water and -l53- extracted with ethyl acetate. The ed organic layers were dried over sodium sulfate, filtered, and concentrated. The residual oil was dissolved in dichloromethane (2 mL), loaded onto a silica gel column (~100cc) eluting with 30% ethyl acetate in hexanes to afford l-ethyl 3 -propen—1-yl 2-benzyl(((3aR, 5R, 6R, 6aR)ethynyl—6-(methoxymethoxy)-2,2- dimethyltetrahydrofuro[2,3-a’][1,3]dioxolyl)methoxy)malonate (261 mg, 86%) (mixture of isomers) as a pale yellow oil.

Step 5: While under nitrogen, a water cooled (14-17 °C) solution of the acetonide from the last step (500 mg, 0.964 mmoL) in acetic acid (3.9 mL) was treated with acetic anhydride (0.965 mL, 10.3 mmoL, 10.7 eq) and trated sulfuric acid (410 uL, 0.326mmoL, 0.34 eq). The resulting solution was stirred for 4 h, diluted with water and extracted with ethyl acetate. The combined organic solution washed with sodium bicarbonate (aqueous, saturated; 100 mL), dried (Na2S04), filtered, and concentrated in vacuo. The al oil was dissolved in dichloromethane (2 mL), and purified on a Biotage flash chromatography system, eluted with hexanes to 50% ethyl acetate in hexanes. A diastereomeric mixture of 1- ethyl 3 -propenyl 2-benzyl(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 yltetrahydrofuran yl)methoxy)-malonate (420 mg, 8%) able s via silica gel chromatography, 40G silica gel ) was isolated as a clear oil.

Step 6: A suspension of 2,6—dichloroadenine (143 mg, 0.76 mmol, 1.01 eq) and MO- bis(trimethy1silyl)acetamide (0.24 mL, 0.97 mmol, 1.29 eq) in anhydrous acetonitrile (5 mL) was treated with a second solution of l-ethyl 3-((E)—prop-1—enyl) 2-benzyl(((2R, 3R, 4R)- 3,4,5-triacetoxyethynyltetrahydrofuranyl)-methoxy)malonate (143 mg, 0.75 mmol) in ous acetonitrile (15 mL), followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (0.18 mL, 1.0 mmol, 1.33 eq). After the addition was complete, the reaction was warmed to 50 °C for 18h, then cooled to room temperature; (Reaction begins a pale-yellow color and after 4h turns to a transparent amber). Once complete, saturated aqueous sodium bicarbonate was added, and the mixture was stirred for 10 minutes.

The crude product was then extracted with ethyl acetate (3x3 0mL) and the combined organic layer is dried (Na2SO4), filtered, and concentrated. The residue was dissolved in romethane and purified on a Biotage flash chromatography , eluted with hexanes to 50% ethyl acetate in hexanes to give l-ethyl 3-propenyl yl(((2R, 3R, 4R,5R)- —154— 3,4-diacetoxy—5-(2,6—dichloro—9H-purinyl)—3-ethynyltetrahydrofuran-Z— hoxy)malonate (as a mixture of isomers) as a white solid (400 mg, 77% yield).

Step 7: A solution of l-ethyl 3-prop-l-en-l—yl 2-benzyl(((2R, 3R, 4R, 5R)—3,4-diacetoxy (2,6-dichloro-9H—purinyl)—3-ethynyltetrahydrofuran-Z-yl)methoxy)-malonate (80 mg, 0.116 mmoL) in anhydrous dioxane (2 mL) was cooled to 0 0C was treated with DIPEA (30 uL, 0.174 mmoL, 1.5 eq) and benzylamine (13 uL, 0.116 mmoL, 1 eq). Once the addition was complete, the solution was warmed to room temperature with continued stirring overnight (18H). The mixture was diluted with ethyl acetate (50 mL) and washed with water (20mL). The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified via Biotage flash chromatography, g with 50% ethyl acetate in hexanes to give l-ethyl 3-propen-l-yl 2-benzyl—2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6— (benzylamino)chloro-9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (as a mixture ofisomers, ~l : 1) as a white solid (75mg, 85% yield).

Step 8: A solution of l enyl yl(((2R, 3R, 4R, 5R)-3,4-diacetoxy—5- (6-(benzylamino)chloro-9H—purinyl)-3 -ethynyltetrahydrofuran-Z-yl)methoxy)malonate from the last step (70 mg, 0.092 mmoL) in THF (1 mL) was treated with a LiOH solution (31 mg, 1.35 mmoL, 15 eq; in 1 mL water) and stirred ght. The resulting solution was ed with 2N HCl to pH 3 and the resulting suspension was stirred for 10 min., then filtered, washed with cold water and dried. The title compound was isolated as a white solid (50 mg, 89% yield). 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 6 7.98 (s. 1H), 7.25-6.84 (m, 10H), 5.85 (d, J = 6.4 Hz, 1H), 4.63 (s, 2H), 4.54 (d, J = 6.4 Hz, 1H), 4.17 (t, J = 3.2 Hz, 1H), 3.88 (qd, J = 10.3, 3.3 Hz, 2H), 3.36-3.16 (m, 2H), 2.49 (s, 1H). HPLC: 9.97 min, 97.0%. ESI-MS (m/Z): [M]+ calcd for ClN508, 608.15, found 608.1.

Example 60 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((tetrahydro-ZH-pyranyl)amino)- 9H-purinyl)—3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 60 The title compound was prepared in a manner ous to that set forth in Example 59, except tetrahydro-2H—pyranamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 6 8.09 (s, 1H), 7.18-7.12 (m, 2H), 7.01 (dd, J = 12.1, 7.2 Hz, 3H), 5.90 (d, J = 6.3 Hz, 1H), 4.57 (d, J = 6.3 Hz, 1H), 4.25 (t, J = 3.1 Hz, 2H), 4.00-3.89 (m, 4H), 3.51 (td, J = 11.6, 2.2 Hz, 2H), 3.42-3.330 (m, 2H), 2.52 (s, 1H), 1.94 (d, J = 13.0 Hz, 2H), 1.57 (td, J = 11.2, 3.5 Hz, 2H). ESI—MS (m/z): [M]+ calcd for C27H28C1N509, 602.16, found 602.5.

Example 61 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((2-(diethylamino)ethyl)—amino)—9H— purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)—malonic acid Ph COZH _N \+ H o N’— N\/\N/\ HOZC 0y \N / / i '_ N\ HO 6H :8 Example 61 The title compound was prepared in a manner ous to that set forth in Example 59, except N1,Nl -diethylethane-1,2-diamine was used in place of benzylamine in step 7. 1HNMR (400 MHz, DMSO-66): 9.01 (s, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 7.23—7.03 (m, 5H), 6.16 (s, 1H), 5.96 (d, J = 7.0 Hz, 1H), 5.84 (d, J = 6.9 Hz, 1H), 4.59 (t, J = 7.1 Hz, 1H), 4.13 (dd, J = 6.7, 2.7 Hz, 1H), .55 (m, 4H), 3.53 (s, 1H), 330—3. 15 (m, 6H), 3.06-2.97 (m, 2H), 126-1. 12 (m, 6H). ESI-MS (m/z): [M]+ calcd for C28H33C1N608, 617.20, found 6175.

Example 62 sis of 2-benzyl(((2R, 35, 4R,5R)—5-(2-chloro-6—(((R)-l—phenylethyl)amino)-9H— purinyl)—3-ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 1 L N\ N /H6 6H \gl Example 62 The title compound was prepared in a manner analogous to that set forth in e 59, except (R)-l-phenylethan-l-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 5 8.25 (s, 1H), .27 (m, 4H), 7.23-6.94 (m, 6H), 5.91 (dd, J = 6.2, 1.7 Hz, 1H), 5.46 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 6.2 Hz, 1H), 4.25 (t, J = 2.4 Hz, 1H), 3.98-3.83 (m, 2H), 3.32 (dd, J = 6.3, 1.7 Hz, 2H), 2.48 (d, J = 1.7 Hz, 1H), 1.59 (dd, J = 6.9, 1.7 Hz, 3H). ESI—MS (m/z): [M]+ calcd for C30H28C1N508, , found 6221.

Example 63 Synthesis of 2-benzyl(((2R,3S, 4R,5R)(2-chloro(((S)phenylethyl)amino)-9H-purin- 9-yl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 63 The title compound was prepared in a manner analogous to that set forth in Example 59, except (S)—l-phenylethan-l-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5: 1) 6 8.11 (s, 1H), 7.40-7.28 (m, 4H), 7.23-6.93 (m, 6H), 5.90 (d, J = 5.8 Hz, 1H), 5.45 (s, 1H), 4.52 (d, J = 5.8 Hz, 1H), 4.35—4.22 (m, 1H), 3.99 (t, J = 2.4 Hz, 2H), 3.42—3.25 (m, 2H), 2.50 (s, 1H), 1.58 (d, J = 6.9 Hz, 3H). ESI-MS (m/z): [M]+ calcd for C30H28C1N508, 622.16; found 622.2.

Example 64 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((tetrahydrofuranyl)-amino)-9H— purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)-malonic acid -l57- Ph 2 _N \fi\ H 0 N’— N / : '_ N\ /Hc') (3H \8 Example 64 The title compound was prepared in a manner ous to that set forth in e 59, except tetrahydrofuran-3 -amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDC13/CD3OD = 5:1) 5 8.10 (s, 1H), 7.19-6.92 (m, 5H), 5.90 (d, J = 6.3 Hz, 1H), 4.72 (s, 1H), 4.58 (d, J = 6.3 Hz, 1H) 4.25 (t, J = 3.1 Hz, 1H), 3.94 (tp, J = 7.0, 4.0, 3.3 Hz, 3H), 3.70 (dt, J = 9.4, 3.6 Hz, 2H), 3.43—3.24 (m, 2H), 2.52 (s, 1H), 2.29 (dq, J = 13.2, 7.6 Hz, 1H), 1.93 (s, 1H). ESI-MS (m/z): [M]+ calcd for C26H26C1N509, 588.14, found 5883.

Example 65 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro((S)hydroxypyrrolidinyl)-9H— purinyl)—3-ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid Ph COZH _N H\ o NI— no OH / : L N\ 116 6H Y Example 65 The title nd was prepared in a manner analogous to that set forth in Example 59, except (S)—pyrrolidin-3 -01 was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 6 8.10 (s, 1H), 7.22-6.92 (m, 5H), 5.92 (d, J = .4 Hz, 1H), 4.55-4.48 (m, 2H), 4.29 (t, J = 3.7 Hz, 1H), 4.25-3.85 (m, 4H), 3.80-3.65 (m, 2H), 3.35—3.24 (m, 2H), 2.51 (s, 1H), 2.08—1.98 (m, 2H). ESI-MS (m/z): [M]+ calcd for C26H26C1N509, 588.14; found 588.2.

Example 66 Synthesis of 2-benzyl(((2R, SS, 4R, 5R)(2-chloro(ethyl(methyl)amino)-9H-purinyl)— 3 yl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid Ph COzH —N \ \+0 0 N’— N\/ HOZC 3—7! / / : '_ N\ /Hc'> ()H Y Example 66 The title compound was prepared in a manner analogous to that set forth in Example 59, except N—methylethanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDC13/CD3OD = 5:1) 5 8.05 (s, 1H), 7.24—7.02 (m, 5H), 5.92 (d, J = 4.8 HZ, 1H), 4.46 (dd, J = 4.8, 1.3 HZ, 1H), 4.32 (dd, J = 4.9, 3.2 HZ, 1H), 4.05 (dd, J = 8.5, 4.0 Hz, 2H), 3.44—3.30 (m, 2H), 3.10-2.85 (m, 7H), 2.53 (s, 1H), 1.22 (t, J = 7.1 Hz, 3H). ESI-MS (m/z): [M]+ calcd for C25H26C1N508, ; found 560.5.

Example 67 Synthesis of 2-benzyl(((2R, 3S, 4R, (2-chloro((2-fluorobenzyl)amino)-9H—purin yl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)ma1onic acid Ph 2 \+ N,——N H El 1 O N HOZC 031’ \N F : '. N\ /H(3 6H \gl Example 67 The title compound was prepared in a manner analogous to that set forth in Example 59, except (2-fluorophenyl)methanamine was used in place of amine in step 7. 1H NMR (400 MHZ, CDCl3/CD3OD = 5:1) 5 8.29 (s, 1H), 7.47-7.36 (In, 1H), 7.26-6.94 (m, 8H), 5.94 (d, J = 6.2 Hz, 1H), 4.82-4.76 (m, 2H), 4.60 (d, J = 6.2 Hz, 1H),4.35-4.23 (m, 1H), 3.98-3.84 (m, 2H), 3.44—3.30 (m, 2H), 2.46 (s, 1H). ESI-MS (m/z): [M]+ calcd for C29H25ClFNsOs, 626.14, found 626.7.

Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((4-fluorobenzyl)amino)—9H-purin yl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 68 The title nd was prepared in a manner analogous to that set forth in Example 59, except (4-fluorophenyl)methanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 5 8.49 (s, 1H), 7.37 (dd, J = 8.4, 5.3 Hz, 2H), 7.24-6.89 (m, 7H), 5.97 (d, J = 6.3 Hz, 1H), 4.72 (s, 2H), 4.63 (d, J = 6.3 Hz, 1H), 47-428 (m, 1H), 4.06-3.87 (m, 2H), 3.46-3.26 (m, 2H), 2.54 (s, 1H). ESI-MS (m/z): [M]+ calcd for C29H25ClFN508, 626.14, found 626.4.

Example 69 Synthesis of 2-benzyl—2-(((2R, 3S, 4R, 5R)—5-(2-chloro(((R)—2,3 -dihydro- 1H—inden— l - yl)amino)-9H—purinyl)—3 -ethynyl-3 ydroxytetrahydrofuranyl)methoxy)-malonic Ph 2 _N H\ H o N,— N,,, / .' L N\ ’16 OH \( Example69 The title compound was prepared in a manner analogous to that set forth in Example 59, except (R)-2,3-dihydro-lH-inden-l-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDCl3/CD3OD = 5: 1) 5 8.30 (s, 1H), 7.29-6.97 (m, 9H), 5.95 (d, J = 6.2 Hz, 1H), 5.81 (t, J = 7.1 Hz, 1H), 4.59 (d, J = 6.3 Hz, 1H), 4.25 (d, J = 3.1 Hz, 1H), 3.94—3.73 (m, 2H), 3.40—3.31 (m, 2H), 3.07 (ddd, J = 14.0, 8.7, 4.8 Hz, 1H), 2.89 (dt, J = 158,77 Hz, 1H), .58 (m, 1H), 2.45 (s, 1H), 2.00 (dd, J = 13.6, 7.1 Hz, 1H). ESI-MS (m/z): [M]+ calcd for C31H28C1N508, 634.16; found 634.8.

Example 70 sis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro(phenethylamino)-9H—purinyl)—3 - ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid -l60- Ph COZH \+ — H o N’— N / : '_ N\ /HO OH Y Example70 The title compound was prepared in a manner ous to that set forth in Example 59, except 2-phenylethan-l-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CDC13/CD3OD = 5:1) 5 8.14 (s, 1H), 7.26-6.91 (m, 10H), 5.91 (d, J = 6.2 Hz, 1H), 4.57 (d, J = 6.2 HZ, 1H), 4.27 (t, J = 3.2 HZ, 1H), 3.96 (t, J = 4.0 HZ, 2H), 3.78 (m, 2H), 3.45—3.29 (m, 2H), 2.93 (t, J = 7.3 Hz,2H), 2.52 (s, 1H). ESI-MS (m/Z): [M]+ calcd for C30H28C1N508, 622.16; found 622.5.

Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(methylamino)-9H—purinyl) ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph 2 _N H O NI— N\ / .' L N\ /H6 6H Y Example 71 The title nd was prepared in a manner analogous to that set forth in Example 59, except methylamine was used in place of benzylamine in step 7. 1HWR (400 MHz, CD3OD) 5 8.18 (s, 1H), 7.29—7.20 (m, 2H), 7.04 (dd, J = 5.1, 1.9 Hz, 3H), 5.99 (d, J = 7.4 Hz, 1H), 4.99 (d, J=7 Hz, 1H), 4.30 (t, J = 3.3 Hz, 11-4.01 (m, 2H), 3.49—3.34 (m, 2H), 3.06 (s, 3H), 2.98 (s, 1H). ESI-MS (m/Z): [M]+ calcd for C23H22ClN508, 532.12, found 532.1.

Example 72 Synthesis of 2-benzyl-2—(((2R, 3S, 4R, 5R)—5 -(2-chloro-6—(((S)-2,3 -dihydro- 1H-inden- l — yl)amino)—9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)-malonic -l6l- Ph 2 _N \+ H o N’— N H020 017’ \N / : '_ N\ /Ho 61-1 \gl Example 72 The title compound was ed in a manner analogous to that set forth in Example 59, except (S)—2,3-dihydro-1H-inden-l-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.14 (s, 41-7.13 (m, 6H), 7.04 (t, J = 3.5 Hz, 3H), 6.01 (d, J = 7.4 Hz, 1H), 5.88-5.76 (m, 1H), 4.99 (d, J = 7.4 Hz, 1H), 4.32 (t, J = 3.3 Hz, 1H), 4.06 (dd, J = 5.5, 3.3 Hz, 2H), 3.53—3.34 (m, 2H), 3.13—3.05 (m, 1H), 3.00 (s, 1H), 2.99-2.87 (m, 1H), 2.67 (dd, J = 12.5, 4.2 Hz, 1H), 2.02 (dd, J = 12.8, 7.7 Hz, 1H). ESI-MS (m/z): [M]+ calcd for C31H28C1N508, 634.16, found 634.5.

Example 73 Synthesis of 2-benzy1(((2R, 35, 4R,5R)(2-chloro(ethylamino)-9H—purinyl)—3- l-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph 2 \7Lo H o N’——N N\/ HOZC y \N HO OH NY Example73 The title compound was prepared in a manner analogous to that set forth in Example 59, except ethylamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.16 (s, 1H), 740—7. 19 (m, 2H), 7.04 (dd, J = 5.1, 1.9 Hz, 3H), 5.98 (d, J = 7.4 Hz, 1H), 4.97 (d, J = 7.4 Hz, 1H), 430 (T, J = 3.3 Hz, 1H), 4.14-3.98 (m, 2H), 3.57 (d, J = 7.8 Hz, 2H), 3.49—3.33 (m, 2H), 2.98 (s, 1H), 1.28 (t, J = 7.2 Hz, 3H).

ESI-MS (m/z): [M]+ calcd for C24H24ClN508, 546.13; found 546.].

Example 74 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(6-((S)—sec-butylamino)chloro-9H—purinyl)ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid -l62- Ph COZH \+ — O N,— H020 017’ N\ \N “M? /:'_ /HOCHE Example 74 The title compound was prepared in a manner analogous to that set forth in Example 59, except (S)—butanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.13 (s, 1H), 7.32—7.15 (m, 2H), 7.14-6.98 (m, 3H), 5.98 (d, J = 7.4 Hz, 1H), 4.97 (d, J = 7.4 Hz, 1H), 4.31 (t, J = 3.2 Hz, 1H), 4.24 (s, 1H), 4.14-3.97 (m, 2H), .33 (m, 2H), 2.99 (s, 1H), 1.63 (q, J = 7.2 Hz, 2H), 1.27 (d, J = 6.5 Hz, 3H), O.97(t, J = 7.4 Hz, 3H). ESI-MS (m/z): [M]+ calcd for C26H28C1N508, 574.16; found 574.1.

Synthesis of 2-benzyl(((2R,3 S,4R,5R)-5—(2-chloro((cyclopropylmethyl)— 1)amino)-9H-purinyl)-3—ethynyl-3,4-dihydroxytetrahydrofuran yl)methoxy)malonic acid PMCOZH H020l7!qufi HO OH Example 75 The title compound was prepared in a manner analogous to that set forth in Example 59, except 1-cyclopropyl-N—methylmethanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.15 (s, 1H), 736-7. 18 (m, 2H), 7.03 (dd, J = 5.2, 2.0 Hz, 3H), 6.00 (d, J = 7.3 Hz, 1H), 4.97 (d, J = 7.3 Hz, 1H), 4.30 (dd, J = 4.1, 2.8 Hz, 1H), 4.07 (qd, J = 10.2, 3.5 Hz, 2H), 3.52—3.31 (m, 7H), 2.98 (s, 1H), 1.20—1.12 (m, 1H), 0.54 (dd, J = 8.2, 1.8 Hz, 2H), 0.45—030 (m, 2H). ESI-MS (m/z): [M]+ calcd for C27H28C1N508, 586.16; found 586.9 Example 76 sis of 2-benzy1(((2R, SS, 4R,5R)(6-((carboxymethyl)amino)chloro-9H-purin yl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid -l63- HOZC \NVC02H HO OH Example 76 The title compound was prepared in a manner analogous to that set forth in Example 59, except 2-amino-N,N—dimethylacetamide was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.21 (s, 1H), 7.38-7.14 (m, 2H), 7.12-6.98 (m, 3H), 6.11 (d, J = 7.4 Hz, 1H), 4.96 (d, J = 7.3 Hz, 1H), 4.30 (q, J = 4.7, 4.0 Hz, 2H), 4.09-4.02 (m, 2H), 3.54-3.33 (m, 2H), 2.97 (s, 1H). ESI—MS (m/z): [M]' calcd for C24H22C1N5010, 574.11; found 5741.

Example 77 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro((2-chlorobenzyl)amino)-9H-purin yl)-3 -ethynyl-3 ,4—dihydroxytetrahydrofuranyl)methoxy)ma1onic acid Ph 2 _N Ho?031 H o N’— NV \N 6;.

/ . N\ /HO OH Y Example77 The title compound was prepared in a manner ous to that set forth in Example 59, except (2-chlorophenyl)—methanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.17 (s, 1H), 7.43 (m, 2H), 7.28 (m, 3H), 7.22 (m, 1H), 7.00 (m, 3H), 5.99 (d, J: 7.4Hz, 1H), 4.98 (d, J: 7.4Hz, 1H), 4.82 (m, 2H), 4.30 (s, 1H), 4.05 (s, 2H), 3.42 (m, 2H), 2.98 (s, 1H). LC-MS: m/z = 597 H); m/z = 292 ose fragment).

Example 78 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((pyridinylmethyl)amino)—9H— purin—9-yl)ethynyl—3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid HO2Cy«W0 /HO ;OH Example 78 The title compound was prepared in a manner ous to that set forth in Example 59, except pyridinylmethanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 9.08 (bs, 1H), 8.73 (d, J: 5.7Hz, 2H), 8.51 (s, 1H), 7.68 (d, J = 5.6Hz, 2H), 7.22 (m, 2H), 7.06 (m, 3H), 5.82 (d, J: 7.7Hz, 1H), 4.93 (d, J: 6.9Hz, 1H), 4.87 (d, J: 7.6Hz, 1H), 4.20 (m, 1H), 4.03 (m, 2H), 3.86 (m, 2H), 3.62 (s, 1H), 3.27 (m, 2H).

HPLC: Room temperature = 5.74 min, 97.7%. LC-MS: m/z = 610 (M+); m/z = 261 (M- ribose fragment).

Synthesis of 2-benzyl-2—(((2R, 3S, 4R, (2-chloro-6—morpholino-9H—purin—9-yl)—3— ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph COzH /=N (\ 33%ijwa: ‘ N\N H0 6H x Example 79 The title compound was prepared in a manner analogous to that set forth in Example 59, except morpholine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.20 (s, 1H), 7.22 (m, 2H), 7.01 (m, 3H), 6.00 (d, J= 7.6Hz, 1H), 4.99 (d, J: 7.6Hz, 1H), 4.30 (m, 1H), 4.22 (m, 4H), 4.04 (m, 2H), 3.78 (m, 4H), 3.47 (m, 2H), 2.99 (s, 1H). HPLC: 8.16 min, 98.2%. LC-MS: m/z = 588 (M+), 544 (M-COzH), m/z = 240 (M-ribose fragment).

Example 80 Synthesis of 2-(((2R, 3S, 4R, 5R)-5—(6-(azepan- l -yl)—2-chloro-9H-purin-9—yl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)—2-benzylmalonic acid Example 80 The title nd was prepared in a manner analogous to that set forth in Example 59, except azepane was used in place of benzylamine in step 7. -l65- 1H NMR (400 MHz, CD3OD) 8 8.16 (s, 1H), 7.22 (m, 2H), 7.00 (m, 3H), 5.99 (d, J: 7.6Hz, 1H), 4.98 (d, J: 7.6Hz, 1H), 4.29 (m, 3H), 4.07 (m, 2H), 3.85 (m, 2H), 3.40 (m, 2H), 2.97 (s, 1H), 1.85 (m, 4H), 1.59 (m, 4H). I-IPLC: 9.67min, 98.1%. LC-MS: m/z = 600 (M+), m/z = 556 (M-COzH), m/z = 252 (M-ribose fragment).

Example 81 Synthesis of yl(((2R, 3S, 4R, 5R)—5—(2-chloro(cyclobutyl(methyl)amino)—9H-purin- 9-yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph 2 \7k /= 0 N HQC X)\W NC) / _' L N\ ”M0 0H \( Example 81 The title compound was prepared in a manner analogous to that set forth in Example 59, except N—methylcyclobutanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.21 (s, 1H), 7.21 (dd, J = 7.0, 2.6 Hz, 2H), 6.99 (m, 3H), .99 (d, J: 7.3 Hz, 1H), 5.74 (br s, 1H), 4.96 (d, J: 7.2 Hz, 1H), 4.28 (dd, J: 4.1, 2.8 Hz, 1H), 4.06 (dd, J: 10.2, 4.2 Hz, 1H), 4.01 (dd, J: 10.2, 2.9 Hz, 1H), 3.45 — 3.31 (m, 5H), 2.96 (s, 1H), 2.35 (q, J = 10.0 Hz, 2H), 2.23 (m, 2H), 1.87 — 1.63 (m, 2H); HPLC: 9.45 min, 98.9%. LC-MS: m/z = 587 (M+H), 543 (M-COzH), m/z = 238 (M-ribose nt).

Synthesis of 2-benzy1(((2R, 3S, 4R, 5R)(2-chloro(isopropyl(methyl)amino)-9H—purin- 9-yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph 2 \ O “F_N “r / : '_ N\ ’10 6H \( Example 82 The title compound was prepared in a manner analogous to that set forth in Example 59, except N—methylpropanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.17 (s, 1H), 7.21 (dd, J: 7.3, 2.2 Hz, 2H), 7.03 — 6.94 (m, 3H), 5.98 (d, J: 7.3 Hz, 1H), 4.97 (d, J: 7.3 Hz, 1H), 4.28 (dd, J: 4.0, 2.8 Hz, 1H), 4.04 (qd, J: 10.2, 3.5 Hz, 2H), 3.45 — 3.31 (m, 6H), 2.96 (s, 1H), 1.25 (d, J: 6.8 Hz, 6H), HPLC: 9.08 min, 99.9%. LC-MS: m/z = 575 (M+H), 531 (M-COzH), m/z = 226 (M-ribose Example 83 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(cyclopropylamino)-9H—purinyl)— 3 -ethynyl-3 ,4-dihydroxytetrahydrofurany1)methoxy)malonic acid Ph 2 l——N \+ H 0 N H020 017mm \V / _' '_ N\ /Hc‘> 6H \8 Example 83 The title compound was prepared in a manner analogous to that set forth in Example 59, except cyclopropanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.14 (s, 1H), 7.23 (dd, J: 6.7, 2.8 Hz, 2H), 7.01 (m, 3H), .97 (d, J: 7.4 Hz, 1H), 4.95 (d, J: 7.4 Hz, 1H), 4.28 (t, J: 3.3 Hz, 1H), 4.10 — 3.97 (m, 2H), 3.49 — 3.30 (m, 2H), 2.99 (m, 1H), 2.96 (s, 1H), 0.92 — 0.78 (m, 2H), 0.66 — 0.54 (m, 2H); HPLC: 7.83 min, 99.1%. LC-MS: m/z = 559 (M+H).

Example 84 Synthesis of 2-benzyl(((2R, 3S, 4R, (2-chloro((pyridin-3 -ylmethyl)amino)—9H— purinyl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)ma1onic acid Example 84 The title compound was ed in a manner analogous to that set forth in Example 59, except pyridinylmethanamine was used in place of benzylamine in step 7. 1H1\H\4R (400 MHz, CD3OD) 5 8.87 (s, 1H), 8.70 (d, J: 5.6 Hz, 1H), 8.56 (d, J: 8.1 Hz, 1H), 8.22 (s, 1H), 7.97 (dd, J: 8.1, 5.7 Hz, 1H), 7.21 (dd, J: 6.5, 3.0 Hz, 2H), 7.07 — 6.90 (m, 3H), 5.97 (d, J: 7.4 Hz, 1H), 4.96 (d, J: 7.4 Hz, 1H), 4.92 (m, 2H), 4.29 (t, J: 3.4 Hz, -l67- 1H), 4.04 (qd, J = 10.2, 3.4 Hz, 2H), 3.38 (m, 2H), 2.97 (s, 1H); HPLC: 5.82 min, 99.9%.

LC-MS: m/z = 261 (M-ribose fragment).

Example 85 Synthesis of 2-benzyl(((2R, SS, 4R, (2-chl oro((3-fluorobenzy1)amino)—9H-purin yl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)ma1onic acid F’h\7LOCOzH o NWHQF H020 y /\ é 5 ' HO 6H NYN The title compound was prepared in a manner analogous to that set forth in Example 59, except (3 -fluorophenyl)methanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.19 (s, 1H), 7.32 (td, J: 8.0, 5.9 Hz, 1H), 7.24 — 7.16 (m, 3H), 7.12 (dd, J: 9.8, 2.3 Hz, 1H), 7.06 — 6.78 (m, 4H), 5.98 (d, J: 7.3 Hz, 1H), 4.94 (d, J: 7.3 Hz, 1H), 4.74 (m, 2H), 4.29 (t, J: 3.3 Hz, 1H), 4.03 (qd, .1: 10.3, 3.5 Hz, 2H), 3.47 — 3.26 (m, 2H), 2.97 (s, 1H); HPLC: 9.04 min, 99.5%. LC-MS: m/z = 627 (M+H), 583 (M- COzH), m/z = 278 (M-ribose fragment).

Example 86 Synthesis of 2-benzyl(((2R, SS, 4R, 5R)—5-(2-chloro((3-chlorobenzy1)amino)-9H-purin yl)-3 yl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)ma1onic acid Ph 2 _N l S O N,— N CI é .—‘ a HO OH NY Example 86 The title compound was prepared in a manner analogous to that set forth in Example 59, except (3 -chlorophenyl)methanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.18 (s, 1H), 7.40 (s, 1H), 7.34 — 7.05 (m, 5H), 6.98 (m, 3H), .97 (d, J: 7.4 Hz, 1H), 4.95 (d, J: 7.4 Hz, 1H), 4.72 (m, 2H), 4.29 (t, J: 3.3 Hz, 1H), 4.09 -l68- WO 46403 — 3.87 (m, 2H), 3.46 — 3.31 (m, 2H), 2.97 (s, 1H); HPLC: 9.45 min, 98.3%. LC-MS: m/z 643 (M+H), 598 (M-COzH), m/z = 294 (M-ribose fragment).

Example 87 Synthesis of 2-benzyl(((2R, 3S, 4R, (2-chloro((4-chlorobenzyl)amino)-9H-purin y1)-3 -ethyny1-3 ,4-dihydroxytetrahydrofuranyl)methoxy)ma1onic acid Ph 2 —N H O N’— N\/©/ O / H020 \ HO OH NYN Example87 The title compound was prepared in a manner ous to that set forth in Example 59, except (4-ch1oropheny1)methanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.17 (s, 1H), 7.36 (d, J: 8.6 Hz, 2H), 7.31 (d, J: 8.5 Hz, 1H), 7.21 (dd, J: 6.8, 2.8 Hz, 2H), 7.02 — 6.96 (m, 3H), 5.97 (d, J: 7.3 Hz, 1H), 4.94 (d, J: 7.3 Hz, 1H), 4.71 (m, 2H), 4.29 (t, J: 3.3 Hz, 1H), 4.03 (qd, J: 10.2, 3.4 Hz, 2H), 3.46 — 3.30 (m, 2H), 2.96 (s, 1H), HPLC: 9.50 min, 98.7%. LC-MS: m/z = 643 (M+H), 598 (M- COzH), m/z = 294 (M-ribose fragment).

Example 88 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(6-(azetidinyl)chloro-9H—purinyl)—3-ethyny1-3,4- dihydroxytetrahydrofuran-Z—yl)methoxy)—2—benzylmalonic acid Ph 2 W o N’——N [D : '_ N\ /Ho 6H :2 Example 88 The title compound was prepared in a manner analogous to that set forth in Example 59, except azetidine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 8 8.25 (s, 1H), 7.24 — 7.08 (m, 2H), 7.10 — 6.85 (m, 3H), 5.97 (d, J: 7.4 Hz, 1H), 4.98 (d, J: 7.3 Hz, 1H), 4.43 (m, 4H), 4.29 (dd, J: 41,28 Hz, 1H), 4.07 (dd, .1: 10.2, 4.2 Hz, 1H), 4.00 (dd, J: 10.2, 2.9 Hz, 1H), 3.42 (d, J: 15.0 Hz, 1H), -l69- 3.34 (d, J: 12.3 Hz, 2H), 2.95 (s, 1H), 2.51 (q, J: 7.7 Hz, 2H); HPLC: 7.58 min, 99.5%.

LC-MS: m/z = 558 (M+H), 554 (M-COzH), m/z = 210 (M-ribose fragment).

Example 89 Synthesis of 2-benzy1(((2R, 3S, 4R, 5R)(2-chloro(dimethylamino)-9H-purinyl) ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph COZH _N \+ o N]— I\\I\ é i ‘ _ N \ HO OH Y The title compound was prepared in a manner analogous to that set forth in Example 59, except dimethylamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.17 (s, 1H), 7.22 (dd, J= 7.5, 2.0 Hz, 2H), 7.05 — 6.89 (m, 3H), 5.98 (d, J: 7.2 Hz, 1H), 4.96 (d, J: 7.3 Hz, 1H), 4.28 (dd, J: 4.0, 2.9 Hz, 1H), 4.04 (qd, J: 10.2, 3.5 Hz, 2H), 3.55 — 3.31 (m, 8H), 2.95 (s, 1H); HPLC: 8.16 min, 999%. LC- MS: m/z = 546 (M+H), 502 (M-COzH), m/z = 198 (M-ribose fragment).

Example 90 sis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro(pyrrolidinyl)—9H—purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofuran—2-y1)methoxy)malonic acid Ph 002H Example 90 The title compound was prepared in a manner analogous to that set forth in Example 59, except pyrrolidine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.21 (s, 1H), 7.21 (dd, J = 7.3, 2.3 Hz, 2H), 7.03 — 6.76 (m, 3H), 5.98 (d, J: 7.3 Hz, 1H), 4.98 (d, J: 7.3 Hz, 1H), 4.29 (dd, J: 4.2, 2.8 Hz, 1H), 4.15 — 3.86 (m, 4H), 3.66 (m, 2H), 3.41 (d, J: 15.0 Hz, 1H), 3.34 (d, J: 15.0 Hz, 1H), 2.95 (s, 1H), 2.02 (m, 4H), HPLC: 8.42 min, 95.6%. LC-MS: m/z = 573 (M+H), 529 H), m/z = 224 (M-ribose fragment). -l70- Example 91 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(cyclopentylamino)-9H-purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofurany1)methoxy)malonic acid Ph 2 _N \+ H o N’— NO é s '—.

HO OH NY Example 91 The title nd was prepared in a manner analogous to that set forth in Example 59, except cyclopentanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.09 (s, 1H), 7.23 (dd, J = 6.7, 2.9 Hz, 2H), 7.01 (m, 3H), .96 (d, J: 7.4 Hz, 1H), 4.94 (d, J: 7.4 Hz, 1H), 4.47 (m, 1H), 4.28 (t, J: 3.3 Hz, 1H), 4.04 (m, 2H), 3.43 (d, J: 14.9 Hz, 1H), 3.34 (d, J: 14.9 Hz, 1H), 2.96 (s, 1H), 2.19 — 1.98 (m, 2H), 1.78 (m, 2H), 1.72 — 1.64 (m, 2H), 1.62 — 1.52 (m, 2H), HPLC: 9.06 min, 989%. LC- MS: m/z = 587 (M+H), 543 (M-COzH), m/z = 238 (M-n'bose fragment), Synthesis of 2-benzyl(((2R, SS, 4R, 5R)(2-chloro-6—((cyclopropylmethyl)amino)—9H— purinyl)—3—ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid The title compound was prepared in a manner analogous to that set forth in Example 59, except cyclopropylmethanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 6 8.14 (s, 1H), 7.18 (d, J: 6.9 Hz, 2H), 7.12 — 6.68 (m, 3H), .92 (d, J: 6.1Hz, 1H), 4.58 (d, J: 6.1 Hz, 1H), 4.28 (t, J: 3.2 Hz, 1H), 3.98(qd,J=10.3, 3.2 Hz, 2H), 3.50 — 3.04 (m, 4H), 2.55 (s, 1H), 1.08 (m, 1H), 0.52 (m, 2H), 0.26 (m, 2H); HPLC: 8.52 min, 97.7%. LC-MS: m/z = 572 (M+H), 528 (M-COzH), m/z = 224 (M-ribose fragment).

Example 93 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro(isopropylamino)—9H-puriny1)—3 - 1-3,4-dihydroxytetrahydrofurany1)methoxy)malonic acid Ph COZH F” H / L N\ / i HO 6H \8 Example 93 The title compound was prepared in a manner analogous to that set forth in Example 59, except propan-Z-amine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.05 (s, 1H), 7.23 — 7.12 (m, 2H), 7.09 — 6.78 (m, 3H), 5.91 (d, J: 6.2 Hz, 1H), 4.59 (d, J: 6.2 Hz, 1H), 4.37 (m, 1H), 4.28 (m, 1H), 3.42 (d, J: 14.8 Hz, 1H), 3.35 — 3.22 (m, 3H), 2.56 (s, 1H), 1.24 (d, J: 6.5 Hz, 6H); HPLC: 8.39 min, 98.9%.

LC-MS: m/z = 560 (M+H), 516 (M-COzH), m/z = 212 (M-ribose fragment).

Example 94 sis of y1(((2R, 3S, 4R,5R)—5—(2-ch1oro((2—hydroxymethylpropyl)amino)- 9H-puriny1)—3 -ethynyl-3 ,4-dihydroxytetrahydrofurany1)methoxy)malonic acid Example 94 The title compound was prepared in a manner analogous to that set forth in Example 59, except 1-aminomethylpropanol was used in place of benzylamine in step 7. 1H-NMR (400 MHz, CD3OD) 5 8.16 (s, 1H) .22 (m, 2H) 7.03-7.01 (m, 3H) 5.97 (d, J:7.4Hz, 1H) 4.95 (d, J:7.4Hz, 1H) 4.28 (t, J:3.2Hz, 1H) 4.05—4.03 (m, 2H) 3.72-3.69 (m, 2H)3.48-3.31 (m, 2H) 2.97 (s, 1H) 1.24 (s, 6H). ESI—MS (m/z): [M]' calcd for C26H28C1N509 589.98, found 588.4.

Example 95 Synthesis of2-benzy1(((2R,3S,4R,5R)(2-chloro(((S)hydroxypropan-2—y1)amino)- 9H-purinyl)—3-ethynyl-3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid -l72- Ph cozH _N H\ o N,— HOZC Ojj’ H1..(\OH / 5 ‘2 Example 95 The title compound was prepared in a manner analogous to that set forth in Example 59, except (S)—2-aminopropanol was used in place of amine in step 7. 1H—NMR (400 MHz, CD3OD) 5 8.18 (s, 1H) 7.24—2.22 (m, 2H) 7.03—7.01 (m, 3H) 5.97 (d, J:7.4Hz, 1H) 4.93 (d, J:7.4Hz, 1H) .35 (m, 1H) 4.32-4.26 (m, 1H) 4.04 (d, J=3.2Hz, 2H) 3.62-3.60 (m, 2H) 3.48-3.32 (m, 2H) 2.96 (s, 1H) 1.29 (d, J=6.7Hz, 3H) ESI-MS (m/z): [M]' calcd for C25H26CleO9 575.96; found 574.2.

Example 96 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(diethylamino)—9H—purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph 002” 9\ O N\/ O / H020 \N é 3 a HO OH “7 Example 96 The title compound was prepared in a manner analogous to that set forth in Example 59, except lamine was used in place of benzylamine in step 7. 1H-NMR (400 MHz, CD3OD) 5 8.15 (s, 1H) 7.23-7.20 (m, 2H) .98 (m, 3H) 5.98 (d, J:7.3Hz, 1H) 4.97 (d, J:7.3Hz, 1H) 4.29 (m, 1H) 4.15-3.83 (m, 6H) 3.43-3.33 (m, 2H) 2.96 (s, 1H) 1.24 (t, J:7.0Hz, 6H). ESI-MS (m/z): [M]' calcd for C26H28C1N589 573.98; found 5723.

Example 97 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro((2-hydroxyethyl)amino)-9H-purin yl)ethynyl-3,4-dihydroxytetrahydrofuran-2—yl)methoxy)ma1onic acid -l73- WO 46403 Ph COZH _N \+ H o N’— N\/\OH N\ N é _: '_ HO OH 4 Example 97 The title compound was prepared in a manner analogous to that set forth in e 59, except 2-aminoethan-l-ol was used in place of benzylamine in step 7. 1H—NMR (400 MHz, CD3OD) 5 8.20 (s, 1H) 7.24—7.22 (m, 2H) 7.04—7.02 (m, 3H) 5.97 (d, J=7.4Hz, 1H) 4.91 (d, J=7.3Hz, 1H) 4.29 (t, J=3.4Hz, 1H)) 4.06-3.98 (m, 2H) 3.76-3.73 (m, 2H) 3.66-3.63 (m, 2H) 3.43—3.33 (m, 2H) 2.96 (s, 1H). ESI—MS (m/z): [M]' calcd for C24H24C1N509 561.93; found 560.2.

Example 98 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)-5—(2-chloro(((R)— l -hydroxypropan-2—yl)amino)- 9H-purinyl)—3 -ethynyl-3 ,4-dihydroxytetrahydrofurany1)methoxy)malonic acid Ph 2 —N \4\ H o N,— HOZC 03—7; N.(\0H : ‘. N\ /H5 (3H Y Example 98 The title compound was prepared in a manner analogous to that set forth in Example 59, except (R)—2-aminopropan-l-ol was used in place of benzylamine in step 7. 1H—NMR (400 MHz, CD3OD) 5 8.12 (s, 1H) .22 (m, 2H) 7.03—7.01 (m, 3H) 5.96 (d, J:7.4Hz, 1H) 4.95 (d, J:7.4Hz, 1H) 4.42—4.32 (m, 1H) 4.28 (t, J:3.3Hz, 1H) 4.08-4.00 (m, 2H) 3.66-3.58 (m, 2H) 3.45—3.33 (m, 2H) 2.97 (s, 1H) 1.27 (d, z, 3H) . ESI—MS (m/z): [M]' calcd for C25H26C1N509 ; found 574.2 Example 99 Synthesis of 2—benzyl—2-(((2R, 3S, 4R, 5R)-5—(2-ch1oro—6-(cyclopropyl(2-hydroxyethyl)amino)- 9H-purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid —174— HOZCmWNfOH /H0 6H The title compound was prepared in a manner analogous to that set forth in Example 59, except 2—(cyclopropylamino)ethan-l-ol was used in place of benzylamine in step 7. 1H—NMR (400 MHz, CD3OD) 5 8.23 (s, 1H) 7.24—7.22 (m, 2H) 7.04—7.01 (m, 3H) 6.02 (d, J:7.4Hz, 1H) 4.96 (d, J:7.3Hz, 1H) 4.30-4.28 (m, 1H) 4.10—4.04 (m, 4H) 3.78 (t, J=5.9Hz, 2H) 3.44—3.32 (m, 3-3.19 (m, 1H) 2.96 (s, 1H) 1.01—0.97 (m, 2H) .74 (m, 2H). e 100 Synthesis of 2-benzyl(((2R, 3S,4R,5R)—5-(2-chloro((R)-3 -hydroxypyrrolidinyl)—9H— purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid H02031’Who—0H /HO 6H Example 100 The title compound was prepared in a manner analogous to that set forth in Example 59, except (R)-pyrrolidinol was used in place of benzylamine in step 7. 1H NMR (400 MHZ, CD3OD) 8 8.24 (s, 1H), 7.23 (d, J = 7.2 Hz, 2H), 7.06-6.96 (m, 3H), 6.01 (d, J = 7.3 Hz, 1H), 5.01 (s, 1H), 4.56 (d, J = 26.1 Hz, 1H), 4.33-4.31 (m, 1H), 4.20 (d, J = 12.5 Hz, 1H), 4.10-4.00 (m, 3H), 3.78 (m, 2H), 3.50-3.35 (m, 2H), 2.97 (s, 1H), 2.14-2.05 (m, 2H).

Example 101 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((S)(hydroxymethyl)—pyrrolidin- l - yl)-9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid COZH l/OH H020y /HO 6H Example 101 -l75- The title compound was prepared in a manner analogous to that set forth in Example 59, except (S-pyrrolidinylmethanol was used in place of benzylamine in step 7. 1H NMR (400 MHz, DMSO-d6) 6 8.37 (s, 1H), 8.34 (s, 1H), 7.15 (m, 2H), 7.01 (m, 3H), 6.16 (br s, 1H), 5.96 (br s, 1H), 5.81 (d, J: 7.5 Hz, 1H), 4.82 (d, J: 7.4 Hz, 1H), 4.18 — 4.08 (m, 1H), 3.94 (m, 2H), 3.71 (m, 2H), 3.50 (m, 2H), 3.20 (s, 4H), 3.13 (s, 1H), 2.33 (m, 1H), 2.04 (m, 1H), 1.98 — 1.89 (m, 1H), 177 (m, 1H), 1.65 (m, 1H), HPLC: 7.22 min, 97.7%.

Example 102 sis of 2-benzyl(((2R, 3S, 4R, 5R)—5—(2-chloro((R)—3 -(hydroxymethyl)-pyrrolidin- l - yl)-9H-purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid COzH 0 H02011’N040” Example 102 The title compound was prepared in a manner analogous to that set forth in Example 59, except (R)-pyrrolidinylmethanol was used in place of amine in step 7. 1H NMR (400 MHz, 6) 6 8.37 (s, 1H), 8.34 (s, 1H), 7.21 — 7.11 (m, 2H), 7.01 (m, 3H), 6.16 (br s, 1H), 5.96 (br s, 1H), 5.81 (d, J: 7.5 Hz, 1H), 4.82 (d, J: 7.5 Hz, 1H), 4.44 (m, 1H), 4.25 — 4.07 (m, 3H), 3.95 (m, 2H), 3.87 — 3.64 (m, 3H), 3.51 (m, 2H), 3.20 (s, 1H), 2.37 — 2.27 (m, 1H), 2.04 (m, 1H), 1.98 — 1.86 (m, 1H), 1.76 (m, 1H), 1.66 (m, 1H), HPLC: Rt = 7.20 min, 970%.

Example 103 Synthesis of 2-benzyl(((2R,3S,4R,5R)(2-chloro((R)(hydroxymethyl)-pyrrolidin-l- yl)—9H-purinyl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid HOZCg7! /H0 614 Example 103 The title compound was prepared in a manner analogous to that set forth in Example 59, except (R)-pyrrolidinylmethanol was used in place of benzylamine in step 7. -l76- 1H NMR (400 MHz, CD3OD) 5 8.21 (s, 1H), 7.28 — 7.16 (m, 2H), 7.08 — 6.87 (m, 3H), 5.99 (d, J= 7.3 Hz, 1H), 4.97 (d, J: 7.3 Hz, 1H), 4.41 (m, 1H), 4.28 (m, 1H), 4.12 — 3.93 (m, 4H), 3.72 (m, 2H), 3.42 (d, J: 15.0 Hz, 1H), 3.33 (d, J: 15.0 Hz, 2H), 2.96 (s, 1H), 2.05 (m, 4H); HPLC: 7.73 min, 98.2%; ESI-MS: m/z = 254 (M-ribose fragment).

Example 104 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)-5—(2-chloro((S)(hydroxymethyl)—pyrrolidin y1)-9H-puriny1)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 104 The title compound was prepared in a manner ous to that set forth in Example 59, except (S)—pyrrolidinylmethanol was used in place of amine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.22 (s, 1H), 7.22 (m, 2H), 7.07 — 6.88 (m, 3H), 5.99 (d, J: 7.3 Hz, 1H), 4.98 (d, J: 7.3 Hz, 1H), 4.44 (m, 1H), 4.29 (dd, J: 4.0, 2.9 Hz, 1H), 4.07 (m, 2H), 4.05 (qd, J: 10.2, 3.5 Hz, 2H), 3.77 (dd, J: 11.0, 4.2 Hz, 1H), 3.66 (dd, J: 11.1, 6.5 Hz, 1H), 3.42 (d, J: 15.1 Hz, 1H), 3.33 (d, J=15.1Hz, 1H), 2.95 (s, 1H), 2.07 (m, 4H), HPLC: 7.77 min, 99.3%; ESI—MS: m/z = 642 (M+ACN).

Example 105 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro(cyclopropyl(methyl)amino)—9H— puriny1)ethyny1-3 ,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid Ph COZH #\ I: O N HOZC Ojj’NW \V - — N Example 105 The title compound was prepared in a manner analogous to that set forth in e 59, except N—methylcyclopropanamine was used in place of benzylamine in step 7. 1H NMR (400 MHz, CD3OD) 5 8.36 (s, 1H), 7.26 — 7.12 (m, 2H), 7.02 (m, 3H), 6.03 (d, J = 7.3 Hz, 1H), 4.97 (d, .1: 7.3 Hz, 1H), 4.30 (dd, .1: 3.9, 2.8 Hz, 1H), 4.19 — 3.97 (m, 2H), 3.57 — 3.29 (m, 5H), 3.21 (m, 1H), 2.96 (s, 1H), 1.05 — 0.85 (m, 2H), 0.83 — 0.62 (m, 2H); HPLC: Rt = 8.41 min, 98.6%, ESI-MS: m/z = 224 (M-ribose fragment).

Example 106 Synthesis of 2-benzyl(((2R, SS, 4R, 5R)(2-chloro-6—((cyclopropylmethyl)amino)—9H— purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)—3 -(methylamino) oxopropanoic acid 0 o o NH 0 NH 0 BnBr Ph AczO Ph O MeOM / 0gN 0 0 AcOH HO S '7'0,, H O S 7'0..

C52003 O .. 0_SO 70 X —2>N2 DMF MeOZC S 7'0 H2804 MeOZC : OMe : : O : .,, X—p : .,, K—> O O MOMO Rh2(OAc)4 MOMC‘) MOMO AcO 0A0 benzene 26—dichloroadenine BSA TMSOTf MeCM I | NH 0 NH O h\ I:N “If aq. LiOH Ph\ 0 NI:N Hf DIPEA Wk d'o ane NI:N Hogs0031’wa .iMeozc m m ; Meozc 033’ W0 : '_ N\ / N\ /HO OH /Ac6 bAc Y “2N\/A AcO OAc YN Cl C Example 106 Step 1: A stirred solution of [(3aR, 5R, 6R, 6aR)—6-ethynyl(methoxymethoxy)-2,2-dimethyl- tetrahydro-2H—furo[2,3-d][1,3]dioxol—5-yl]methanol (480 mg, 1.87 mmol) and methyl 2- diazo(methylcarbamoyl)acetate (440 mg, 2.8 mmol, prepared ing to literature: European l ofOrganic Chemistry, 2014 (24), 5302-5311) in anhydrous benzene (20 mL) under en was treated with rhodium tetraacetate (16 mg, 0.04 mmol) and heated to 60 °C for 4 h. The resulting mixture was cooled to room temperature and concentrated. The resulting oil was ved in romethane, loaded onto a silica gel column eluting with -100% ethyl acetate in hexane to afford methyl 2-{[(3aR, 5R, 6R, -ethynyl (methoxymethoxy)—2,2-dimethyl-tetrahydro—2H-furo[2, 3 -d][1,3]dioxolyl]methoxy } (methylcarbamoyl)acetate (455 mg, 63% yield) as a diastereomeric pair.

Step 2: A solution of methyl 2-{[(3aR, 5R, 6R, 6aR)ethynyl(methoxymethoxy)-2,2- dimethyl-tetrahydro-2H—furo[2,3-d][1,3]dioxolyl]methoxy}(methylcarbamoyl)acetate (450 mg, 116 mmol) and benzyl bromide (0.97 mL, 8.13 mmol) in anhydrous DMF (4 mL) was treated with cesium carbonate (757 mg, 2.32 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (10 mL), diluted with diethyl ether (70 mL) and washed with saturated aqueous sodium chloride (50 mL) twice.

The organic layer was dried with NaSO4 and concentrated to give a yellow oil. The residue was purified by silica gel column and eluted with 10- 70% ethyl acetate in hexane to afford a diastereomeric mixture methyl 2-benzyl(((3aR,5R, 6R, 6aR)—6-ethynyl-6—(methoxy- methoxy)-2,2-dimethyltetrahydrofuro[2, 3 -d] [ l , 3 ]dioxol-5—yl)methoxy)-3 —(methylamino)-3 - (mwmmmmeGanflméwWDwadwmflfi.

Step 3: While under nitrogen, an ice cooled stirred solution of methyl yl (((3aR, 5R, 6R, 6aR)—6-ethynyl(methoxymethoxy)—2,2-dimethyltetrahydrofuro[2,3 -d] [ l ,3 ]- dioxolyl)methoxy)(methylamino)oxopropanoate (500 mg, 1.05 mmol) in acetic acid (4 mL) was treated with acetic anhydride (1 mL, 11.15 mmol) and trated sulfuric acid (0.02, 0.35 mmol). The reaction solution was slowly warmed to room ature. After 4 hours, reaction was diluted with water and extracted with ethyl acetate (80 mL each). The organic solution was washed with saturated sodium bicarbonate (100 mL), dried over NazSO4 mflcmwmfifififlflemmmmoflwwdbwhafinmdemwmmemmWMfiwbyflwh tography to e (3R, 4R, 5R)(((2-benzylmethoxy(methylamino)-l,3- dioxopropanyl)oxy)methyl)ethynyltetrahydrofuran-2,3,4-triyl tate as an anomer/diastereomeric mixture.

Step 4: A suspension of 2-6—dichloroadenine (48 mg, 0.25 mmol) and N,O—bis(trimethylsilyl)- acetamide (0.08 mL, 0.32 mmol) in anhydrous acetonitrile (7 mL) was treated with a second solution of (3R, 4R, 5R)—5-(((2—benzyl— l -methoxy-3—(methylamino)—l,3-dioxopropan—2- yl)oxy)methyl)ethynyltetrahydrofuran-2,3,4-triyl triacetate (130 mg, 0.25 mmol) in ous acetonitrile (10mL), followed by se addition of trimethylsilyl trifluoro- methanesulfonate (0.06 mL, 0.33 mmol). Once the on was complete, the reaction was heated to 50 0C for 18h, cooled to room temperature and quenched with saturated sodium bicarbonate solution (80 mL). After stirring for a 5 minutes the solution was thracted with ethyl acetate (3x80mL), dried over NazSO4 and concentrated. The residue was dissolved in dichloromethane and purified by flash chromatography to provide (2R, 3R, 4R, (((2- benzyl- l -methoxy(methylamino)— l ,3 -dioxopropanyl)oxy)methyl)(2,6-dichloro-9H— -l79- purin—9-yl)—3-ethynyltetrahydrofuran—3,4-diyl diacetate (135 mg, 83% yield) as a foamy solid (diastereomer pair).

Step 5: While under nitrogen, a solution of (2R, 3R, 4R, 5R)(((2-benzyl-1—methoxy (methylamino)-1, 3 -dioxopropan-2—yl)oxy)methyl)—5-(2,6-dichloro—9H—purinyl)—3 -ethynyltetrahydrofuran-3 ,4-diyl diacetate (70 mg, 0.11 mmol) in e (2 mL) was cooled to 0 °C and treated with diisopropylethylamine (0.03 mL, 0.16 mmol) and cyclopropylamine (0.01 mL, 0. 13 mmol), and warmed to room temperature with stirring overnight. The reaction mixture was diluted with ethyl acetate (80 mL), washed with water (50 mL) and saturated aqueous sodium chloride (50 mL). The organic layer was dried over NazSO4 then filtered and concentrated. The residue was dissolved in dichloromethane and purified by flash column chromatography to afford (2R, 3R, —2-(((2-benzylmethoxy(methylamino)-1,3— dioxopropan—2-yl)oxy)methyl)(2—chloro—6-((cyclopropylmethyl)amino)—9H—purinyl)—3- ethynyltetrahydrofuran-3,4-diyl diacetate (70 mg, 95% yield) as an off-white solid (diastereomeric pair).

Step 6: To solution of (2R, 3R, 4R, 5R)(((2-benzylmethoxy-3 -(methylamino)-1,3-dioxo- propanyl)oxy)methyl)(2-chloro((cyclopropylmethyl)amino)-9H—purinyl) ethynyltetrahydrofuran-3,4-diyl diacetate (70 mg, 0.10 mmol) in THF (1 mL) was treated with LiOH (24 mg, 1.02 mmol) in water (1 mL) and stirred at room temperature overnight.

Reaction pH was ed to 4-5 using cold 2 N HCl. Upon itation, the suspension was stirred for another 10 min. The solid was collected, washed with cold water and dried to provide 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro—6-((cyclopropylmethyl)amino)-9H—purin yl)-3—ethynyl—3,4-dihydroxytetrahydro-furan—2-yl)methoxy)—3-(methylamino)oxopro- panoic acid (45 mg, 75% yield) as an ite solid (diastereomeric pair). 1H NMR (400 MHz, CDCla/CD3OD = 5:1) 5 8.01 (s, 0.45H), 7.48 (s, 0.55H), 7.22—7.03 (m, 5H), 5.86 (dd, J = 4.7, 3.0 Hz, 1H), 4.43 (dd, J = 8.5, 4.6 Hz, 1H), 4.31-4.06 (m, 2H), 3.84- 3.72 (m, 1H),3.45-3.21 (m, 4H), 2.62 (d, J = 40.9 Hz, 1H), 2.46 (d, J = 8.1 Hz, 3H), 1.05 (dq, J = 8.0, 3.7 Hz, 1H), 0.51 (ddd, J = 8.1, 4.0, 1.6 Hz, 2H), 0.31-0.18 (m, 2H). ESI-MS (m/z): [M]+ calcd for C27H29C1N6O7, 585.18, found 585.9.

Example 107 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(6-(benzylamino)—2-chloro—9H—purinyl)—3- l-3,4-dihydroxytetrahydrofuranyl)methoxy)—3-(methylamino)—3-oxopropanoic acid H I:N “Q /N o 0:1 WN O é .' L HO OH NYN Example 107 The title compound was ed in a manner analogous to that set forth in Example 106, except benzylamine was used in place of cyclopropylamine in step 5. 1H NMR (400 MHz, CDCl3/CD3OD = 5:1) 6 8.03 (s, 0.46H), 7.52 (d, J: 2.7Hz, 0.54H), 7.42—7.04 (m, 10H), 5.89 (t, J: 4.3 Hz, 1H), 4.73 (m, 2H), 4.44 (dd, J: 6.0, 4.5 Hz, 1H), 4.33—4.15 (m, 2H), 3.79 (dd, J: 10.6, 4.5 Hz, 1H), 3.45—3.27 (m, 2H), 2.62 (d, J: 36.6 Hz, 1H), 2.48 (d, J: 13.2 Hz, 3H). ESI-MS (m/Z): [M]+ calcd for C30H29C1N6O7, 621.18, found 621.4.

Example 108 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)(2-chloro((2-chlorobenzyl)amino)-9H—purin y1)-3 -ethynyl-3 ,4-dihydroxytetrahydrofurany1)methoxy)—3 -ethoxy-3 -oxopropanoic acid \/O O N / - - - N\ / - \( Example108 The title compounds is prepared in a manner analogous to that set forth in Example 59, except only 5 equivalents of m hydroxide are used in step 8. 1H NMR (400 MHz, CD3OD) 5 8.16 (s, 1H), 7.42 (m, 2H), 7.26 (m, 2H), 7.21 (m, 2H), 6.99 (m, 3H), 5.97 (d, J: 7.6Hz, 1H), 4.96 (d, J: 7.6Hz, 1H), 4.82 (m, 2H), 4.28 (m, 1H), 4.03 (m, 2H), 3.75 (m, 2H), 3.38 (m, 2H), 3.22 (m, 2H), 2.97 (s, 1H) 1.29 (t, J: 7.6Hz, 3H).

HPLC: 9.43 min, 96.2%. LC-MS: m/z = 642, 597 (M-COzH), m/z = 292 (M-ribose fragment).

Example 109 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro((pyridinylmethyl)amino)—9H— purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydrofuranyl)methoxy)-3 -ethoxy-3 -oxopropanoic Example 109 The title compounds is prepared in a manner analogous to that set forth in e 59, except only 5 equivalents of lithium hydroxide are used in step 8. Compound was isolated as ~2:1 mixture of diastereomers. 1H NMR (400 MHz, DMSO-d6) of major isomer: 5 8.73 (d, J: 5.9Hz, 2H), 8.15 (s, , 7.98 (d, J: 5.9Hz, 2H), 7.23 (m, 2H), 7.06 (m, 3H), 6.00 (m, 1H), 5.00 (m, 2H), 4.10 (m, 4H), 3.39 (m, 2H), 3.12 (s, 0.80H), 1.17 (m, 3H). 1H NMR (DMSO-d6) of minor isomer: 5 8.73 (d, J: 5.9Hz, 2H), 8.31 (s, 0.32H), 7.98 (d, J: 5.9Hz, 2H), 7.23 (m, 2H), 7.06 (m, 3H), 6.00 (m, 1H), 5.00 (m, 2H), 4.10 (m, 4H), 3.39 (m, 2H), 3.01 (s, 0.41H), 1.17 (m, 3H).

HPLC: 6.25 min, 94.8%. LC-MS: m/z = 638 (M+), 594 (M-COzH), m/z = 259 (M-ribose fragment).

Example 110 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(2-chloro(isopropy1amino)—9H-purinyl)—3-ethynyl- 3 ,4-dihydroxytetrahydrofuranyl)methoxy)((5—methylisoxazol-3 -yl)methyl)malonic acid /=N H o N HO C O / /Ho 6H Y Example 110 The title compound was ed in a manner analogous to that set forth in Example 59, except 3-(bromomethy1)methy1isoxazole was used in place of benzyl bromide in step 4 and propanamine is used in place of benzylamine in step 7. -l82- 1H-NMR (400 MHz, CD3OD) 5 8.46 (s, 1H) 5.99 (d, J:7.6Hz, 1H) 5.95 (s, 1H) 5.07 (d, J:7.6Hz, 1H) 4.41—4.38 (m, 1H) 4.31—4.29 (m, 1H) 4.07—4.05 (m, 1H) 3.99-3.88 (m, 1H) 3.50-3.38 (m, 2H) 2.95 (s, 1H) 2.05 (s, 3H) 1.27 (d, J:6.5Hz, 6H). ESI-MS (m/z): [M]+ calcd for C23H25C1N609 564.93; found 5661 Example 1 1 1 Synthesis of 2-(((2R,3S,4R,5R)—5-(2-chloro((4-fluorobenzyl)amino)-9H—purinyl) ethynyl-3,4—dihydroxytetrahydrofuranyl)methoxy)((5-methylisoxazol yl)methyl)malonic acid //N\ F COZH _N Hg 0 N/_ N HOZC 03—7, /\ é 5 '- HO 6H N7“ Example 111 The title nd was prepared in a manner analogous to that set forth in Example 59, except 3-(bromomethyl)methylisoxazole was used in place of benzyl bromide in step 4 and (4-fluorophenyl)methanamine is used in place of benzylamine in step 7. 1H-NMR (400 MHZ, CD3OD) 6 8.62-8.58 (br s, 1H) 7.41-7.38 (m, 2H) 7.07-7.01 (m, 2H) 6.01 (d, J=7.4Hz, 1H) 5.96 (s, 1H) 5,09 (d, z, 1H) 4.82-4.71 (m, 2H) 4.31-4.29 (m, 1H) 4.06 (dd, J=10.0,3.8Hz, 1H) 3.97 (dd, J=10.1,3.1Hz, 1H) .32 (m, 2H) 3.18 (s, 3H) 2.96 (s, 1H).

Example 112 sis of 2-(benzo[d]thiazolylmethyl)—2-(((2R,3S, 4R, 5R)(2-chloro—6-((4- fluorobenzyl)amino)—9H—purin—9-yl)—3—ethynyl-3,4-dihydroxytetrahydrofuran—Z- yl)methoxy)malonic acid S,N F K 0 NF Mg H020 op! /\ é 5 '— HO oH NYN Example 112 The title compound was prepared in a manner analogous to that set forth in Example 59, except 2-(bromomethyl)benzo[d]thiazole is used in place of benzyl bromide in step 4 and rophenyl)methanamine was used in place of benzylamine in step 7. 1H-NMR (400 MHz, CD3OD) 6 857-854 (br s, 1H) .70 (m, 2H) 7.45-7.41 (m, 2H) 7.23—7.20 (m, 1H) 7.12-7.16 (m, 1H) 7.09—7.04 (m, 2H) 5.94 (d, J:7.3Hz, 1H) 5.15 (d, J:7.1Hz, 1H) 4.77—4.72 (m, 2H) 4.35—4.32 (m, 1H) 4.20 (dd, J:10.1,2.7Hz, 1H)4111 (dd, J:10.1,3.1Hz, 1H) 3.99-3.86 (m, 2H) 2.77 (s, 1H).

Example 113 Synthesis of 2-(((2R, SS, 4R, 5R)(6-aminochloro-9H—purinyl)-3 yl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)-3 -oxo-3 -(pyrrolidin— l -yl)propanoic acid Example 113 The title compound was prepared in an analogous manner to e 59 except ethyl 2-diazooxo(pyrrolidinyl)propanoate was used instead of l-ethyl 3-(prop-l-en-l-yl) 2-diazomalonate in Step 3 and ammonia is used in place of benzylamine in Step 7. The product is ed as a 55/45mixture of diastereomers.

Major diastereomer 1H-NMR (400 MHz, CD3OD) d 8.80 (s, 1H) 5.99 (d, J=7.4Hz, 1H) 5.05 (d, J=7.4Hz, 1H) 4.88 (s, 1H) 4.28-4.26 (m, 1H) 4.13 (dd, J=10.7,2.5Hz, 1H) 4.00 (dd, , 3.9Hz, 1H) 3.66-3.39 (m, 4H) 3.17 (s, 1H) 1.89-1.79 (m, 4H). Minor diasteomer 1H- NMR (400 MHz, CD3OD) 6 8.89 (s, 1H) 6.03 (d, J=7.4Hz, 1H) 5.05 (d, J=7.4Hz, 1H) 4.86 (s, 1H) 4.28-4.26 (m, 1H) 3.90-3.86 (m, 2H) 3.66-3.39 (m, 4H) 3.16 (s, 1H) 1.89-1.79 (m, 4H). ESI—MS (m/z): [M]' calcd for C19H21C1N607 480.86; found 479.1 Example 1 14 Synthesis of 2-(((2R, SS, 4R,5R)—5-(2—chloro—6-(cyclopentylamino)—9H—purin—9-yl)—3 —ethynyl- 3 ydroxytetrahydrofuran-Z-yl)methoxy)oxo-3 -(pyrrolidin- l -yl)propanoic acid Example 114 The title compound was prepared in an analogous manner to Example 59 except ethyl 2-diazooxo(pyrrolidin—1-yl)propanoate was used instead of l-ethyl 3—(propenyl) 2-diazomalonate in Step 3 and cyclopentanamine is used in place of benzylamine in Step 7.

The product is isolated as a 55/45 mixture of diastereomers.

Major diastereomer.1H NMR (400 MHz, CD3OD) d 8.72 (s, 1H) 5.96 (d, J=7.4Hz, 1H) 5.04 (d, z, 1H) 4.87 (s, 1H) 4.52-4.48 (m, 1H) 4.28-4.25 (m, 1H) 4.14 (d, J=10.5Hz, 1H) 4.01 (dd, J=10.6,5.2Hz, 1H) .36 (m, 4H) 3.17 (s, 1H) 2.10-2.04 (m, 2H) 1.84—1.77 (m, 6H) 1.69-1.58 (m, 4H) Minor reomer IHNMR (400 MHz, CD3OD) 5 8.64 (s, 1H) 6.00 (d, J=7.4Hz, 1H) 5.01 (d, J=7.4Hz, 1H) 4.85 (s, 1H) 4.52-4.48 (m, 1H) 4.28—4.25 (m, 1H) 3.92-3.86 (m, 2H) .36 (m, 4H) 3.16 (s, 1H) 2.10—2.04 (m, 2H) 1.84-1.77 (m, 6H) .58 (m, 4H) (.ESI-MS (m/z): [M]' calcd for C24H29C1N607 548.98; found 547.3. e 1 15 Synthesis of 3-amino(((2R, 3S, 4R, 5R)—5—(2-chloro(cyclopentylamino)-9H-purinyl)—3- ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)-3 -oxopropanoic acid TBDPSO N \ N BSAMTMSOV TBDPSO ONWC' TBAF, AcOH eC THF _ . + </ | / : : N A AcO OAc N 0' H Aco 0Ac A126 OAc N191“ H2NOJHKlkOEtOlNl=NRr12(OAc)4 COZH c0251 c0251 HN2 $0 ONWHfi1 NH4QH,THF\Oz aq.LIOH,THFHN2 $0/ O-NWMO HNm)\2 - « \ <15 OH AcO 0A1: Aco 0A1: N:(N Example 115 Step 1: While under nitrogen, a suspension of 2,6-dichloroadenine (2.91 g, 15.4 mmoL, 1.01 eq) and N,0-bis(trimethylsilyl)acetamide (4.87 mL, 19.6 mmoL, 1.29 eq) in anhydrous acetonitrile (90 mL). Next, a solution of (2R, 3R, 4R, 5R)-2,4-bis(acetyloxy){[(terl— butyldiphenylsilyl)oxy]methyl}-4—ethynyloxolan—3-y1 acetate (8.2 g, 15.22 mmoL) in anhydrous acetonitrile (10 mL) was added, followed by dropwise addition of trimethylsilyl WO 46403 trifluoromethanesulfonate (3.67 mL, 20.3 mmoL, 1.33 eq). The reaction was warmed to 50 0C for 18h, then cooled to room temperature. (Reaction begins a pale-yellow color and after 4hmmsmaUmwmmnmmm)SummwammmswmmanmmmeOmLqume and the mixture was stirred for ten minutes. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) and the combined organic layer was dried (Na2S04), filtered, and trated. The residue was dissolved in dichloromethane /ethyl acetate (~3 mL, 1:1), loaded onto a silica gel column (~300 cc), and eluted with 0-30% ethyl acetate in s to provide (2R, 3R, 4R, 5R)—2-(((lerZ-butyldiphenylsilyl)oxy)methyl)-5—(2,6-dichloro-9H-purin—9- yl)ethynyltetrahydrofuran-3,4-diyl diacetate (8.2 g, 81%) as a white solid.

Step 2: A solution of (2R, 3R, 4R, 5R)—2-(((ZerZ-butyldiphenylsilyl)oxy)methyl)(2,6-dichloro- 9H-purinyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (1.6 g, 2.4 mmoL) in anhydrous THF (25 mL) was cooled to 0 oC and treated with acetic acid (0.192 mL, 3.36 mmoL, 1.4 eq) a 1 N solution of tetrabutylammonium fluoride in THF (3.36 mL, 3.36 mmoL, 1.4 eq). After the addition was complete, the reaction was warmed to room temperature with stirring for 3h.

TmnwamnmmmmummmmEmedapmfikdfiaflmhammmCMmmmgmmw(0w 50% ethyl acetate in hexanes to afford (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purinyl) ammllmwmmmaMWHMMMdMM6AdMdemM0%g8&QMaWMEmmr Step 3: While under nitrogen, a solution of ((2R, 3R, 4R, 5R)—5-(2,6-dichloro-9H—purinyl) ethynyl(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (172 mg, 0.40 mmol) and ethyl 3-(aminooxy)diazooxopropanoate (160 mg, 1.02 mmoL, 2.5 eq) in anhydrous toluene (3 mL) was treated with m (II) acetate dimer (5 mg, 0.011 mmoL, 2.8 mol%) and wmmaho&WCfix5h.flwrwamnwwcmwmmMaLmflpwfikdfiaflwhummm chromatography (25-75% ethyl acetate in romethane) to afford (2R, 3R, 4R, 5R)(((1- aminoethoxy-1,3-dioxopropan—2-yl)oxy)methyl)(2,6-dichloro-9H—purinyl) ethynyltetrahydrofuran-3,4-diyl diacetate (101 mg, 45% in ~85: 15 mixture of diastereomers) Mawmhmgws Step 4: While under nitrogen, a solution of (2R, 3R, 4R, 5R)—2-(((1-aminoethoxy-1,3-dioxo- propanyl)oxy)methyl)-5—(2,6-dichloro-9H—purin—9-yl)-3—ethynyltetrahydrofuran—3,4-diyl diacetate (157mg, 0.28mmol) in dioxane (2.5 mL) was d with diisopropylethyl-amine -l86- (0.100 mL, 061 mmoL, 2.2 eq) and cyclopentylamine (0.065 mL, 0.066mmoL, 2.33 eq).

After stirring at room ature for 18 h, the mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL), dried (NazSO4), filtered, and concentrated to provide crude (2R, 3R, 4R, 5R)(((1 -amino-3 -ethoxy- l ,3 propanyl)oxy)methyl)—5-(2-chloro (cyclopentylamino)—9H—purinyl)—3 -ethynyltetrahydrofuran-3 l diacetate.

Step 5: The ing residue from the previous step was stirred in ammonium hydroxide and ethanol (1:1/vzv, 10 mL) at room temperature overnight. The mixture was concentrated, dissolved in THF (2.5 mL) and treated with lithium hydroxide (23 mg, 0.96 mmoL, 3.4 eq) dissolved in water (2.5 mL). The mixture was stirred at room temperature with onal gentle heating for ~3h, then neutralized with 1N HCl to pH~6 and concentrated in vacuo. The crude product was dissolved in water and purified by reverse phase HPLC and dried by lyophilization to provide the title compound (52 mg, 37% for 3 steps) as a voluminous white solid. 1H NMR (400 MHz, D20) of major isomer: 5 8.30 (s, 1H), 5.81 (m, 1H), 4.88 (d, J: 6.6Hz, 1H), 4.80 (d, J: 6.8Hz, 1H), 4.24 (m, 2H), 4.20 (bs, 1H), 3.83 (m, 2H), 3.01 (s, 1H), 1.85 (m, 2H), 1.49 (m, 6H). 1H NMR (400 MHz, D20) of minor isomer: 8 8.39 (s, 1H), 5.81 (m, 1H), 4.88 (d, J: 6.6Hz, 1H), 4.80 (d, J: 6.8Hz, 1H), 4.24 (m, 2H), 4.20 (bs, 1H), 3.83 (m, 2H), 2.99 (s, 1H), 1.85 (m, 2H), 1.49 (m, 6H). HPLC: Rt = 7.08 min, 93.0%. ESI-MS for C20H23C1N607 calcd. , found 493.2 (M-); ESI—MS for C10H11ClN5 calcd. 236.07, found 2360 (M-ribose fragment).

Example 116 Synthesis of 2-(((2R, 3S, 4R,5R)—5-(2—chloro—6-(cyclopentylamino)—9H—purinyl)—3-ethynyl- 3,4-dihydroxytetrahydrofuranyl)methoxy)malonamide Example 116 The title compound was prepared as a second product from step 5 in the synthesis of e 115. It was isolated as a voluminous white solid (8.5 mg, 6%). -l87- 1H NMR (400 MHz, DMSO—ds): 8.57 (s, 0.5H), 8.31 (s, 1H), 7.73 (s, 1H), 7.38 (m, 1.5H), 7.21 (m, 1.5H), 7.05 (m, 0.5H), 6.87 (m, 0.5H), 6.20 (m, 1H), 6.02 (d, J: 7.0Hz, 1H), 5.79 (d, J= 7.8Hz, 1H), 5.02 (s, 1H), 4.73 (s, 1H), 4.39 (m, 1H), 4.18 (m, 1H), 3.79 (m, 1H), 3.68 (s, 1H), 1.85 (m, 2H), 1.49 (m, 6H). HPLC: Rt = 6.64 min, 97.1%. ESI-MS for C1N7O6 calcd. 493.15, found 492.3 (M-); ESI—MS for C10H11C1N5 calcd. 236.1, found 236.1 (M-ribose fragment).

Example 117 Synthesis of 2-(((2R, 3S, 4R, 5R)(2—chloro—6-(methylamino)-9H—purin-9—yl)ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)malonic acid Example 117 The title compound was prepared in a manner analogous to that set forth in Example 59, except methylamine was used in place of benzylamine in step 7 and step 4 is eliminated. 1H NMR (400 MHz, CD3OD) 5 8.88 (s, 1H), 6.05 (d, J: 7.6Hz, 1H), 5.03 (d, J: 7.6Hz, 1H), 4.62 (s, 1H), 4.26 (m, 1H), 4.04 (m, 1H), 3.90 (m, 1H), 3.11 (s, 1H), 3.07 (s, 3H). HPLC: Rt = .92 min, 97.9%. ESI-MS for C16H16ClN508 calcd. 441.07, found 442.5 (NH); ESI—MS for N5 calcd. 182.02, found 184.2 (M-ribose fragment).

Example 118 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-(benzylamino)chloro-9H—purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid — H HO 0 NI— N O N ; L N\ /H6 6H \8 Example 18 The title compound was ed in a manner analogous to that set forth in Example 59, except step 4 was eliminated. 1H NMR (400 MHz, CD30D) 5 8.87 (s, 1H), 7.39 (m, 2H), 7.33 (m, 2H), 7.26 (m, 1H), 6.06 (d, J: 7.6Hz, 1H), 5.02 (d, J: 7.6Hz, 1H), 4.76 (m, 2H), 4.62 (s, 1H), 4.26 (s, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.10 (s, 1H). HPLC: Rt = 7.83 min, 98.2%. ESI-MS for C22H20CleOs calcd. 517.10 found 516.7 (M-), ESI-MS for C12H9C1N5 calcd. 258.05, found 258 (M-ribose fragment).

Example 119 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-chloromorpholino-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran—2-yl)methoxy)—2-(phenylsulfonyl)acetic acid Example 119 The title compound was prepared in an analogous manner to e 59 except ethyl 2-diazo(phenylsulfonyl)acetate was used instead of l-ethyl penyl) 2- alonate in Step 3, morpholine was used in place of benzylamine in Step 7 and Step 4 is eliminated. 1H NMR (400 MHz, DMSO—ds) of major : 5 8.40 (s, 1H), 7.83 (m, 2H), 7.66 (m, 2H), 7.53 (m, 1H), 5.83 (m, 1H), 5.50 (d, J: 7.8Hz, 1H), 4.80 (d, J: 7.8Hz, 1H), 4.16 (m, 4H), 3.98 (m, 1H), 3.76 (m, 4H), 3.63 (s, 1H). 1H NMR (400 MHZ, DMSO-ds) of minor isomer: 6 8.41 (s, 1H), 7.83 (m, 2H), 7.66 (m, 2H), 7.53 (m, 1H), 5.83 (m, 1H), 5.50 (d, J: 7.8Hz, 1H), 4.66 (d, J: 7.8Hz, 1H), 4.16 (m, 4H), 3.98 (m, 1H), 3.76 (m, 4H), 3.61 (s, 1H). HPLC: Rt = 7.83 (minor), 8.18 min (major), 99.6% (40:60). ESI-MS for C26H26C1N509 calcd. 587.14, found 588 (M+), ESI-MS for C24H24C1N509S calcd. 593.10, found 592 (M-); ESI-MS for C23H23C1N507S calcd. 548.10, found 548 (M-COzH), ESI-MS for C9H9C1N50 calcd. 238.05, found 240 (M-ribose fragment).

Example 120 Synthesis of 2-(((2R, 3S, 4R, 5R)—5-(2-chloro(cyc1opentylamino)—9H—purinyl)—3-ethynyl- 3 ,4-dihydroxytetrahydrofurany1)methoxy)(methylsulfonyl)acetic acid Example 120 The title compound was prepared in an analogous manner to Example 59 except ethyl 2-diazo(methylsulfonyl)acetatewas used instead of 1-ethyl 3-(propenyl) 2- diazomalonate in Step 3, cyclopentanamineis used in place of benzylamine in Step 7 and Step 4 is eliminated. 1H NMR (400 MHz, DMSO—ds) of major isomer: 6 8.47 (s, 1H), 5.85 (m, 1H), 5.36 (m, 1H), .01 (m, 1H), 4.86 (d, J = 8.0Hz, 1H), 4.42 (m, 2H), 4.33 (m, 1H), 4.25 (m, 2H), 4.14 (m, 1H), 4.00 (m, 1H), 3.37 (s, 1H), 3.05 (s, 3H), 1.97 (m, 2H), 1.72 (m, 2H), 1.57 (m, 4H). 1H NMR (400 MHz, DMSO-ds) of minor isomer: 5 8.39 (s, 1H), 5.33 (m, 1H), 5.36 (m, 1H), 4.68 (d, J = 8.0Hz, 1H), 4.42 (m, 2H), 4.33 (m, 1H), 4.25 (m, 2H), 4.14 (m, 1H), 4.00 (m, 1H), 3.37 (s, 1H), 3.05 (s, 3H), 1.97 (m, 2H), 1.72 (m, 2H), 1.57 (m, 4H). HPLC: Rt = 8.02 min, 98.4%.

ESI-MS for C20H24C1NsOsS calcd. 529.10, found 530 (M+), ESI-MS for C10H11C1N5 calcd. 236.07, found 238 ose fragment).

Examples 121 & 122 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminocarbamoyl-9H-purinyl)ethyny1-3,4- dihydroxytetrahydrofuranyl)methoxy)benzyl-3—ethoxy—3 -oxopropanoic acid R, 3S, 4R, 5R)—5-(6-aminocarbamoyl-9H-purinyl)-3 -ethynyl-3,4— dihydroxytetrahydrofuranyl)methoxy)—2-benzylmalonic acid o N(BOC)2 o NH2 O 08 (N 0 QB l NaCN DBACO (,N \N EC 0 N o NACI DMSO EtO o N o NACN _ \ / 60(3 16h _ —Ac05 bOAc —AcO¢ LOAC iaq. LiOH, THF O NH2 0 OH <91“N HO 0AJN o N/JWI/NHZ’“ <N811:: o N/Sl/NHZ 0 lg H6 ’OH e 122 Example 121 Step 1: To a solution of diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-(N,N ’- bis(tert—butoxycarbonyl)amino)—2—chloro—9H—purinyl)—3-ethynyltetrahydrofuran yl)methoxy)malonate (1.00 g, 1.17 mmol, 1 eq) in DMSO (10 mL) and H20 (2 mL) was added 1,4-diazabicyclo[2.2.2]octane (128 uL, 1.17 mmol, 1 eq) and NaCN (114.20 mg, 2.33 mmol, 2 eq). The solution was stirred at 60 °C for 3 h bfore it was diluted with water (15 mL) and ted with ethyl acetate (3 X 15 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried by NazSO4, and filtered and concentrated. The crude residue was purified by Combi-flash (silica gel, 30—70% EtOAc in petroleum ether) to give diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-(N,N ’-bis(tert-butoxycarbonyl)- amino)—2-cyano-9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (312 mg, 40% yield) as a yellow gum.

Step 2: To a solution of diethyl 2-benzyl-2—(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-(N,N ’- bis(1erl—butoxycarbonyl)amino)—2-cyano-9H—purin—9-yl)-3—ethynyltetrahydrofuran—2- yl)methoxy)malonate (50 mg, 75.23 umol, 1 eq) in DCM (1.7 mL) was added TFA (0.3 mL) at 0 °C. The solution was stirred at 20 °C for 1 h before it was d with saturated aq.

NaHCO3 to adjust the pH to 9. The mixture was extracted with ethyl acetate (3 x 3 mL). The organic was concentrated to give crude diethyl 2-(((2R, 3S, 4R, 5R)(6-aminocyano-9H— purinyl)—3 -ethynyl-3 ,4-dihydroxytetra-hydrofuranyl)methoxy)—2-benzylmalonate (45 mg) as a yellow gum.

Step 3: To a solution of crude diethyl 2-(((2R, 3S, 4R, 5R)(6-aminocyano-9H-purinyl)— 3-ethynyl-3,4-dihydroxytetra-hydrofuran—2-yl)methoxy)—2—benzyl—malonate (65 mg, 115.14 umol, 1 eq) in MeCN (2 mL) was added 7,8,9-hexahydro-2H—pyrimido[1,2-a]- dine (TBD) (1 M aq., 461 uL, 4 eq). The reaction mixture was stirred at 20 0C for 18 h before it was trated. The crude residue was purified by preparative HPLC and the fractions were dried by lization to give 2-(((2R, 3S, 4R, 5R)(6-aminocarbamoyl- 9H-purinyl)ethynyl-3,4—dihydroxytetrahydrofuran-2—yl)methoxy)benzyl-3—ethoxy—3- oxopropanoic acid (Example 121) (4.1 mg, 5% yield) as a white solid and 2-(((2R,3S,4R,5R)— -(6-aminocarbamoyl-9H-purinyl)ethyny1-3,4-dihydroxytetrahydrofuran yl)methoxy)benzylmalonic acid (Example 122) (2.2 mg, 3% yield) as a white solid. -l9l- Example 121; 1H NMR (400 MHz, CD3OD) 5 ppm 8.19~8.39 (m, 1H) 7.26 (br d, J=5.88 Hz, 2H) 7.03 — 7.12 (m, 3H) 6.20 (dd, J=9.69, 7.19 Hz, 1H) 4.91 — 4.97 (m, 1H) 4.29 (br s, 1H) 3.98 — 4.24 (m, 4H) 3.41 — 3.53 (m, 1H) 3,31 — 3.40 (m, 1H) .08 (m, 1H) 1.18 (q, J=7.25 Hz, 3H), LC/MS [M + H] = 555.1.

Example 122: 1H NMR (400 MHz, CD3OD) 6 ppm 8.504 (s, 1H) 7.16 — 7.28 (m, 2H) 7.07 (br s, 3H) 6.20 (d, J=5.88 Hz, 1H) 4.92 — 4.99 (m, 1H) 4,37 (br s, 1H) 3.97 (br d, J=3.63 Hz, 2H) 3.32 — 3.48 (m, 2H) 3.01 (s, 1H), LC/MS [M + H] = 527.0.

Example 123 Synthesis of (1 , 35, 4R, 5R)(6-aminochloro-9H-purinyl)-3 -ethyny1-3 ,4- dihydroxytetrahydrofurany1)methoxy)methoxyoxoethy1)phosphonic acid 0 O N(BOC)2 BCOMe o N(Boc)2 o NH2 M90 OMe N N N \ q 10m. (1‘ \N </ l 1 N2 M604: [ TMSBr,MeCN \N //'\ H04]:Q\4?~0Me (ii I A HO :20,” / M80 0 Ho 0 N X07! N 3' X07! N c1 Rh2(OAc)4,toluene 0' —AcO: i"0Ac A95 iOAO A95 iOAC iaq. NaOH, THF 0 NH2 ,N .N H04,”8.29011. < l A HO O : O 'N N Cl H6 “OH Example123 Step 1: A mixture of (2R,3R,4R,5R)—5-(6-(N,N’-bis(lerl—butoxycarbonyl)amino)-2—chloro— 9H-puriny1)—3-ethyny1(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (565 mg, 0.926 mmol, 10 eq) and methyl 2-diazo-2—(dimethoxyphosphoryl)acetate (247 mg, 1.20 mmol, 1.3 eq) was azeotroped twice with toluene and the resulting oil was solved in toluene (5.7 mL). The reaction solution was d at ambient temperature under argon atmosphere and fitted with a jacketed reflux ser. Rhodium(II) acetate (0.185 mmol, 82 mg, 0.2 eq) was added and the reaction heated at 75°C for 9 h before it was cooled to room temperature. The reaction mixture was concentrated and the resulting oil was purified by flash silica gel column chromatography to provide (2R, 3R, 4R, 5R)—5 -(6-(N,N’ -bis(terz‘-butoxy- -l92- carbonyl)acetamido)—2-chloro-9H-purinyl)((1—(dimethoxyphosphoryl)—2-methoxy-2— oxoethoxy)methyl)-3 yltetrahydrofuran-3 l diacetate.

Steps 2—3: Deprotection of the product from the previous step was performed according to the procedure described for step 4 in Example 121. Aq. NaOH solution was used instead of KOEt that lead to the carboxylic acid. The title compound was isolated as a white solid from preparative reversed-phase HPLC. 1H NMR (CD3OD, 300 MHz) 5 8.08 (s, 1H), 6.06 (bs, 1H), 5.06—5.08 (d, J: 5 Hz, 1H), 4,28 (s, 1H), 3.90—4.10 (m, 2H), 3.79 (s, 3H), 3.98 (bs, 2H), 3.13 (s, 1H); LC/MS [M + H] = 478.2.

Example 124 sis of (l-(((2R,3S,4R,5R)(2-chloromorpholino-9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)ethoxy—2-oxoethyl)phosphonic acid r) o o 00 00 % \OEtp",OEt 1 N2 Etc—“FfjOEt HO </NN N10 TMSBr MeCN N/kc EtO HOSE—fjoa [hr/Am :0: 'N Rh2(OAc)4. toluene Acd I'OAc :Acd bAc :Acd bAc (l-(((2R, 3S, 4R, 5R)—5-(2-chloromorpholino-9H—purin-9—yl)-3 -ethynyl-3,4-dihydroxytetrahydrofuran methoxy)—2-ethoxyoxoethyl)phosphonic acid is prepared in a manner analogous to that set forth in Example 59, except ethyl 2-diazo(diethoxyphos- phory1)acetate in place of 2-diazomalonate in step 3, morpholine is used in place of benzylamine in step 7 and step 4 is eliminated. Compound was isolated as a 1:1 mixture of diastereomers. 1H NMR (400 MHz, DMSO-ds) of major isomer: 6 8.59 (s, 1H), 5.90 (m, 1H) 5.00 (d, J: 7.0Hz, 1H), 4.25 (m, 2H), 4.05 (m, 4H), 3.99 (m, 1H), 3.83 (m, 1H), 3.75 (m, 4H), 3.01 (s, -l93- 1H) 1.05 (t, J: 7.1Hz, 3H). 1H NMR (400 MHz, DMSO-ds) of minor isomer: 5 8.48 (s, 1H), 5.88 (m, 1H), 4.94 (d, J: 6.9Hz, 1H), 4.25 (m, 2H), 4.05 (m, 4H), 3.99 (m, 1H), 3.83 (m, 1H), 3.75 (m, 4H), 3.01 (s, 1H), 0.99 (t, J= 7.1Hz, 3H). HPLC: minor isomer = 6.63 min; major isomer = 6.65 min, 98.6%. LC-MS: m/z = 562 (M+); m/z = 240 ose fragment). e 125 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)-3—ethynyl-3 ,4-dihydroxy(5-(trifluoromethy1)—3H— imidazo[4,5-b]pyridin-3—y1)tetrahydrofurany1)methoxy)malonic acid «N O O O 0E1 I1l 0 CE 0 0“ N , N u N CF, </ ,\ aqLiOH <’ l\ BO 0 —> 8HO , / 0 N $010 E10 0 N O 0 N BSA.TMSOTf N CF3 THF 01:3 \ MeCN _ _ .

AC6 me 120‘: EOAC H6 "OH Example 1 12 Proceeding as described in Example 15 above but substituting 6-amino chloroadenine with 5-(trifluoromethy1)-3H—imidazo[4,5-b]pyridine provided the title compound as a White solid. 1H NMR (CD3OD, 300 MHz) 5 8.82 (bs, 1H), 8.23 (d, J=8 Hz, 1H), 7.78 (d, J=8 Hz, 1H), 7.29—7.26 (m, 2H), 7.03—7.00 (m, 3H), 6.32 (d, J=7 Hz, 1H), 5.10 (d, J=7 Hz, 1H), 4.37—4.36 (m, 1H), 4.08 (d, J=3 Hz, 2H), 3.42 (dd, J=15, 28 Hz, 2H), 2.98 (s, 1H); LC/MS [M + H] = 5352.

Example 126 Synthesis of 2—(((2R, 3S, 4R, 5R)—5-(6-amino-2—ch1oro—9H-purin—9-y1)—3 —ethyny1—3 ,4- dihydroxytetrahydrofurany1)methoxy)—2-(thiazoly1methy1)malonic acid 0 O N \N o NH2 0 OEt s \ 0 CE (/ 1 A o oH \=N N 'HCI H N’ \ CI </ . 1 E10 0 —> EC 0 0 0 ”0 O N / GAO C52003,DMF OAc o N \ 1.BSA,TMSOTf C.

Q \ . _ SVN . . MecN S\N _ Aco‘ ’OAc Aco‘ ’OAC IOH,THF v —HO‘: _OH Example 126 ding as described in Example 15 above but substituting allyl bromide with 4— (chloromethy1)thiazole provided the title compound as a white solid. —194— 1H NMR (CD3OD, 300 MHz) 5 8.76 (bs, 1H), 8.57 (bs, 1H), 7.36 (bs, 1H), 6.00 (d, J=7 Hz, 1H), .95 (m, 1H), 4.35 (bs, 1H), 4.08—4.04 (m, 2H), 3.66—3.64 (m, 2H), 2.98 (s, 1H); LC/MS [M + H] = 524.9.

Example 127 Synthesis of 2-(((2R, SS, 4R, 5R)—5-(2-acetylamino—9H-purinyl)ethynyl-3,4- dihydroxytetrahydrofuran-2—yl)methoxy)—2—benzylmalonic acid N(Boc)2 NH2 )”)3 N(Boc)2 8f” Boo 0,4-DMAP2 N NAG «Nf: Pd(PPh3)2C|2 3°C «gfi H DMF —AcO ’o «BSA TMSOTflMeCN NH2 NH2 0 NH2 OEt N NW4—aq. LiOH THF N1 \ 1Naq. HCI (I l N EtO :CNJLéf‘— E10 0 N NW _ EtO —HO ’0OH —AcO Acd ”OAc Example127 Step 1: To a suspension of 6—amino—2-chloroadenine (3.0 g, 17.69 mmol, 1 eq) in DCM (60 mL) was added 4-DMAP (2.16 g, 17.69 mmol, 1 eq), TEA (21.48 g, 212.30 mmol, 29.55 mL, 12 eq) and (Boc)20 (30.89 g, 141.53 mmol, 8 eq). The sion was stirred at 20°C for 18 h before it was diluted with saturated aq. NH4C1 (100 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was washed with brine (200 mL), dried by , filtered and concentrated. The crude residuewas purified by Combi-fiash (silica gel, 0—20% EtOAc in petroleum ether) to give tert-butyl 6-(N,N’ -bis(terZ-butoxycarbonyl)amino) chloro-9H-purinecarboxylate (904 mg, 11% yield) as a yellow gum.

Step 2: To a solution of tert—butyl 6—(N,N’ -bis(tert-butoxycarbonyl)amino)—2—chloro—9H- purinecarboxylate (900 mg, 1.92 mmol, 1 eq) in DMF (12 mL) was added Pd(PPh3)2C12 (134.43 mg, 191.52 umol, 0.1 eq) and tributyl(1-ethoxyvinyl)stannane (832 uL, 2.46 mmol, 1.29 eq) under N2 atmosphere. The sion was stirred at 95 °C for 3 h before it was diluted with saturated aq. KF solution (8 mL) and stirred at 20 °C for 1 h. The mixture was extracted with ethyl acetate (2 x 8 mL). The ed organic layer was washed with water (20 mL), brine (15 mL), dried by Na2S04, filtered and concentrated. The crude residue was -l95- d by flash (silica gel, 30—70% EtOAc in petroleum ether) to give tert—butyl N— (Zert—butoxycarbonyl)amino -(2-(1-ethoxyvinyl)—9H—puriny1)carbamate (256 mg, 33% yield) as a white solid.

Step 3: To a solution of the product from the last step (60 mg, 109.38 umol, 1 eq) and diethyl 2-benzyl(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 —ethynyltetrahydrofuranyl)methoxy)—ma1onate (53.22 mg, 131.26 umol, 1.2 eq) in MeCN (1 mL) was added BSA (65 uL, 262.52 umol, 2.4 eq). The solution was stirred at 65 °C for 0.5 h before it was cooled to 25 OC and followed by addition of TMSOTf (24 uL, 131.26 umol, 1.2 eq). The ing solution was stirred at 65 °C for 1 h before it was diluted with ted aq. NaHCO3 (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layer was trated. The crude residue was purified by preparative TLC (EtOAc) to give diethyl 2-benzyl(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6- amino(1-ethoxyvinyl)—9H—purin—9-y1)-3—ethynyltetrahydrofuran—2-y1)-methoxy)malonate (42 mg, 55% yield) as a colorless gum.

Step 4: To a solution of diethyl 2-benzyl(((2R, 3R, 4R, 4-diacetoxy(6-amino(1- ethoxyvinyl)-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)-malonate (40 mg, 57.66 umol, 1 eq) in THF (1.5 mL) was added 1M aq. HCl aq. (0.5 mL, 867 eq). The mixture was stirred at 20 °C for 21 before it was d with saturated aq. NaHCO3 (5 mL) and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organic layer was dried by Na2S04, filtered and concentrated to provide crude diethyl 2-benzyl (((2R, 3R, 4R, 5R)—3 ,4—diacetoxy-5 -(2—acetyl—6-amino—9H—purinyl)—3 -ethynyltetrahydrofuranyl )methoxy)malonate (40 mg) as a light yellow gum.

Step 5: To a solution of crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-acetyl- 6-amino-9H—purin—9-y1)-3—ethynyltetrahydrofuran—2-yl)methoxy)malonate (30 mg, 45.07 umol, 1 eq) in THF (4 mL) was added 1M aq. LiOH aq. (901 uL, 20 eq). The mixture was stirred at 20 0C for 6 before it was acidified with 1N aq. HCl to pH 6 and concentrated. The crude residue was purified by preparative HPLC and the fraction was dried by lyophilization to give the title compound (1.4 mg, 6% yield) as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.43 (bs, 1H), 7.14—6.98 (m, 5H), 6.06 (d, J=6.4 Hz, 1H), 4.89 (d, J=6.8 Hz, 1H), 4.26 (m, 1H), 3.94—3.91 (m, 2H), 3.30—3.21 (m, 2H), 2.91 (s, 1H), 2.61 (s, 3H); LC/MS [M + H] = 5260. e 128 Synthesis of R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z—yl)methoxy)-2—(thiophen-Z-ylmethyl)malonic acid 0 O N 0 CE: \\ o OEt (I 1A S N N CI BO 0 —> ho“ EtO o o 0 052003. DMF OAc 1. BSA, TMSOTf i Q , . \ S ‘ . MeCN Acd bAc Acd bAc 2- aq. LIOH, THF Example 128 Proceeding as described in Example 15 above but substituting allyl bromide with 2- (bromomethyl)thiophene provided the title compound as a White solid. 1H NMR (CD3OD, 300 MHz) 5 8.37 (bs, 1H), 7.10 (d, J=5 Hz, 1H), 6.93—6.72 (m, 2H), 6.00 (d, J=7.2 Hz, 1H), 4.98 (d, J=7.6 Hz, 1H), 4.23 (bs, 1H), 4.06 (bs, 2H), 3.62—3.58 (m, 2H), 2.94 (s, 1H); LC/MS [M + H] = 5239.

Example 129 Synthesis of 2-(((2R, 3S, 4R,5R)—5-(2-chloro(cyclopentylamino)—9H—purinyl)—3-ethynyl- 3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)-2—(phenylsulfonyl)acetic acid QI0 OH N 0 NF N 05° 0 / _ _ /H<‘5 5H NYN e 129 The title compound was prepared in an analogous manner to Example 59 except ethyl 2-diazo(phenylsulfonyl)acetate was used instead of l-ethyl 3-(propen—1-yl) 2—diazo malonate in Step 3, cyclopentanamine is used in place of benzylamine in Step 7 and Step 4 is eliminated.

LC/MS [M + H] = 592.0. -l97- Example 130 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-chloro—6-(methylamino)-9H—purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-Z—yl)methoxy)—2—(4-(l-ethyloxo—1,2-dihydropyridin-3 - zyl)malonic acid O O O N q «~15 WN A—>N Br 0 QB 0 N o N BO O ::03' N CI K2C03,DMF o _S 7 Acd 9OAC /\N Example 130 Proceeding as described in Example 20 above but substituting diethyl 2- (((2R, 3R, 4R, 5R)—3 ,4—diacetoxy-5 -(6—N,N’ -(bi s-(lert—butoxycarbonyl)amino)chloro-9H— purinyl)—3-ethynyltetrahydrofuran-Z-yl)methoxy)malonate with diethyl 2-(((2R, 3R, 4R,5R)- 3,4-diacetoxy(6-((lert-butoxycarbonyl)(methyl)amino)chloro-9H-purinyl)ethynyl- tetrahydrofuran-Z-yl)methoxy)malonate provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.04 (s, 1H), 7.58 (dd, J=6.7, 1.9 Hz, 1H), 7.27—7.38 (m, 5H), 6.35 (t, J=6.9 Hz, 1H), 5.95 (d, J=7.8 Hz, 1H), 4.77 (d, J=7.8 Hz, 1H), 4.28 (t, J=2.6 Hz, 1H), 3.96—4.13 (m, 4H), 3.38—3.57 (m, 2H), 3.05 (s, 1H,) 2.99 (m, 3H), 1.32 (t, J=7.3 Hz, 3H); LC/MS [M + H] = 653.1.

Example 131 Synthesis of R, 3S, 4R, 5R)—5—(6-chloro-3 -methyl- azolo[3 ,4-b]pyridin- l -yl)-3 - ethynyl-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)(4-(2-oxotetrahydropyrimidin- 1 (2H)- yl)benzyl)malonic acid -l98- 0“ t-B OK OH 0 Cl OH o=N/—\_c| JLNDA Tin: —>“N ANjig SOCIZ, DCM )L /E>A —> HN N H N2 DCM THF ”b k» 0 CE ‘0 O aq. TFA DCM o E10 C52003 DMF o ‘—o )LN ‘. ., \. K‘— AcO )LN AcO 0 HNk) :Oj/jcz:EooHOH HNQ 4-DMAP pyridine O O OOinom'iin g1,Cl O OH aq. LiOH N/ \ _>THF HO 0 \N / 0 N Cl DBU TMSOTf 0 MeCN . . .

HNLN AcO¢ ’OAc WbN A00 HNLN H6 "0H K) Example 131 Step 1: To a solution of (4-aminophenyl)methanol (27.65 g, 224.44 mmol, 1 eq) in a mixture of anhydrous DCM (100 mL) and anhydrous THF (50 mL) maintained at 25 °C was added 1- chloro-3 -isocyanatopropane (26.83 g, 224.44 mmol, 1 eq) se. The reaction e became slightly exothermic and turned yellow as a precipitate was formed within 15 minutes.

The mixture was stirred for 1.5 h before hexanes (50 mL) was added. The mixture was stirred for additional 15 min before the solid product was collected by filtration, rinsing with a mixture ofDCM and hexanes (5:1 = vzv). Upon drying ed 1-(3-chloropropyl)(4- (hydroxymethyl)phenyl)urea (38.45 g) as a light yellow solid. .

Step 2: To a solution of 1-(3-chloropropyl)—3-(4-(hydroxymethyl)phenyl)urea (30.00 g, 123.6 mmol, 1.0 eq) in THF (300 mL) at 25 °C was added a solution of 1M t-BuOK in THF (247.2 mL, 247.2 mmol, 20 eq) dropwise while stirring vigorously with a mechanical stirrer. The resulting heterogeneous mixture was stirred at 25 °C for 6 h before it was cooled to 0 °C and acidified to pH 5—6 with 2N aq. HCl. The organic volatile was then removed under d pressure. The crude solid was taken up in MeOH (75 mL) and concentrated. The resulting solid mixture was rinsed with a solution of 7% MeOH in DCM (220 mL) under gentle heating and the solid was d off. The solid was rinsed again with 7% MeOH in DCM (150 mL) and filtered. The combined rinse was concentrated to give the desired crude 1-(4- (hydroxymethyl)phenyl)tetrahydropyrimidin-2(1H)-one as a yellowish solid (27.68 g).

W0 20191246403 Step 3: Tbawwmmmdkmw14¢mewmwwmmmflMmemmmmmmflU0 one (15.00 g, 72.74 mmol, 1 eq) in DCM (250 mL) was added a solution of thionyl chloride (1061 mL, 145.48 mmol, 2 eq) at 25 0C under a N2 atmosphere. The mixture was stirred at 0C for 8 h before it was diluted with EtOAc (250 mL) and stirred for 30 min. The solid was collected by filtration, rinsed with EtOAc and dried to provide crude chloro— methyl)phenyl)tetrahydropyrimidin-2(lhO—one (15.00 g).

Step 4: To a solution of diethyl 2-(((3aR, 5R, 6R, -acetoxy-2,2-dimethyl(prop-l-yn-l- yl)tetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (7.04 g, 16.99 mmol, 1 eq) in DMF (70 mL) was added CS2CO3 (11.07 g, 33.98 mmol, 2 eq) and crude 1-(4-(chloro- methyl)phenyl)tetrahydropyrimidin-2(1H)—one (5.09 g, 25.49 mmol, 1.5 eq) at 20 CC. The mixture was stirred at 20 °C for 5 h before it was diluted with H20 (300 mL) and extracted ‘MmEKMcOxlmnm)Tmcmmmwogmmwwnwmw%deMflmm%%OmU, mmmwaNm&MJMMwmwammewiTMcmwpmwawupmfiaflwflwhmma gel column chromatography % e in DCM) to provide diethyl 2- (((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetrahydrofuro[2,3 -d][1,3]dioxol-5 - yl)methoxy)—2-(4-(2-oxotetrahydropyrimidin-l(2H)-yl)benzyl)malonate (9.62 g, 94% yield) as a solid.

Step 5: To a solution of diethyl 2-(((3aR,5R, 6R, 6aR)acetoxy-6—ethynyl-2,2-dimethyl- ydrofuro[2, 3 -d] [ l ,3 ] dioxol-5 -yl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2110- yl)benzyl)malonate (17.31 g, 28.72 mmol, 1 eq) in DCM (90 mL) was added H20 (18 mL) and TFA (90 mL, 1.22 mol, 42 eq) at 0 °C. The reaction mixture was stirred at 20—25°C mefiwwcmwwnmwumhnmmwdmwwm.mefidwwwamflmmflwMI DCM (2 x50 mL) under reduced pressure to provide the crude product diethyl 2- (((2R, 3S, 4R)—3 -acetoxy-3 -ethynyl-4, 5 -dihydroxytetrahydrofuran-2—yl)methoxy)—2—(4-(2- oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonate which was used in the next step without funherpunficafion.

Step 6: To a solution of crude diethyl 2-(((2R,3S,4R)—3-acetoxyethynyl-4,5-dihydroxy- tetrahydrofuranyl)methoxy)—2-(4-(2-oxotetrahydropyrimidin- l (2]10-yl)benzy1)malonate (17.23 g, crude) in DCM (170 mL) was added 4-DMAP (374 mg, 3.06 mmol, 0.1 eq), A020 nL,18377rnnufl,6eq)andpyrkhne(l9781nL,245021nnufl,8eq)at0°C1 The reaction mixture was stirred at 20—25°C for 16 h before it was concentrated under reduced pressure. The residue was solved in EtOAc (200 mL), washed with 1N aq. HCl (150 mL), 10% aq. CquO4 (150 mL), saturated aq. NaHCO3 (150 mL) and brine (150 mL), dried over NazSO4, filtered and concentrated to provide crude diethyl 2-(4-(2-oxotetrahydro- pyrimidin-1(2110-yl)benzyl)(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuran yl)methoxy)malonate (19.24 g) as a foam which was d onto the next step without fufiherpufificafion.

Step 7: mnfionofmudedmflmd2(4424mowndwdmmwmnMHPKZHnybmuyDQ- (((2R,3R,4R)-3,4,5—triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (450 mg, 0.70 mmol, 1 eq) and 6-chloromethyl-lH-pyrazolo[3,4-b]pyridine (128 mg, 0.77 mmol, 1.1 eq) in MeCN (4 mL) was added DBU (315 uL, 2.09 mmol, 3.0 eq) at 0 oC. The solution was stirred at 0 0C for 5 min and followed by addition of a solution of TMSOTf (566 uL, 3Bnme45apmhkCNCMMQdmmMW.flwsdenwmsmmdMOOCfiHOShmm then stirred at 70 °C for 16 h before it was allowed to cool to 25 °C and adjusted the pH to 9 meMmmwanMHOI.memmmwwemmaahmmemflawmwa40mL)Tm combined c layer was dried with NazSO4, filtered and concentrated. The crude residue which was purified by Combi-fiash on silica gel (0—10%MeOH in DCM) to give diethyl 2- (((2R, 3R, 4R, 5R)—3 ,4-diacetoxy(6-chloro-3 -methyl- 1H-pyrazolo[3 ,4-b]pyridin- l -yl)-3 - ethynyltetrahydrofuranyl)methoxy)—2-(4—(2-oxotetrahydropyrimidin-1(2110-yl)benzyl)— mammeESmg49%ymM)%aydbwgmn Step 8: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-chloro—3-methyl-1H- pyrazolo[3 ,4-b]pyridin-1—yl)-3 -ethynyltetrahydrofuran-2—yl)methoxy)(4-(2-oxotetrahydro- pyrimidin-l(2]10-yl)benzyl)malonate (296 mg, 392 umol, 1 eq) in THF (6 mL) was added aq.

LKHlsdufion(2hL‘196nflg10eq) ThesdufionumssfinedatSOoClbr2hbefineflm organic volatile was removed under reduced pressure. To the water layer was added 1N HCl to adjust the pH to 5—6. The mixture was concentrated to give crude product which was purified by preparative HPLC (Column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water %FA)—ACN]; B%: %, 10min). The product was isolated by WO 46403 lyophilization to give 2-(((2R,3S,4R,5R)(6—chloro—3-methyl-1H—pyrazolo[3,4-b]pyridin—l— yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin- l(2H)-yl)benzyl)malonic acid (32 mg) as a white solid.. 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.27 (d, J=8.28 Hz, 1H), 7.31 (d, J=8.28 Hz, 1H), 6.97 (d, J=8.53 Hz, 2H), 6.81 (d, J=8.53 Hz, 2H), 6.49 (s, 1H), 6.20 (s, 1H), 6.13 (d, J=7.53 Hz, 1H), 5.97 (s, 1H), 4.98 (d, J=7.53 Hz, 1H), 4,13 (dd, J=8.4l, 2.64 Hz, 1H), 3.93—3.99 (m, 1H), 3.84—3.9l(m, 1H), 3.64 (s, 1H), 3.42—3.52 (t, J=5.60 Hz, 2H), 3.17—3.23 (m, 2H), 3.05— 3.16 (m, 2H), 2.45 (s, 3H), 1.90 (m, 2H); LC/MS [M + H] = 614.3.

Example 132 Synthesis of 2-(((2R, 3S, 4R, 5R)—5-(2-chlorooxo- lH-purin-9(6hO-yl)-3 yl-3 ,4- dihydroxytetrahydrofuran-2—yl)methoxy)-2—(4-(2-oxotetrahydropyrimidin— 1 (2H)- yl)benzyl)malonic acid 0 CI 0 O O O OH N \N aq. LiOH </ i NH HO O N O NA OAc CIHNLN Cl BSA TMSOTfo MeCN O . . . . '4ij AcO AOc(5 ’OAc Ho‘ ’OH K) Example 132 Step 1: To a solution of 2,6—dichloro-9H—purine (3 79.97 mg, 2.01 mmol) in MeCN (5 mL) was added BSA (956 uL, 3.87 mmol) at 25°C. The reaction mixture was stirred at 65°C for 0.5 h and then cooled back to 25°C. To this mixture was added diethyl 2-(4-(2—oxotetra- hydropyrimidin-1(2110-yl)benzyl)(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 yltetrahydrofuran- 2-yl)methoxy)malonate (1 g) in MeCN (5 mL) and TMSOTf (419 uL, 2.32 mmol) at 25 °C and further stirred at 65 0C for 5 h. The on mixture was allowed to cool to 25 0C before it was quenched with saturated aq. NaHCO3 (10 mL) and extracted with EtOAc (3 x 5 mL).

The combined organic layer was washed brine (10 mL), dried over anhydrous NazSO4, filtered and trated. The crude reisude was purified by flash silica gel column chromatography (0—10% MeOH in DCM) to provide diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy (2,6-dichloro-9H-purinyl)—3-ethynyltetrahydrofuranyl)methoxy)—2-(4-(2- oxotetrahydropyrimidin-l(2H)-yl)benzyl)malonate (365 mg) as a foam.

Step 2: WO 46403 To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(2,6-dichloro-9H—purin—9- yl)-3 -ethynyltetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2110- yl)benzyl)malonate (180 mg) in THF (2 mL) was added LiOH'HzO (97.39 mg, 2.32 mmol, 10 eq) in H20 (1 mL) at 25°C. The reaction mixture was stirred at 40°C for 2 h before the organic volatile was removed under reduced pressure. The aqueous phase was acidified to pH 5—6 with 1N aq. HCl and concentrated under d re. The crude residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um, mobile phase: [water (0.225%FA)-ACN]; B%: 13%—33%, 10min) and dried by lyophilization to provide 2-(((2R, 3S, 4R, 5R)(2-chlorooxo— 1H—purin-9(6ID-yl)—3 -ethynyl-3 ,4-dihydroxy- tetrahydrofuran-Z-yl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2H)-y1)benzyl)malonic acid (15 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 6 ppm 8.62 (s, 1H), 7.24 (d, J=8.31 Hz, 2H), 7.03 (d, J=8.31 Hz, 2H), 6.32 (d, J=6.48 Hz, 1H), 4.61 (d, J=6.48 Hz, 1H), 4.28—4.34 (m, 1H), 3.92—4.04 (m, 2H), 3.55—3.66 (m, 2H), 3.33—3.40 (m, 4H), 3.02 (s, 1H), 1.99—2.06 (m, 2H); LC/MS [M + H] = 617.2.

Example 133 Synthesis of 2—(((2R,3S, 4R,5R)ethynyl-3,4-dihydroxy(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2110-yl)tetrahydrofuran—2-yl)methoxy)—2-(4-(2—oxotetrahydropyrimidin- 1(2110-yl)benzyl)malonic acid 0 0 o o o 0 GE o OE! >—< 0 OH >—< \ )=o / NH aq. LiOH / NH NH THF BO 0 E10 0 N 0 0 o _> HO 0 OAc —< N—< BSA,TMSOTf o o o MeCN o o . _ . _ , )LN Aco‘ ’OAc )LN Aco‘ ’OAC )LN Ho‘ ”OH HNU HN\\) HNk) e 133 Step 1: To the mixture of 5—methylpyrimidine-2,4(lH,3I-D—dione (100 mg, 792.94 umol, 1 eq) in MeCN (2 mL) was added BSA (490 uL, 1.98 mmol, 2.5 eq). The mixture was stirred at 85°C for 0.5 h. The mixture was cooled to 0°C and followed by addition of a solution of diethyl 2-oxotetra-hydropyrimidin— 1 (2]10-yl)benzyl)—2-(((2R, 3R, 4R)-3,4,5-triace- toxyethynyltetrahydrofuranyl)methoxy)malonate (385 mg) in MeCN (2 mL) and TMSOTf (430 uL, 2.38 mmol, 3.0 eq) was added dropwise. The e was stirred at 65°C under N2 atmosphere for 5 h before it was allowed to cool to 25 °C and quenched with saturated aq. NaHCO3 (10 mL). The mixture was extracted with EtOAc (3 x 5 mL). The organic layers were combined, dried over Na2S04, filtered and concentrated in vacuo. The crude compound was purified by silica gel column chromatography (0—5% MeOH in DCM) to provide diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxyethynyl(5-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2110-yl)tetrahydrofuran—2-yl)methoxy)—2-(4-(2—oxotetrahydropyrimidin- 1(2H)-yl)benzyl)malonate (208 mg, 37% yield) as a solid.

Step 2: To a on of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxyethynyl(5-methyl-2,4- dioxo-3,4-dihydropyrimidin-1(2H)-y1)tetrahydrofuran-Z-yl)methoxy)(4-(2-oxotetrahydro- pyrimidin-1(2hO-yl)benzyl)malonate (200 mg, 280.62 umol, 1 eq) in THF (2 mL) was added LiOH'HzO (58.88 mg, 1.40 mmol, 5 eq) in H20 (1 mL) at 20-25°C. The reaction mixture was stirred at 40°C for 1 h before the organic volatile was removed under reduced pressure.

The aqueous phase was acidified to pH is 5—6 with 1N aq. HCl and concentrated under reduced pressure, The crude residue was purified by preparative HPLC (column: YMC- Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225%FA)—ACN], B%: 13%- 33%, 10min) and then followed by lyophilization to provide 2-(((2R,SS,4R,5R)-3 yl- 3 ydroxy-5 -(5-methyl-2,4-dioxo-3 ,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran yl)methoxy)(4—(2-oxotetrahydropyrimidin-1(2H)-yl)benzyl)malonic acid (49 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 6 ppm 7.83 (d, J=0.75 Hz, 1H), 7.33 (d, J=8.28 Hz, 2H), 7.11 (d, J=8.28 Hz, 2H), 6.06 (d, J=7.78 Hz, 1H), 4.44 (d, J=7.78 Hz, 1H), 4.16 (t, J=2.26 Hz, 1H), 3.92—4.05 (m, 2H), 3.47—3.65 (m, 3H), .41 (m, 3H), 2.98 (s, 1H), 2.04 (m, 2H), 1.62 (s, 3H); LC/MS [M + H] = 5731.

Example 134 Synthesis of 2-(((2R, 3S, —5-(2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2]10-yl)-3 -ethynyl-3 ,4- oxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2H)- yl)benzyl)malonic acid —204— WO 46403 o o o 0 0a 0 OH aq. LiOH / NH BO 0 0 o _. HO 0 GAO N—< BSA TMSOTfO o \ \ o MeCN o , , , _ )LN Acd ’oAc )LN HO ’OH HNK) HN\J Example 134 Proceeding as described in Example 133 above but substituting thymine with uracil provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 7.91 (d, J=80 Hz, 1H), 7.31 (d, J=8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H), 6.01 (d, J=7.5 Hz, 1H), 5.20 (d, J=8.0 Hz, 1H), 4.36 (d, J=7.5 Hz, 1H), 4.17 (t, J=2.4 Hz, 1H), 3.99 (dd, J=18.8, 2.5 Hz, 2H), 3.55—3.66 (m, 2H), 3.44—3.52 (m, 1H), 3.33—3.38 (m, 3H), 3.01 (s, 1H), 1.99 = 559.1. — 2.10 (m, 2H), LC/MS [M + H] Example 135 Synthesis of R, 3S, 4R, 5R)(4-aminooxopy1imidin-l (2H)-yl)-3 -ethynyl-3 ,4- oxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin-1 (2110- yl)benzyl)malonic acid \_:)H=o 0 NH2 0 OH ,—< aq.Li0H / \N o N—<: _> HO 0 GAO N—< BSA TMSOTf o MeCN 0 _ , )LN ACO HNbN A00 HNXN Ho‘ OH \J Example 135 Proceeding as described in Example 133 above but substituting thymine with ne provided the title compound as a white solid. 1H NMR (400 MHz, DMSO-dp) 5 ppm 7.92—8.05 (m, 1H), 7.76—7.92 (br s, 1H), 7.45—7.62 (s, 1H), 7.03—7.19 (m, 4H), 6.55 (s, 1H), 5.91—5.99 (m, 1H), 5.87 (d, J=6.80 Hz, 1H ), 5.80 (d, J=6.00 Hz,1H), 5.57 (d, J=7.20 Hz, 1H), 4.13 (t, J=6.80 Hz, 1H), 4.02—4.08 (m, 1H), 3.68— 3.82 (m, 2H), 3.50—3.57 (m, 2H), 3.22 (s, 1H), 3.19—3.22 (m, 3H), 1.82—1.99 (m, 2H), LC/MS [M + H] = 558.3.

WO 46403 Example 136 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-ch1oro—6-((cyc1opropylmethyl)amino)-9H-purinyl) ethyny1-3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2H)- yl)benzyl)malonic acid 0 N \ N O NH O NH 0 QB </ | A 0 GE N 0 OH N N N/ \ CI N aq. LiOH \ H </ I </ THF l BO 0 EC 0 N HO 0 N O O A —> 0 OAc N N9k BSA, TMSOTf c1 Cl \ \ \ 0 MeCN O O . . . . . .

)LN Aco‘ ’OAc )LN Aco‘ ’OAc LN Ho‘ ’OH HNK) HNK) HN\J Example 136 Proceeding as descnbed in Example 133 above but substituting thymine with 2- chloro-N—(cyclopropylmethyl)-9H—purinamine ed the title compound as a white solid. 1H NMR (400 MHz, CD30D) 6 ppm 8.22 (s, 1H), 7.28 (br d, J=8.03 Hz, 2H), 7.03 (d, J=8.28 Hz, 2H), 5.97 (d, J=7.28 Hz, 1H), 4.72—4.77 (m, 1H), 4.28 (s, 1H), 3.95—4.05 (m, 2H), 3.34—3.52 (m, 8H), 3.05 (s, 1H), .02 (m, 2H), 1.11—1.20 (m, 1H), 0.51—0.59 (m, 2H), 0.34 (q, J=4.85 Hz, 2H), LC/MS [M + H] = 670.1.

Example 137 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-ch1oro—6-(methy1amino)-9H—puriny1)ethyny1-3,4- dihydroxytetrahydrofuran-Z-yl)methoxy)(4-(3 -(2-hydroxyethy1) oxotetrahydropyrimidin- 1 (2]10-y1)benzy1)malonic acid OH OTBDPS 0TBDPS OTBDPS 1. NaH,THF — Aczo DMAP _ 2. TBDPSCI, NaH 03 \ / ne.DCM \/ TBAF O —>O > O > >—NH Oy— O DMF >—N 2. NaBH >—N THF HN\_/—C| War =/—N\_) Ho:/_N\—N) y” c| BOW SOCI2DMF$60 1. TFA, H20 DCM 2. Acgo, Py 052003 DMF AcO\/\N\\) HN/ o HN/ (IN O OH I /N \N N A < I A HNC' LIOH HooONNCl BSA, TMSOTf THF 0 :L:., MeCN )LN H5 'OH Hoka) Examp|e137 Step 1: To a solution of compound 1-(3-chloropropy1)(4-(hydroxymethyl)pheny1)urea (5 g, .60 mmol, 1 eq) in THF (100 mL) at 0°C was added NaH (9.89 g, 247.22 mmol, 60% in mineral oil, 12 eq). The reaction mixture was stirred at 25°C for 1.5 h before it was then added TBDPSCl (6.80 g, 24.72 mmol, 1.2 eq) and stirred further for additional 1.5 h. To the reaction mixture was then added allyl bromide (9.97 g, 82.41 mmol, 4 eq) and stirred further for 16 h. To the reaction mixture was added H20 (50 mL) and the resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2S04, d and concentrated. The crude residue was purified by silica gel column chromatography and eluted with EtOAc in eum ether (0—30%) to provide l(4-(((z‘ert—butyldiphenylsilyl)oxy)methyl)phenyl)tetrahydropyrimidin- 2(1H)-one (6 g, 60% yield) as an oil.

Step 2: To a on of compound 1-allyl(4-(((terl-butyldiphenylsilyl)oxy)methy1)- phenyl)tetrahydropyrimidin-2(MED-one (6 g, 12.38 mmol, 1 eq) in a mixture of MeOH (60 mL) and DCM (30 mL) at -78 °C, ozone (15 psi) was introduced until the blue color of the solution persisted for 20 minutes. The excess of ozone was removed by bubbling nitrogen gas for 10 minutes. To this reaction mixture was added NaBH4 (937 mg, 24.76 mmol, 2 eq) and the mixture was allowed to reach 0 oC and stirred for 15 h at 25°C. The mixture was poured into 1N aq. HCl (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried (Na2S04), filtered and concentrated to give crude 1-(4-(((lert—butyldiphenylsilyl)oxy)methyl)phenyl)—3-(2- hydroxyethyl)tetrahydropyrimidin-2(1H)-one (6.6 g) as an oil which was used directly in the nextstep.

Step 3: Toasdufionofmude1{4(«kwbbugddnfiwnybflyDoxyflnmhprhmndy3{2- hydroxyethyl)tetrahydropyrimidin—2(IIfl-one (12.38 mmol, 1 eq) in DCM (40 mL) and pyridine (3.00 mL, 3714 mmol, 3 eq) at 25°C was added AC2O (2.32 mL, 24.76 mmol, 2 eq) and 4-DMAP (151 mg, 1.24 mmol, 0.1 eq). The mixture was stirred for 2 h before it was qmehWhEOfiMfl)TMmMmmmwmmmdmmBQMGxflMi)Tm combined c layer was washed with water (2 x 30 mL), brine (30 mL), dried over NazSO4, filtered and concentrated to provide the crude 2—(3-(4-(((tert-butyldiphenylsilyl)- thyl)phenyl)—2-oxotetrahydropyrimidin-1(2110-yl)ethyl acetate which was used in the next step directly.

Step 4: Toasdufionofmude243{4(«kvpbuqdmphmndmhdkmyflnmhybphmndy2- oxotetrahydropyrimidin-1(2H)-yl)ethyl acetate (6.57 g, 12.38 mmol, 1 eq) in THF (40 mL) was added 1 M TBAF solution in THF (18.57 mL, 1.5 eq) at 0°C. The mixture was stirred at °C for 1 h before H20 (100 mL) was added. The reaction mixture was ted with EtOAc (4 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over Na2S04, filtered and concentrated. The water phase was further extracted with CHzClz (4 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over NMKMfiMmMmmemmwmmmwmmmmwmtCmmmwhwwmmwfimwe product and further purified on silica gel column chromatography (40—100% EtOAc in petroleum ether) to provide 2-(3 -(4—(hydroxymethyl)phenyl)oxotetrahydropyrimidin- -yl)ethyl acetate (3.14 g) as as a white soild.

Step 5: To a mixture of 2-(3-(4-(hydroxymethyl)phenyl)oxotetrahydropyrimidin-l(2H)- yl acetate (1.28 g, 438 mmol, 1 eq) and DMF (3.37 uL, 43.79 umol, 0.01 eq) in DCM (25 mL) at 0°C was added SOClz (5 mL, 68.92 mmol, 15.74 eq). The mixture was d at 50°C for 2 h before it was concentrated to give crude 2-(3—(4-(chloromethyl)phenyl)oxo— tetrahydropyrimidin—1(2I-D-yl)ethyl acetate (1.51g) which was used in the next step without fufiherpunficafion.

Step 6: To a solution of crude 2-(3 -(4-(chloromethyl)phenyl)oxotetrahydropyrimidin- l(2H)-yl)ethyl e (1.51 g, 4.38 mmol, 1 eq) and of diethyl 2-(((3aR,5R, 6R, 6aR)—6- acetoxy-2,2—dimethyl(propyn—1-yl)tetrahydrofuro[2,3 —d][1,3]dioxol—5-yl)methoxy)- malonate (1.91 g, 4.60 mmol, 1.05 eq) in DMF (8 mL) was added CszCO3 (4.28 g, 13.14 mmol, 3 eq) . The mixture was stirred at 25°C for 16 h before it was diluted with H20 (40 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with saturated aq. NH4C1 (2 x 15 mL), water (2 x 15 mL), brine (15 mL), dried over Na2S04, fidemmamwmmWiTMnmmwwmpmfiwbywbmnfimmflgmflwmmmwgd % EtOAc in eum ether) to provide diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxy ethynyl-2,2-dimethyltetrahydrofuro[2,3 -d][1,3]dioxol-5 thoxy)(4—(3 -(2-acetoxyethyl )oxotetrahydropyrimidin-1(2hO-yl)benzyl)malonate (2.20 g, 68% yield) as a yellow Step 7: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyl- tetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)(4-(3 -(2-acetoxyethyl)oxotetrahydro— pyrimidin—l(2H)—yl)benzyl)malonate (2.20 g, 3.19 mmol, 1 eq) in DCM (7.5 mL) was added TFA (7.5 mL, 101,30 mmol, 32 eq) and H20 (1.5 mL). The mixture was stirred at 25°C for 16 h before it was diluted with water (20 mL), Then the pH of the mixture was adjusted to 7— 8mmNfimOmwdTMMMmRMewwammwwmmflfihMxmmD/Mmme organic phase was washed with brine (10 mL), dried over anhydrous NazSO4, filtered and concentrated to provide crude diethyl 2-(((2R,3S,4R)—3-acetoxyethynyl-4,5-dihydroxy- tetrahydrofuranyl)methoxy)(4-(3 -(2-acetoxyethyl)oxotetrahydropyrimidin-1(2110- fl»muflhmkmfie@lg)waydbwgmn To a solution of the above crude product (2.1 g, 3.19 mmol, 1 eq) in DCM (15 mL) was added AC2O (1.79 mL, 19.14 mmol, 6 eq), ne (2.06 mL, 25.52 mmol, 8 eq) and 4- DMAP (3 8.97 mg, 319.00 umol, 0.1 eq). The mixture was stirred at 25°C for 2 h before it was diluted with EtOAc (100 mL), sequentially washed with 1N aq. HCl (2 x 30 mL). The organic layer was washed with water (20 mL), saturated aq. NaHCO3 solution (2 x 20 mL), water (20 mL), and brine (10 mL). The organic layer was dried over MgSO4 and concentrated to provide crude diethyl 2-(4-(3—(2-acetoxyethyl)oxotetrahydropyrimidin- l(2H)-yl)benzyl)(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuranyl)methoxy)- te (2.3 g) as a yellow foam.

Step 8: To a solution of 2-chloro-N—methyl-9H-purinamine (151.59 mg, 825.68 umol, 1.1 eq) in MeCN (3 mL) was added BSA (408.19 uL, 1.65 mmol, 2.2 eq). The mixture was stirred at 65°C for 0.5 h before it was cooled to 0 °C and followed by addition of l 2-(4- (3 -(2—acetoxyethyl)—2—oxotetrahydropyrimidin-1(2H)-yl)benzyl)-2—(((2R,3R,4R)-3 ,4, 5 - triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (550 mg, crude) in MeCN (3 InL)andTh4SOTf(4069luL,225nnnd,3eq) Thenfixnnevmssfinedat65°Cfor3h before it was allowed to cool to 25 °C and quenched with saturated aq. NaHCO3 (20 mL).

The reaction mixture was extracted with EtOAc (4 x 20 mL). The combined c layer was washed with water (10 mL), brine (10 mL), dried over Na2S04, filtered and concentrated.

The crude residue was purified by flash column chromatography on silica gel (30 — 70% EtOAc in petroleum ether) first and then further purified by preparative TLC (7% MeOH in DCM) to e diethyl 2-(4-(3 -(2-acetoxyethyl)oxotetrahydropyrimidin-1(2H)- yl)benzyl)(((2R, 3R, 4R, 5R)-3 ,4-diacetoxy(2-chloro(methylamino)-9H-purinyl)-3 - ethynyltetrahydrofuranyl)methoxy)malonate (180 mg, 22% yield) as a foam.

Step 9: To a solution of diethyl 2-(4—(3 -(2-acetoxyethyl)oxotetrahydropyrimidin-1(2I-D- yl)benzyl)(((2R, 3R, 4R, 5R)-3 ,4-diacetoxy(2-chloro—6-(methylamino)—9H—purinyl)—3 - ethynyltetrahydrofuranyl)methoxy)malonate (180 mg, 210.21 umol, 1 eq) in THF (1 mL) was added saturated aq. LiOH solution (1.5 mL). The e was stirred at 50°C for 2 h Whmflwogmmvdmk“mnmwwdmmflmmwwpmwmerMeflhfmemmmmww ed to 2—3 with 6N aq. HCl solution and then concentrated. The crude residue was purified by preparative HPLC (column: YMC-Actus ODS—AQ 150*30 5u; mobile phase: [water (O.225%FA)—ACN], B%: %,15min) to provide 2-(((2R,3S,4R,5R)—5-(2-chloro- 6-(methylamino)—9H—purinyl)—3-ethyny1-3,4-dihydroxytetrahydrofuranyl)methoxy) (4-(3—(2-hydroxyethyl)oxotetrahydropyrimidin-1(2]10-yl)benzyl)malonic acid (71.8 mg, W%ymMflmaWMRmmd 1H NMR (400 MHz, CD3OD) 5 ppm 8.14 (s, 1H), 7.27 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.0 Hz, 2H), 5.96 (d, J=7.5 Hz, 1H), 4.76 (d, J=7.4 Hz, 1H), 4.26 (br s, 1H), 4.04 (s, 2H), 3.66 (t, J=5.6 Hz, 2H), 3.36—3.55 (m, 8H), 3.05 (m, 4H), 1.96—2.04 (m, 2H); LC/MS [M + H] = 6741.

Example 138 Synthesis of 2-(((2R, 3S, 4R, 5R)(2—chloro—6-((cyc1opropylmethyl)amino)—9H-purinyl) ethynyl-3 ,4-dihydroxytetrahydrofurany1)methoxy)(4-(3 -(2-hydroxyethyl) oxotetrahydropyrimidin— 1 (21-D—y1)benzy1)mal onic acid 0 N We\ N EH 0 o OEt </ | X 0 0E: N o N N/ CI </ / \N aq LiOH H THF EC 0 EtO o N / 6/?NH \ \ 0 MeCN o p . A , )‘N Acd bAc LN Acd bAc )‘N AcO\/\N AcO\/\N HO\/\N Example 138 Proceeding as described in Example 137 above but substituting 2-chloro-N—methyl- 9H-purinamine with 2-chloro-N—(cyclopropylmethyl)-9H—purin—6-amine provided the title nd as a white solid. 1H NMR (400 MHz, CD3OD) 8 ppm 8.09 (s, 1H), 7.28 (d, J=8.3 Hz, 2H), 7.01 (d, J=8.3 Hz, 2H), 5.96 (d, J=7.5 Hz, 1H), 4.74 (d, J=7.3 Hz, 1H), 4.26 (t, J=2.8 Hz, 1H), 4.04 (d, J=2.3 Hz, 2H), 3,62—369 (m, 2H), .54 (m, 4H), 3.34—3.42 (m, 6H), 3.06 (s, 1H) 1.97—205 (m, 2H), 1.09—1.21 (m, 1H), .61 (m, 2H), 0.34 (q, J=4.8 Hz, 2H); LC/MS [M + H] = Example 139 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-chl oro(isopropylamino)-9H-purinyl)ethyny1- 3,4-dihydroxytetrahydrofuran-Z-y1)methoxy)—2-(4-(3 -(2—hydroxyethy1)—2- oxotetrahydropyrimidin- 1(2H)—yl)benzyl)malonic acid NK/km 0 0 I N//LNHN o o aq LiOH THF <N/ILNHN QBSA TMSOTfO QMeCN g)’*0 Acobe ~20be )LN HO\/\N\\) Example 139 Proceeding as bed in Example 137 above but substituting 2-chloro-N—methyl— 9H-purinamine with 2-chloro-N—isopropyl-9H-purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.08 (s, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.02 (d, J=8.3 Hz, 2H), 5.95 (d, J=7.5 Hz, 1H), 4.73 (d, J=7.5 Hz, 1H), 4.39 (br s, 1H), 4.26 (t, J=2.5 Hz, 1H), 4.04 (d, J=2.0 Hz, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.37—3.52 (m, 9H), 1.97—2.04 (m, 2H), 1.30 (d, J=6.3 Hz, 6H), LC/MS [M + H] = 702.1.

Example 140 Synthesis of R, 3S, 4R, 5R)—5—(2-chloro(isopropylamino)-9H—purinyl)—3-ethynyl- 3 ,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin-1(21-D- yl)benzyl)malonic acid O N \ 0 0 0 CE: {/N ll 0 0 N/C NN/ILNH aq. LiOH THF NN//LNH O MeCN _ . .

)‘N ACOc (11%“ Acd NXN Hd HN\\) HU HNK) Example 140 Proceeding as described in Example 133 above but substituting thymine with 2- chloro-N—isopropyl-9H-purinamine ed the title compound as a white solid. 1H NMR (400 MHz, CD30D) 8 ppm 8.16 (s, 1H) 7.32 (d, J=8.44 Hz, 2H) 7.08 (br d, J=8.31 Hz, 2H) 5.99 (d, J=7.46 Hz, 1H) 4.81 (d, J=7.46 Hz, 1H) 4.41 (br s, 1H) 4.26 - 4.31 (m, 1H) 3.97 — 4.12 (m, 2H) 3.40 - 3.57 (m, 4H), 3.33 - 3.37 (m, 2H), 3.03 (s, 1H), 1.99 (m, 2H), 1.31 (m, 6H), LC/MS [M + H] = 658.3.

Example 141 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-chloro—6-(methylamino)-9H—purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-2—yl)methoxy)(4-(2-oxotetrahydropyrimidin—1(2H)— yl)benzyl)malonic acid WO 46403 \ \ O N 0 NH 0 \N NH 0 DE (/N |J\ 0 CB N o N/ CI </ I \N aq. LiOH E10 0 N o / 0 MeCN _ _ ‘ HN)\\N Acd HNXN Acd bAc HNLN K) k) K) Example 141 Proceeding as described in Example 133 above but substituting thymine with 2- chloro-N-methyl-9H-purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.20 (s, 1H), 7.27 (d, J=8.13 Hz, 2H), 7.00 (d, J=8.00 Hz, 2H), 5.97 (d, J=7.38 Hz, 1H), 4.80 (d, J=7.38 Hz, 1H), 4.27 (s, 1H), 4.04 (m, 2H), 3.37 - 3.50 (m, 4H), 3.31 (d, J=1.13 Hz, 3H), 3.06 (s, 2H) 3.04 (s, 1H), 1.90 - 2.00 (m, 2H), LC/MS [M + H] = 630.2.

Example 142 Synthesis of 2—(((2R, 3S, 4R, 5R)—5-(6-amino-2—chloro—9H-purin—9-yl)—3 —ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(thiazolylmethyl)malonic acid OWOEt (I: iNim 0 BO 0 0 NH2 OAc 052003 DMF OAc 1 BSA TMSOTf / MeCN Ac0¢ yOAc 2. aq. LiOH, THF Example 142 Proceeding as described in Example 15 above but substituting allyl e with 2- (bromomethyl)thiazole provided the title compound as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.56 (s, 1H), 7.56 (d, J=3.4 Hz, 1H), 7.33 (d, J=3.4 Hz, 1H), 6.00 (d, J=5.6 Hz, 1H), 4.68 — 4.73 (m, 1H), 4.38 (dd, J=6.3, 3.4 Hz, 1H), 3.98 — 4.07 (m, 2H), 3.85 (s, 2H), 3.00 (s, 1H); LC/MS [M + H] = 524.9.

Example 143 sis of 2—(((2R, SS, 4R, 5R)(6-amino-2—chloro-9H-purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuran—2-yl)methoxy)—2-(thiazol-S-ylmethyl)malonic acid 0 S O O NH2 0 OEt ( 0 GE: / (HN/ IN:k 0 OH N N CI </ l \i EtO o —> 0 / OAc CSZCO3,DMF EStO HO O N OAc 1.,BSA TMSOTf o N CI \ MeCN "I 2. aq. LiOH THF <\N\ .- A00 OAC :Ho‘ 5, Example143 Proceeding as described in Example 15 above but substituting allyl bromide with 5— (chloromethyl)thiazole provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.75 (s, 1H), 8.47 (s, 1H), 7.72 (s, 1H), 6.03 (d, J=7.3 Hz, 1H), 4.97 (d, J=7.3 Hz, 1H), 4.36 (dd, J=4.3, 3.0 Hz, 1H), 4.12 - 4.18 (m, 1H), 4.04 - 4.10 (m, 1H), 3.63 = 524.9. — 3.79 (m, 2H), 3.00 (s, 1H), LC/MS [M + H] Example 144 Synthesis of 2-(((2R, SS, 4R, 5R)(6—amino-2—chloro—9H-puriny1)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methooxy)(4—(pyrrolidinyl)benzyl)malonic acid CHLOE; En ch03 E10 0 K2C03 E0 :0 K—>co2 3 0U' DMF A—CO )<.DMA 80°c HOE A—cO Ow;3<—> A—cO 04% O NH2 0 QB N \ N TFA H20 A620 </ I A O” —> OAC Eto o N o N/ CI Pyndlne BSA TMSOTf A—cO 0 A—co‘ MeCN Ac EtO — X 7! _ 5 ‘4, AcO OAc O NHz O OH N aq.L|OH. </ 1‘“ HO 0 N A o N Cl HO OH Exam ple 144 Step 1: To a on of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (10.0 g, 24.13 mmol, 1 eq) in DMF (100 mL) was added CszCO3 (23.59 g, 72.39 mmol, 3 eq) and 1—(bromomethyl)—4-iodo—benzene (10.75 g, 36.20 mmol, 1.5 eq). The suspension was stirred at 20°C for 1 h before it was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (4 x 50 mL).

The combined organic layer was washed with water (2 x 200 mL), brine (200 mL), dried over anhydrous NazSO4, filtered and concentrated. The crude residue was d by flash column tography on silica gel (5— 20% of EtOAc in petroleum ether) to provide diethyl 2-(((3aR, 5R, 6R, -acetoxyethynyl-2, 2-dimethyltetrahydrofuro[2, 3 -d][1,3]- dioxolyl)methoxy)(4-iodobenzyl)malonate (11.83 g, 74% yield) as a white solid as a white solid.

Step 2: —214— To a solution of diethyl 2-(((3aR,5R, 6R, 6aR)—6-acetoxyethynyl—2,2-dimethyltetra— hydrofuro[2,3-d][1,3]dioxolyl)methoxy)(4-iodobenzyl)malonate (2.00 g, 3.17 mmol, 1 eq) in DMA (22 mL) was added K2CO3 (1.32 g, 9.52 mmol, 3 eq), CuI (120.84 mg, 634.50 umol, 0.2 eq) and proline (438.30 mg, 3.81 mmol, 1.2 eq). The green suspension was stirred at 80°C under N2 atmosphere for 16 h before it was allowed to cool and poured into water (40 mL) and 2N aq. LiOH (1 mL). The mixture was extracted with ethyl acetate (2 X 30 mL).

The resulting aq. layer was ed to pH 5 with 1N aq. HCl solution and then ted with ethyl acetate (2 x 40 mL). The combined organic layer was washed with water (80 mL), brine (80 mL), dried over NazSO4, d and concentrated to give crude (S)(4-(2- , 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetrahydrofuro[2,3 -d][1,3]dioxol-5 - yl)methoxy)ethoxy(ethoxycarbonyl)oxopropyl)phenyl)pyrrolidinecarboxylic acid (390 mg) as a yellow gum.

Step 3: To a solution of crude (4-(2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2- dimethyltetrahydrofuro[2, 3 —d][1,3]dioxol-5—yl)methoxy)—3—ethoxy—2-(ethoxycarbonyl)-3 - oxopropyl)phenyl)pyrrolidinecarboxylic acid (420 mg, 680.01 umol, 1 eq) in DMF (5 mL) was added K2CO3 (282 mg, 2.04 mmol, 3 eq) and EtI (81.58 uL, 1.02 mmol, 1.5 eq). The mixture was stirred at 20°C for 0.5 h before it was diluted with water (10 mL), and extracted with ethyl acetate (2 x10 mL). The ed organic layer was washed with water (20 mL), brine (20 mL), dried over NazSO4, and filtered and concentrated to give crude diethyl 2- (((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetrahydrofuro[2,3 -d][1,3]dioxol-5 - yl)methoxy)—2-(4-((S)(ethoxycarbonyl)pyrrolidinyl)benzyl)malonate (330 mg) as a yellow foam.

Step 4: To a solution of crude diethyl aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2- dimethyltetrahydrofuro[2, 3 —d][1,3]dioxol—5-yl)methoxy)—2-(4-((S)(ethoxycarbonyl)pyro- lidin—1-yl)benzyl)malonate (330 mg, crude) in DCM (4 mL) was added H20 (0.8 mL) and TFA (4 mL) at 0°C. The solution was stirred at 20°C for 4.5 h before it was quenched with saturated aq. NaHCO3 to adjust the pH to 9. The mixture was extracted with ethyl acetate (2 x 8 mL). The combined organic layer was washed with brine (20 mL), dried over NazSO4, filtered and concentrated to crude diethyl 2—(((2R,3S,4R)acetoxyethynyl-4,5-dihydroxy- tetrahydrofuranyl)methoxy)—2-(4—((S)—2—(ethoxycarbonyl)pyrrolidinyl)benzyl)malonate (285 mg) as a yellow foam.

Step 5: To a solution of crude diethyl R,3S,4R)—3-acetoxyethynyl-4,5-dihydroxytetra- hydrofuran—2-yl)methoxy)—2-(4-((S)—2-(ethoxycarbonyl)pyrrolidin- l -yl)benzyl)malonate (28 5 mg) in pyridine (4 mL) was added 4—DMAP (172 mg, 1.41 mmol, 3 eq) and AczO (352.60 uL, 3.76 mmol, 8 eq). The solution was stirred at 20°C for 16 h before it was diluted with water (10 mL), and extracted with ethyl e (3 x 10 mL). The combined organic layer was washed with brine (20 mL), dried by Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (20-50% of ethyl acetate in petrol ether) to give diethyl 2-(4-((S)(ethoxycarbonyl)pyro-lidinyl)benzyl)—2- (((2R,3R,4R)-3,4,5—triacetoxyethynyltetrahydrofuranyl)methoxy)-malonate (220 mg, 51% yield for four steps) as a yellow gum.

Step 6: To a suspension of diethyl (S)—2-(ethoxycarbonyl)pyrrolidin-l—yl)benzyl) (((2R, 3R, 4R)-3,4,5-triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (50 mg, 72.50 umol, 1 eq) and 6-chloropurine (15 mg, 86.99 umol, 1.2 eq) in MeCN (1 mL) was added BSA (44.80 uL, 181.24 umol, 2.5 eq). The suspension was stirred at 65°C for 0.5 h before it was cooled down to 0°C and followed by addition of TMSOTf (32.75 uL, 181.24 umol, 2.5 eq). The mixture was stirred at 65°C for 1 h before it was poured into saturated aq.

NaHCO3 (3 mL). The reaction mixture was extracted with ethyl acetate (3 x 3 mL). The combined organic layer was trated. The crude e was purified by preparative TLC (petroleum ether : EtOAc=2: 1) to give diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6- amino—2-chloro-9H—purin-9—yl)ethynyltetrahydrofuran-2—yl)methoxy)-2—(4-((S)—2—(ethoxy- carbonyl)pyrrolidinyl)benzyl)malonate (33 mg, 57% yield) as a yellow gum.

Step 7: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(4—((S)—2-(ethoxycarbonyl)pyrrolidin- 1-yl)benzyl)malonate (28 mg, 35.03 umol, 1 eq) in THF (2 mL) was added 1M aq. LiOH (701 uL, 20 eq). The mixture was stirred at 20°C for 4.5 h before the organic volatile was removed under reduced pressure. The aq. layer was acidified to pH 6 with 1N aq. HCl on before it was concentrated. The crude residue was purified by preparative HPLC -2l6- (Column: YMC-Triart Prep C18 150*40mm*7um; mobile phase: [water %FA)—ACN]; B%: 15%-35%, 10 min.) and dried by lyophilization to provide 2-(((2R,3S, 4R,5R)—5-(6- aminochloro-9H—purinyl)ethynyl—3,4-dihydroxytetrahydrofuran—2-y1)methoxy)(4- (pyrrolidin-l-y1)benzy1)malonic acid (2.6 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 8 ppm 8.21 (s, 1H), 7.05 (d, J=8.53 Hz, 2H), 6.26 (d, J=8.53 Hz, 2H), 5.98 (d, J=7.53 Hz, 1H), 4.92 - 5.02 (m, 1H), 4.29 - 4.33 (m, 1H), 4.09 (dd, 6, 238 Hz, 1H), 3.97 (dd, J=10.04, 3.01 Hz, 1H), 3.38 (d, J=14.56 Hz, 1H), 3.23 (d, J=14.56 Hz, 1H), 3.02 = - 3.09 (m, 4H), 3.00(s, 1H), 1.89 - 1.97 (m, 4H), LC/MS [M + H] 5871. e 145 Synthesis of 2-(((2R,3S,4R,5R)(6-amino(ethylthio)-9H-purinyl)ethyny1-3,4- oxytetrahydrofuranyl)methoxy)benzylmalonic acid 0 NBocz o NBOCQ NH2 0 OEt N 0E1 1 id NaSEt <’N 1N1 TFA BO 0:0,N N N EtO000::IiOfNN DMF20°C 0—:HNO' s/\ 0—0» [Niw Ac(§ 6A0 A60 1OAc " AcO 0A0 O NH2 0 OH N aq.LiOH,THF (’ l —> HO 0 N o MAS“ Hci~ 6H Example 145 Step 1: To a mixture of diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-(bis-(z‘ert— butoxycarbonyl)amino)—2-chloro-9H-puriny1)ethynyltetrahydrofuran—2-yl)methoxy)— malonate (300 mg, 349.53 umol, 1 eq) in DMF (3 mL) was added NaSEt (88.20 mg, 1.05 mmol, 3 eq). The mixture was stirred at 20°C for 20 h before it was partitioned between water (15 mL) and EtOAc (15mL). The aqueous phase was extracted with EtOAc (2 X 10 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous NazSO4, and filtered and concentrated under reduced pressure to to provide crude diethyl 2- benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino(ethylthio)-9H—purinyl)-3 -ethynyl- tetrahydrofuranyl)methoxy)malonate (310 mg) as an oil which was used for next step without further purification.

Step 2: To a mixture of crude diethyl 2-benzy1(((2R, 3R, 4R, 5R)—3,4-diacetoxy-5—(6-amino- 2-(ethylthio)-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (310 mg) in DCM (3 mL) was added TFA (1.5 mL, 2026 mmol). The mixture was stirred at 20°C for 2 h before it was neutralized to pH 7~ 8 with saturated aq. NaHCO3. The reaction mixture was extracted with EtOAc (3 x 20 mL). The combined extract was washed with brine (15 mL), dried over ous NazSO4, filtered and concentrated under reduced pressure to provide crude diethyl y1(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-amino(ethylthio)-9H—purin- 9-yl)—3-ethynyltetrahydrofuran-Z-yl)methoxy)malonate as a foam.

Step 3: To a mixture of crude diethyl 2-benzy1(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino- 2-(ethylthio)-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (280 mg, crude) in THF (3 mL) was added saturated aq. LiOH (3 mL). The e was stirred at 55°C for 1 h before it was cooled to room temperature. The reaction mixture was extracted with EtOAc (3 x 8 mL). The aqueous phase was adjusted to pH 2-3 with 2M aq. HCl before it was extracted with EtOAc (4 x lOmL), dried over anhydrous NazSO4, filtered and concentrated. The crude product was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um;mobile phase: [water(0.225%FA)-ACN]; B%: 23%-43%,11 min) and dried by lyophilization to give 2-(((2R, 3S, 4R, 5R)(6—amino(ethylthio)-9H-purin yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)benzylmalonic acid (4.4 mg) as a white powder. 1H NMR (400 MHz, 6) 5 ppm 12.59 — 1432 (m, 2H), 8.30 (s, 1H), 7.33 (s, 2H), .21 (m, 5H), 6.15 (s, 1H), 6.00 (d, J=6.78 Hz, 1H), 5.82 (d, J=7.53 Hz, 1H), 5.01 (s, 1H), 4.14 (dd, J=6.40, 2.64 Hz, 1H), 3.99 (d, J=13.05 Hz, 1H), 3.83 (s, 1H), 3.58 (s, 1H), 3.17 — 3.18 (m, 2H), 2.99 — 3.13 (m, 2H), 1.31 (t, J=7.28 Hz, 3H); LC/MS [M + H] = 5440.

Example 146 Synthesis of R, 3S, 4R, 5R)—5-(6-amino-2—chloro-9H—purinyl)—3-ethyny1-3,4- dihydroxytetrahydrofuranyl)methoxy)(4-(1 -(2-methoxyethyl)oxo-l ,2- dihydropyridiny1)benzy1)malonic acid 0 N(Boc)2 Br / \/\Cl Br HO o CBr4 12:12:113 —> —> HN \ K2003.acetone /0\/\N \ Pd(dppf)CI2 K2C03 \ \ ofN \ dioxane H20 / \ 1<2coa DMF N(Boc)2 0 NH: 0 ”Hz O (NyrgNlNA —k 0 c1 aq. LiOH ; —> A06 'OAc Example 148 Proceeding as ed in Example 11 above but substituting chloro(methoxy)— methane with 1-chloromethoxyethane provided the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.41 (s, 1H), 7.80 (s, 2H), 7.60 (dd, J=6.78, 2.01 Hz, 1H), 7.46 (dd, , 2.01 Hz, 1H), 7.35 (d, J=8.28 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 7.19 — 7.24 (m, 1H), 6.26 — 6.31 (m, 1H), 5.82 (d, J=7.78 Hz, 1 H,) 4.86 (d, J=7.78 Hz, 1H), 4.17 (d, J=1.76 Hz, 1H), 4.10 (t, J=5.14 Hz, 2H), 4.02 (dd, J=10.29, 4.77 Hz, 1H), 3.78 — 3.85 (m, 1H), 3.54 = 669.0. — 3.64 (m, 3H), 3.29 (d, J=2.01 Hz, 2H), 3.24 (s, 3H), LC/MS [M + H] Example 147 Synthesis of 2-(((2R, SS, 4R, 5R)-5—(2-chloro—6-(methylamino)-9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuran—Z-yl)methoxy)-2—(4-(2-oxo-1,2—dihydropyridin—3 - yl)benzyl)malonic acid 0 o 0 0 NH 0E1 o OEt (,N pl 0 OEt N N’ </N l TFA/DCM/HZO A0204DMAP H c1 E10 0 N NAG :3—70 EtO E10 0 o o o .. .0 pyridine OAc BSA, TMSOTf .,I )v :3—7:.,I MeCN 5 a, Aco‘ 0 Aco‘ 0A0 1 AcO OAc HO HQ \ ,Boc \ Boc E‘OH O N N’ \ Boc20, TEA O OH \ TFA DMAP,DCM <:, l N10 —. //'\ —> EtO o N Pd(dppf)CIzK2003 c1 DOM HO 0 :0: 'N Z dioxane, H20. _ O aq. LiOH, THF Example 147 Step 1: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl—2,2-dimethyltetra— hydrofuro[2,3-d][1,3]dioxolyl)methoxy)—2-(4-iodobenzyl)malonate (2.0 g, 3.17 mmol, 1 eq) in DCM (15 mL) was added H20 (3 mL) and TFA (15 mL) at 0°C. The on was stirred at 25°C for 16 h before it was quenched with saturated aq. NaHCO3 (150 mL). The mmmmwwmmmwMthwmwmwQXMmmm.Nmamhmdmgmdwmww washed with brine (200 mL), dried over Na2SO4, filtered and concentrated to give crude diethyl 2-(((2R, 3S, 4R)-3 -ethynyl-3 ,4, 5 -trihydroxytetrahydrofuranyl)methoxy)—2-(4- iodobenzyl)malonate (1.74 g) as a yellow foam.

Step 2: To a solution of diethyl 2-(((2R,3S,4R)ethyny1-3,4,5-trihydroxytetrahydrofuran hoxy)—2-(4-iodobenzyl)malonate (1.74 g, 3.17 mmol, 1 eq) in pyridine (20 mL) was added 4-DMAP (1.16 g, 9.52 mmol, 3 eq) and AczO (2.38 mL, 2539 mmol, 8 eq). The solution was d at 25°C for 3 h before it was diluted with water (60 mL) and extracted with ethyl acetate (2 X 60 mL). The combined organic layer was washed with water (100 mL), brine (100 mL), dried over Na2S04, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (10 — 50% of ethyl e in petroleum ether) to give diethyl 2-(4-iodobenzy1)(((2R, 3R, 4R)-3,4,5-triacetoxyethynyl- tademmmnameaMmedmmfiU85g8&6flddfinhwwEm)maydbwfimm.

Step 3: To a solution of diethyl 2-(4—iodobenzyl)-2—(((2R, 3R, 4,5-triacetoxyethynyl- tetrahydrofuranyl)methoxy)malonate (1.00 g, 1.48 mmol, 1 eq) in MeCN (12 mL) was added 2-chloro-N—methyl-9H—purin—6-amine (327 mg, 1.78 mmol, 1.2 eq) and BSA (916 uL, 3.71 mmol, 2.5 eq). The suspension was stirred at 65°C for 0.5 h before it was cooled down to 0°C and followed by addition of TMSOTf (804 uL, 4.45 mmol, 3 eq). The resulting mixture was stirred at 65°C for 1.5 h before it was d with saturated aq. NaHCO3 (10 mDmflwmmmmmaWM%mu2xMmDNMMmmmwmymdme%W%Md with brine (25 mL), dried over NazSO4, filtered and concentrated, The crude residue was purified by flash column chromatography on silica gel (10 — 50%ethyl acetate in petroleum ether) to give diethyl 2-(((2R, 3R, 4R, 5R)—3,4—diacetoxy(2—chloro—6-(methylamino)-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(4-iodobenzyl)malonate (595 mg, 50% ymw)%aydbwsdm.

Step 4: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(2-chloro(methyl- amino)—9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(4-iodobenzyl)malonate (592 mg, 741.88 umol, 1 eq) in DCM (8 mL) was added 4—DMAP (18 mg, 148.38 umol, 0.2 eq), TEA (413 uL, 2.97 mmol, 4 eq) and (Boc)20 (324 mg, 1.48 mmol, 2 eq). The solution was d at 20°C for 2 h before it was diluted with ted aq. NH4C1 (20 mL) and extracted with ethyl acetate (2 X 20 mL). The combined organic layer was washed with brine (40 mL), dried over NazSO4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (15 — 50% of ethyl acetate in petroleum ether) to give diethyl 2-(((2R, 3R, 4R, 5R)—3 ,4-diacetoxy(6-((lert—butoxycarbonyl)(methyl)amino) chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)—2-(4-iodobenzyl)malonate (560 mg, 84% yield) as a foam.

Step 5: To a mixture of diethyl 2-(((2R, 3R, 4R, 4-diacetoxy-5—(6-((terl—butoxycarbonyl)- (methyl)amino)chloro-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)—2-(4- iodobenzyl)malonate (660 mg, 734.89 umol, 1 eq) and roxypyridin—3-yl)boronic acid (204.18 mg, 1.47 mmol, 2 eq) in dioxane (6 mL) and H20 (2 mL) was added Pd(dppf)C12 (53.77 mg, 73.49 umol, 0.] eq) and K2CO3 (304.70 mg, 2.20 mmol, 3 eq). The yellow mixture was degassed with N2 gas for 10 min before the mixture was stirred at 70°C for 2.5 h The mixture was diluted with water (5 mL) and extracted with ethyl e (3 x 5 mL). The ed organic layer was dried over NazSO4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (50 — 100% of ethyl acetate in petroleum ether) to give diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-((terl—butoxycarbonyl )(methyl)amino)—2-chloro-9H—purinyl)—3 -ethynyltetrahydrofuranyl)methoxy)- 2-(4—(2—oxo—l,2-dihydropyridinyl)benzyl)malonate (146 mg) as a foam.

Step 6: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-((tert—butoxycarbonyl)- (methyl)amino)chloro-9H-purin—9-yl)-3—ethynyltetrahydrofuranyl)methoxy)—2-(4-(2— oxo-1,2-dihydropyridinyl)benzyl)malonate (145 mg, 167.58 umol, 1 eq) in DCM (6 mL) was added TFA (1.5 mL, 20.26 mmol, 121 eq). The solution was stirred at 25°C for 1 h before it was neutralized with ted aq. NaHCO3 solution. The mixture was extracted with ethyl acetate (3 x 12 mL). The combined organic layer was washed with bline (30 mL), dried over Na2S04, filtered and concentrated. The crude was purified by preparative TLC -22l- (ethyl acetate) to give diethyl R, 3R, 4R, 5R)-3,4—diacetoxy(2—chloro—6-(methylamino)— 9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)(4-(2-oxo-1,2-dihydropyridin yl)benzyl)malonate (110 mg) as a solid.

Step 7: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy—5-(2-chloro(methyl- amino)-9H—purinyl)—3 -ethynyltetrahydrofuran-2—yl)methoxy)-2—(4-(2-oxo-1,2-dihydro— nyl)benzyl)malonate (105 mg, 137.23 umol, 1 eq) in THF (4.5 mL) was added aq.

LiOH solution (1 M, 1.5 mL, 11 eq). The mixture was stirred at 25°C for 4 h before the organic volatile was removed under reduced pressure. The aq. layer was acidfied to pH 6 with 1N aq. HCl solution and concentrated. The crude residue was purified by preparative HPLC (Column: iart Prep C18 150*40mm*7um, mobile phase: [water (0.225%FA)- ACN]; B%: 20%-40%, 10min) and dried by lization to give 2-(((2R,3S,4R,5R)(2- chloro(methylamino)—9H—purinyl)-3 -ethynyl—3,4-dihydroxytetrahydrofuranyl)- methoxy)—2-(4-(2-oxo-1,2-dihydropyridin-3 -yl)benzyl)malonic acid (6.6 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) 5 ppm 8.44 (s, 1H), 8.23 (d, J=3.75 Hz, 1H), 7.48 (d, J=6.63 Hz, 1H), 7.39 (d, J=7.00 Hz, 2H), 7.34 (d, J=5.63 Hz, 1H), 7.13 - 7.22 (m, 2H), 6.15 - 6.29 (m, 2H), 6.00 (d, J=6.75 Hz, 1H), 5.82 (d, J=7.38 Hz, 1H), 4.71 — 4.89 (m, 1H), 4.16 (dd, J=4.94, 2.56 Hz, 1H), 3.86 — 4.05 (m, 1H), 3.53 — 3.83 (m, 1H), 3.51 (s, 1H), 3.48 — 3.30 (m, 5H overlapped under water peark), 2.90 (d, J=4.38 Hz, 3H), LC/MS [M + H] = 624.9. e 148 Synthesis of 2-(((2R, SS, 4R, 5R)-5—(2-chloro—6-(methylamino)-9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuran—2-yl)methoxy)—2-(4-(3—methyl—2-oxotetrahydropyrimidin-1(2I10- yl)benzyl)malonic acid WO 46403 2019/038245 orsops OTBDF’S OH on o o 051 NaH,Me|,DMF TBAF,THF som DMF o —,o —.o +»0 + EtO o hm hm 2“ [mM y“ :L) O Acd ’0 052C03, DMF BSA, TMSOTf, MeCN Example 148 Step 1: To a solution of 1-(4—(((tert—butyldiphenylsilyl)oxy)methyl)phenyl)tetrahydro- pyrimidin-2(1]10-one (7.33 g, 16.48 mmol, 1 eq) in DMF at 0 °C was added NaH (725 mg, 6WMnmmammLB13mdedeQ.memmmW%mhmdfifl5mmamHNMWwby wmmdeHflm1mmflfi92mmdflew.memmmmmwmwufimmfimmO— °C over 16 h before it was diluted with H20 (100 mL) and extracted with EtOAc (3 X 50 mL). The combined organic layer was washed with brine (100 mL), dried over NazSO4, filtered and concentrated. The crude was purified by flash column chromatography on silica gel (0—50% EtOAc in petroleum ether) to provide 1—(4-(((terl—butyldiphenylsilyl)oxy)— methyl)phenyl)methyltetrahydropyrimidin-2(1H)—one (3.68 g, 48% yield) as a colourless Step 2: To a solution of 1-(4-(((tert-butyldiphenylsily1)oxy)methyl)phenyl)-3 -methyltetra- hydropyrimidin-2(1110-one (3.68 g, 8.02 mmol, 1 eq) in THF (35 mL) was added TBAF in THF (1.5 M, 10.70 mL, 2 eq) at 0°C. The reaction mixture was stirred at 25°C for 1.5 h before it was diluted with H20 (20 mL) and extracted with EtOAc (3 x 50 mL). The combined c layer was washed with brine (50 mL), dried over Na2S04, filtered and cmwmmdflwmmwwwfiwMflMmmmMMmMgwmmflkmdwflé MeOH in DCM) to provide 1-(4-(hydroxymethyl)phenyl)-3 -methyltetrahydropyrimidin- 2(1H)—one (1.06 g, 60% yield) as a yellow solid.

Step 3: To a on of hydroxymethyl)phenyl)methyltetrahydropy1imidin—2(1H)— one (1.06 g, 4.81 mmol, 1 eq) in DCM (10 mL) and DMF (0.1 mL) was added SOC12 (698 uL, 9.62 mmol, 2 eq) at C. The reaction mixture was stirred for 0.5 h and additional amount of SOClz (419uL, 5.77 mmol, 1.2 eq) was added. The resulting mixture was stirred at 40°C for 1 h before it was trated. The residue was azeotroped with DCM (3 X 10 mL) under reduced pressure to provide crude chloromethyl)phenyl)-3 -methyltetra- hydropyrimidin-2(lhO-one which was used in the next step without further purification.

Step 4: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxoly1)methoxy)malonate (1.78 g, 4.30 mmol, 1 eq) in DMF (20 mL) was added CszCO3 (4.21 g, 12.91 mmol, 3 eq) at 25°C. The reaction mixture was stirred for 0.5 h and followed by addition of crude 1-(4-(chloromethyl)phenyl)methyltetrahydro- pyrimidin-2(1]10-one (1.13 g). The reaction mixture was stirred at 25°C for 16 h before it was d with H20 (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The crude was purified by column tography on silica gel (0—10% of MeOH in DCM) to provide diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyl- tetrahydrofuro[2, 3 -d][1,3]dioxol-5 -yl)methoxy)(4-(3 -methyloxotetrahydropyrimidin- 1(2H)-y1)benzyl)malonate (2.63 g, 78% yield) as a brown foam.

Step 5: To a solution of diethyl 2-(((3aR,5R, 6R, 6aR)acetoxy-6—ethynyl-2,2-dimethyltetra- hydrofuro[2,3 -d][1,3]dioxol—5 -yl)methoxy)—2-(4-(3—methyl—2-oxotetrahydropyrimidin- 1 (2110- yl)benzyl)malonate (2.62 g, 4.25 mmol, 1 eq) in DCM (25 mL) at 0°C was added TFA (25 mL, 337.65 mmol, 79 eq) and H20 (25 mL, 138.77 mmol, 33 eq). The reaction mixture was d at 20-25°C for 16 h before it was concentrated under reduced pressure. The residue was azeotroped with DCM (3 x 20 mL) under reduced pressure to provide crude diethyl 2- (((2R,3S, 4R)—3-acetoxyethynyl-4,5-dihydroxytetrahydrofuran-2—yl)methoxy)-2—(4-(3- methyloxotetrahydropyrimidin-1(2fD-yl)benzyl)malonate (2.57 g) as a syrup which was used in the next step without further purification.

Step 6: To a solution of crude diethyl 2-(((2R,3S,4R)—3-acetoxyethyny1-4,5-dihydroxytetra- hydrofuranyl)methoxy)(4-(3 -methyloxotetrahydropyrimidin-1(2H)-yl)benzyl)- —224— malonate (2.57 g) in DCM (25 mL) at 20-25°C was added A020 (2.39 mL, 25.50 mmol, 6 eq), 4-DMAP (51.92 mg, 425.00 umol, 0.1 eq) and pyridine (2.74 mL, 3400 mmol, 8 eq) .

The reaction mixture was stirred at 25°C for 16 h before it was concentrated under reduced pressure. The residue was re-dissolved in EtOAc (50 mL), washed with 1N aq. HCl (40 mL), 10% aq.Cu2SO4 (40 mL), saturated aq. NaHCO3 (40 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated to provide crude diethyl 2-(4-(3—methyl—2-oxotetrahydro- din- 1 (2]10-yl)benzyl)(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuran yl)methoxy)malonate (262 g, 53% yield for two steps) which was used in the next step without further purification.

Step 7: To a solution of 2-chloro-N—methyl—9H—purinamine (181 mg, 983.86 umol, 1.3 eq) in MeCN (2.5 mL) under N2 atmosphere was added BSA (468 uL, 1.89 mmol, 2.5 eq) at 20- °C. The reaction mixture was stirred at 65°C for 0.5 h before it was cooled to 25°C. To this mixture was added crude diethyl 2-(4—(3 -methyloxotetrahydropyrimidin-1(21-D- yl)benzyl)-2—(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuranyl)methoxy)malonate (500 mg, 756.81 umol, 1 eq) in MeCN (2.5 mL) and TMSOTf (205 uL, 1.14 mmol, 1.5 eq) and stirred at 65°C for 5 h before it was quenched with saturated aq. NaHCO3 (10 mL).

The mixture was then ted with EtOAc (3 x 10 mL). The ed organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography on silica gel column (0—10% MeOH in DCM) to provide diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-chloro(methylamino)-9H— purin—9-yl)-3—ethynyltetrahydrofuranyl)methoxy)(4-(3 -methyloxotetrahydropyrimidin-1 (2hO-yl)benzyl)malonate (530 mg, 60% yield) as a foam.

Step 8: To a solution of l 2-(((2R, 3R, 4R, 4-diacetoxy(2-chloro(methyl- amino)-9H—purinyl)—3—ethynyltetrahydrofuranyl)methoxy)(4-(3 —methyloxotetra- hydropyrimidin-l(2110-yl)benzyl)malonate (540 mg, 688.59 umol, 1 eq) in THF (6 mL) was added 2O (288.96 mg, 6.89 mmol, 10 eq) in H20 (3 mL) at 25°C. The reaction mixture was stirred at 40°C for 2 h before the organic volatile was removed under reduced pressure. The aq. phase was acidified to pH 2 — 3 with 1N aq. HCl solution and then ThamhwwpmmwbymwmmwflflflflammmYMOAmmBMHCB mm*5um, mobile phase: [water (0.225%FA)-ACN], B%: 23%-43%, 10min) and dried by lization to provide 2—(((2R, 3S, 4R, (2-chloro-6—(methylamino)—9H-purin- 9-yl)—3-ethynyl-3,4-dihydroxytetrahydrofurany1)methoxy)—2-(4-(3 -methyloxotetra- hydropyrimidin-1(2H)-yl)benzyl)malonic acid (776 mg, 17% yield) as a white solid. 1H NMR (400 MHz, DMSO-dd) 5 ppm 1300—1393 (S, 2H), 8.37 (s, 1H), 8.23 (d, J=5.01 Hz, 1H), 7.11 (d, J=8.31 Hz, 2H), 6.90 (d, J=8.19 Hz, 2H), 6.15 (s, 1H), 5.98 (s, 1H), 5.81 (d, J=7.58 Hz, 1H), 4.82 (s, 1H), 4.15 (dd, J=4.34, 3.00 Hz, 1H), 3.96 (m, 1H), 3.78 (m, 1H), 3.53 (s, 1H), 3.43—3.52 (m, 2H), 3.23 (m, 2H), 3.20—3.10 (m, 4H pped with solvent water peak), 2.91 (m, 2H), 2.81 (s, 3H), 1.95 (m, 2H), LC/MS [M + H] = 644.1.

Example 149 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro-9H—purinyl)—3-ethynyl-3,4- oxytetrahydrofuranyl)methoxy)—2-(4-(3-methyloxotetrahydropyrimidin- l (2110- yl)benzyl)malonic acid Example 149 Proceeding as described in Example 148 above but substituting 2—chloro-N—methyl- 9H-purinamine with 2-chloro-9H—purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.21 (s, 1H), 7.26 (m, J=8.28 Hz, 2H), 6.96 (m, J=8.28 Hz, 2H), 5.97 (d, J=7.53 Hz, 1H), 4.70-4.83 (m, 1H), 4.27 (t, J=2.76 Hz, 1H), 3.99—4.07 (m, 2H), 3.32—3.52 (m, 6H), 3.05 (s, 1H), 2.87 (s, 3H), 2.00 (quin, J=5.83 Hz, 2H), LC/MS [M + H] = 630.2.

Example 150 Synthesis of 2-(((2R, 3S, 4R, 5R)(2-chloro((cyclopropylmethyl)amino)-9H-purinyl) ethynyl-3,4-dihydroxytetrahydrofuran-Z—yl)methoxy)-2—(4-(3 -methyl-2— oxotetrahydropyrimidin- l (2]10-yl)benzyl)malonic acid K, Y Y 0 O NH 0 NH 0 DE GE! 0 0H ,N:L/LN N \ N ' N10 I A E10 0 </NN I :;ONlm HO 0 (/N O <HI N/Kc' LiOH o N CI o : BSA,TMSOTf,MeCN o : S / \NLN p.

Aco‘ OAC AcO )LN Ho‘ ’OH \ \ Example 150 Proceeding as described in Example 148 above but substituting 2-chloro-N—methyl— 9H-purinamine with ro-N-(cyc1opropylmethy1)-9H-purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CDsOD) 5 ppm 8.12 (s, 1H), 7.27 (d, J=8.28 Hz, 2H), 7.00 (d, J=7.68 Hz, 2H), 5.96 (d, J=7.53 Hz, 1H), 4.70 (d, J=7.53 Hz, 1H), 4.26 (t, J=2.89 Hz, 1H), 4.03 (br s, 2H), 3.33—3.54 (m, 8H), 3.05 (s, 1H), 2.88 (s, 3H), 1.97—2.04 (m, 2H), 1.11-1.20 (m, 1H), 0.53—0.59 (m, 2H), 0.34 (m, 2H); LC/MS [M + H] = 684.3. e 151 Synthesis of 2-(((2R, 3S, 4R, (2-chloro—6-(isopropylamino)-9H-purin—9-yl)—3—ethynyl— hydroxytetrahydrofuran-2—y1)methoxy)(4-(3 -methy1oxotetrahydropyrimidin- 1(2H)—yl)benzyl)malonic acid 4f“N \ n NACI BSA TMSOTf MeCN 3L Example 151 Proceeding as described in Example 148 above but substituting 2—chloro-N-methyl- 9H-purinamine with 2-chloro-N-isopropyl-9H-purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.08 (s, 1H), 7.28 (d, J=8.28 Hz, 2H), 7.00 (d, J=8.53 Hz, 2H), 5.95 (d, J=7.53 Hz, 1H), 4.66—4.80 (m, 1H), 4.32-4.48 (m, 1H), 4.25 (t, J=2.89 Hz, 1H), 4.00-4.08 (m, 2H), 3.34—3.53 (m, 6H), 3.05 (s, 1H), 2.88 (s, 3H), 1.94-2.06 (m, 2H), 1.24—1.35 (m, 6H); LC/MS [M + H] = 672.1.

Example 152 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminoch1oro-9H—purinyl)-3 -ethyny1-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)—2-(4—(2-oxo-3 -propyltetrahydropyrimidin-1(2H)- y1)benzyl)malonic acid o NH2 0 NH2 0 NH2 0 CE \ OEt 0 OH < N l 10¢”? ( [\N EtO O:L 0 H ZOE—ll ;mNO LiOH HO O N O N C O BSA TMSOTf MeCN o : S 2 )LN Aco‘ 0A0 AcO )LN H0 'OH \/‘N\\) \PNb ) Example 152 Proceeding as descnbed in Example 148 above but substituting MeI and 2—chloro—N— methyl-9H—purinamine with l-bromopropane and 2-chloro-9H—purinamine provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 6 ppm 8.15 (s, 1H), 7.28 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 5.97 (d, J=7.5 Hz, 1H), 4.75 (d, J=7.6 Hz, 1H), 4.27 (s, 1H), 3.99 — 4.11 (m, 2H), 3.46 — 3.54 (m, 2H), 3.35 — 3.44 (m, 4H), 3.16 — 3.27 (m, 2H), 3.05 (s, 1H), 1.97 — 2.03 (m, 2H), 1.50 — 1.58 (m, 2H), 0.88 (t, J=7.4 Hz, 3H); LC/MS [M + H] = 658.1. e 153 Synthesis of 2-(((2R,3S,4R,5R)(2-chloro(isopropylamino)—9H—puriny1)ethynyl- 3 ,4-dihydroxytetrahydrofuran—Z-y1)methoxy)—2-(4-(1—(2-hydroxyethyl)oxo-1,2- dihydropyridiny1)benzy1)malonic acid 0 o HN/k o HN/k OQOE‘ 1.TFA,H20,DCM OQOE' OQOEt /N Br 2, A020, ne J\ < l A EtO + :L., )fO DCM EtO (“1:10 :3—7,O H Cl O 0 0 EtO O N GAO O N Cl BSA,TMSOTf,MeCN : S / TBDpsofN \ \ 0 A05 bAc Acd ’OAC \ HN/k HN’k J KZCOSDMF To a solution of diethyl aR, 5R, 6R, 6aR)—6-acetoxyethynyl—2,2-dimethyltetra— hydrofuro[2,3-d][1,3]dioxolyl)methoxy)malonate (4.13 g, 9.97 mmol, 1 eq) in DCM (40 mL) at 20 °C was added TFA (40 mL, 540.24 mmol, 54 eq) and H20 (4 mL, 222.03 mmol, 22 eq). The mixture was stirred at 20 0C for 15 h before it was ed by ted aq.

NaHCO3 (200 mL) and extracted with EtOAc (5 X 50 mL). The combined organic layer was washed brine (200 mL), dried over anhydrous NazSO4, filtered and concentrated to give crude diethyl 2-(((2R, 3S, 4R)—3 -acetoxy-3 -ethynyl-4, 5 -dihydroxytetrahydrofuranyl)- methoxy)malonate (4.14 g) as a light yellow syrup which was used in the next step directly.

To a solution of the above crude product (4.14 g, 12.46 mmol, 1 eq) in pyridine (40 mL) was added AczO (9.33 mL, 99.67 mmol, 8 eq) and 4-DMAP (3.81 g, 31.15 mmol, 2.5 eq). The e was stirred at 20 °C for 16 h before it was quenched by water (150 mL) and the resulting solution was extracted with EtOAc (4 x 50 mL). The combined organic layer was washed with 0.5 N aq. HCl (120 mL) and water (2 x 100 mL), brine (100 mL), dried owmdemmbhfiOgmwmdmdamwmmmdTmemmhmflmwwwpmmmflwflwh column chromatography on silica gel (30—50% EtOAc in petroleum ether) to provide diethyl 2-(((2R, 3R, 4R)-3,4,5-triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (2.60 g) as a syrup.

Step 2: To a on of diethyl 2-(((2R, 3R, 4R)-3,4,5-triacetoxy-3—ethynyltetrahydrofuran—2- yl)methoxy)malonate (1.2 g, 2.62 mmol, 1 eq) and 2-chloro-N-isopropyl-9H—purinamine (665 mg, 3.14 mmol, 1.2 eq) in MeCN (15 mL) was added BSA (1.62 mL, 6.54 mmol, 25 eq). The suspension was stirred at 65°C for 0.5 h before it was cooled down to 0°C. To this solution was added TMSOTf (1.45 g, 6.54 mmol, 1.18 mL, 2.5 eq). Then the mixture was d at 65°C for 2.5 h before it was quenched by ted aq. NaHCO3 (50 mL) and the rammguwmmW%@MdemmeAu4xmnm)TMcmmmwogmmmems MMMWmmemMfimJMmMMwmmmmlHmwwmmwmmflwmm column chromatography on silica gel (30 — 50% of EtOAc in petroleum ether) to provide diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(2-chloro(isopropylamino)—9H-purinyl)—3 - ethynyltetrahydrofuranyl)methoxy)malonate (814 mg, 51% yield).

Step 3: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(2-chloro(isopropyl— amino)-9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (120 mg, 197 umol, WO 46403 1 eq) in DMF (1 mL) was added K2C03 (81.56 mg, 590.15 umol, 3 eq) and 3-(4-(bromo- methyl)phenyl)(2-((ZerZ-butyldiphenylsilyl)oxy)ethyl)pyridin-2(MED-one (161 mg, 295 umdjjem.memmmW%smmdm20%Hmd5hbfidefiw&dmmmuthmmUO mL) and extracted with EtOAc (4 x 5 mL). The combined organic layer was washed with water (2 x 30 mL), dried over anhydrous NazSO4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (30 — 60% of EtOAc in petroleum ether) to provide diethyl 2-(4-(1-(2—((l‘erl—butyldiphenylsilyl)oxy)ethyl)oxo-l,2-dihydro- n-3 -yl)benzyl)—2-(((2R, 3R, 4R, 5R)-3 ,4—diacetoxy(2—chloro—6-(isopropyl-amino)-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (154 mg) as a colorless oil.

Step 4: To a solution of diethyl 2-(4-(1-(2-((ZerZ-butyldiphenylsilyl)oxy)ethyl)oxo-1,2- dihydropyridin-3 -yl)benzyl)(((2R, 3R, 4R,5R)-3 ,4-diacetoxy-5 -(2-chloro(i yl— amino)-9H—purinyl)—3-ethynyltetrahydrofuran-2—yl)methoxy)malonate (150 mg, 139 umol, 1 eq) in THF (1 mL) was added TBAF (1 M, 209 uL, 1.5 eq) and AcOH (5.98 uL, 104.59 umol, 0.75 eq) at 0 OC. The mixture was stirred at 20 0C for 16 h before it was d with water (5 mL) and the resulting solution was extracted with EtOAc (3 x 5 mL). The combined mymdwflwumRMWflmmmwflwfimeflwmflwmmmmdTmemmms purified by preparative TLC (petroleum ether: EtOAc = 1:4) to provide diethyl 2- (((2R, 3R, 4R, 5R)-3 ,4-diacetoxy-5 —(2-chloro(i ylamino)—9H—purinyl)-3 -ethynyl- tetrahydrofuranyl)methoxy)(4—(1-(2-hydroxyethyl)-2—oxo-1,2-dihydropyridin-3 - yl)benzyl)malonate (51 mg, 32% yield) as a white solid.

Step 5: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-chloro(isopropyl- amino)—9H—purin-9—yl)—3 -ethynyltetrahydrofuran-2—yl)methoxy)-2—(4—(1-(2—hydroxyethyl)—2— oxo-1,2-dihydropyridinyl)benzyl)malonate (50 mg, 60 umol, 1 eq) in THF (0.5 mL) was added sat.LiOH.aq (2.51 mg, 60 umol, 0.5 mL, 1 eq). The mixture was stirred at 20 °C for 2.5 h before the organic volatile was removed under reduced pressure. The ing aq. solution was acidified to pH 2 with 2 N aq. HCl solution and concentrated. The residue was further purification by preparative HPLC n: YMC-Triart Prep C18 150*40mm*7um; mobile phase: [water (0.225%FA)—ACN]; B%: 28%-48%, 10min) to e 2- (((2R,3S,4R,5R)(2—chloro—6-(isopropylamino)-9H—pu1in—9-yl)-3—ethynyl—3,4-dihydroxy— WO 46403 tetrahydrofuranyl)methoxy)—2-(4—(1-(2-hydroxyethyl)-2—oxo-1,2—dihydropyn' din—3 - yl)benzyl)malonic acid (10.8 mg, 26% yield) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.08 (s, 1H), 7.55 (dd, J=6.7, 1.9 Hz, 1H), 7.21 — 7.42 (m, 5H), 6.34 (t, J=6.8 Hz, 1H), 5.95 (d, J=7.3 Hz, 1H), 4.74 (d, J=7.3 Hz, 1H), 4.24 - 4.39 (m, 2H), 4.00 — 4.14 (m, 4H), 3.76 — 3.87 (m, 2H), 3.40 — 3.54 (m, 2H), 3.06 (s, 1H), 1.24 (dd, J=6.4, 2.9 Hz, 6H); LC/MS [M + H] = 697.0.

Examples 154 & 155 Synthesis of 2—(((2R, SS, 4R, (6-amino-2—chloro-9H—purinyl)—3 -ethynyl-3 ,4- dihydroxytetrahydrofuran—2-yl)methoxy)—2-(4-(4-methyloxopiperazin—1-yl)benzyl)malonic 2—(((2R, 3S, 4R, 5R)-5 -(6—amino-2—chloro—9H—purinyl)—3 -ethynyl-3 ,4— dihydroxytetrahydrofuranyl)methoxy)—2-(4-((2- ((carboxymethyl)(methyl)amino)ethyl)amino)benzyl)malonic acid 2‘\ @014 0 TFA' DCM O 0 J HCHO SOCIZ. DMF —> 8k,“ N E10 0 N + Boc’ CULCSZCOS NJ DCM DMF’d'°Xa”e HNJ NaBchN 2LNNJ Boc’ MeOH /NJ — XOTIO 0)< 032005,, DMFJ O NH2 NH2 0 O o 0E1 </N (,qu OE! 0 0E! [\N 1) TFA, H20, DCM BO 0 N A H N’J‘CI o EC 0 o N CI o ‘— o S I‘MOAC 2) AcZO, 4—DMAP ‘5 7"‘0 — — . pyridine‘DCM O . J ,, )< 005 0A3 0 N A06 ’OAc N Acd N Aco‘ / /N\) /N\) aq.LiOH NH: NH; OH </“ 11 OH </” / ‘1 0:9,” / N 01 + :30,” N CI — : 'a O 5 '9 HO OH )\ HO OH Example 154 N Example 155 To a mixture of tert-butyl 3-oxopiperazinecarboxylate (8.7 g, 43.45 mmol, 1.2 eq) and (4-iodophenyl) methanol (8.5 g, 36.32 mmol, 1 eq) in DMF (10 mL) and e (90 mL) was added CuI (1.03 g, 5.43 mmol, 0.15 eq) , 2-(hydr0xymethyl)methyl-propane—1,3- diol (653 mg, 5.43 mmol, 0.15 eq) and CszCO3 (35.39 g, 108.62 mmol, 3 eq). The mixture was stirred at 110 °C under N2 atmosphere for 14 hours before it was cooled. The inorganic solid was filtered off and the filtrate was concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with ethyl e (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried by Na2S04, filtered and concentrated. The crude residue was purified by flash silica gel chromatography (0 — 10% of EtOAc in petroleum ether) to provide lert—butyl 4—(4-(hydroxymethyl)phenyl)—3-oxopiperazine-1—carboxylate (6.1 g, 55% ymMflmaWMESdm.

Step 2: To a solution of lert—butyl 4-(4-(hydroxymethy1)phenyl)—3-oxopiperazine carboxylate (2 g, 6.53 mmol, 1 eq) in DCM (10 mL) was added TFA (5.00 mL, 67.53 mmol, .34 eq) at 0 oC. The mixture was stirred at 25 °C for 3 h before it was concentrated. The residue was diluted with water (20 mL) and extracted with a mixture ofDCM and MeOH (50: 1=v:v, 2 x 20 mL). The ed organic layer was concentrated to provide crude 1—(4- (hydroxymethyl)phenyl)piperazinone (2.45 g) as a ess oil.

Step 3: To a solution of crude 1-(4-(hydroxymethyl)phenyl)piperazinone (2.45 g, 11.88 mmol, 1 eq) in MeOH (15 mL) was added HCHO (720 uL, 26.12 mmol, 22 eq), AcOH (5 mL, 87.42 mmol, 7.4 eq). The mixture was stirred at 25 0C under N2 atmosphere for 15 h before NaBH3CN (2.05 g, 32.65 mmol, 2.75 eq) was added and the resulting mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10 — 40% ofMeOH in EtOAc) to give 1-(4- (hydroxymethyl)phenyl)—4-methylpiperazin—2-one (1.23 g) as a colorless oil.

Step 4: To a solution of 1-(4—(hydroxymethyl)phenyl)—4-methylpiperazin-2—one (1.23 g, 5.58 mmol, 1 eq) in DCM (2 mL) was added DMF (0.2 mL) and SOC12 (810 uL, 11.17 mmol, 2 eq). The e was d at 25 °C for 30 min to give white sion before it was concentrated under reduced pressure to give crude 1-(4-(chloromethyl)phenyl)methyl- piperazinone (1.27 g, 95% yield) as a white solid which was used in the next step directly.

Step 5: To a solution of diethyl 2-(((3aR, 5R, 6R, 6aR)acetoxy-6—ethynyl-2,2-dimethyltetra- hydrofuro[2,3—d][1,3]dioxol—5-yl)methoxy)malonate (1.4 g, 3.38 mmol, 1 eq) in DMF (15 mL) was added CszCO3 (3.30 g, 10.14 mmol, 3 eq) and crude 1-(4-(chloromethyl)-phenyl)—4- methylpiperazinone (1.21 g, 5.07 mmol, 1.5 eq). The mixture was stirred at 25 °C for 1 h mmmfiwwfiMmdmdeWMEWMCM%MMwiTMcmwnmmwwwpmmwby flash column chromatography on silica gel (O—50% MeOH in EtOAc) to give diethyl 2- (((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetrahydrofuro[2, 3 -d][1,3]dioxol-5 - yl)methoxy)(4-(4-methyloxopiperazin- l -y1)benzyl)malonate (1.02 g).

Step 6: To a solution of diethyl 2-(((3aR,5R, 6R, 6aR)acetoxy-6—ethynyl-2,2-dimethyltetra- uro[2,3—d][1,3]dioxol—5-yl)methoxy)—2-(4-(4—methyl—2-oxopiperazin—1-yl)benzyl)- malonate (1.02 g, 1.65 mmol, 1 eq) in DCM (5 mL) and water (1 mL, 55.51 mmol, 34 eq) was added TFA (4.99 mL, 6736 mmol, 41 eq). The mixture was stirred at 25 °C for 20 h before it was concentrated to give crude diethyl R,3S, 4R)ethynyl-3,4,5-trihydroxy- tetrahydrofuran-2—yl)methoxy)—2-(4-(4-methyl-2—oxopiperazin-1—yl)benzyl)malonate (1.13 g) as an oil.

To a solution of diethyl 2-[[(2R,3S,4R)—3-ethynyl-3,4,5-trihydroxy-tetrahydrofuran yl]methoxy]—2-[[4-(4—methyl—2-oxo—piperazinyl)phenyl]methyl]propanedioate (1. 13 g, 2.11 mmol, 1 eq) in DCM (10 mL) was added 4-DMAP (25.78 mg, 211.00 umol, 0.1 eq) pyridine (1.07 mL, 13.2 mmol, 6.3 eq) and AC2O (927 uL, 9.9 mmol, 4.7 eq). The mixture was stirred at 25 °C for 16 h before it was concentrated. The residue was diluted with EtOAc (20 mL) and 1N aq. HCl (10 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (4 x 20 mL). The combined organic layer was washed with water (50 mL), brine (50 mL) and dried over anhydrous , filtered and concentrated to provide crude l 2-(4-(4-methyloxopiperazinyl)benzyl)—2-(((2R,3R,4R)—3,4,5- triacetoxyethynyltetrahydrofuranyl)methoxy)malonate (674 mg) as an syrup.

Step 7: To a solution of 2-chloro-9H-purinamine (76 mg, 450.46 umol, 1.2 eq) in dichloroethane (3 mL) was added BSA (204 uL, 825.84 umol, 2.2 eq). The mixture was stirred at 65°C for 0.5 h before it was cooled to 0°C and crude diethyl 2-(4-(4—methyl—2- oxopiperazin- l nzyl)—2-(((2R, 3R, 4R)-3 ,4, 5 -triacetoxy-3 -ethynyltetrahydrofuran yl)methoxy)malonate (248 mg, 375.38 umol, 1 eq) in dichloroethane (1 mL) and TMSOTf (102 uL, 563.07 umol, 1.5 eq) was added. The mixture was stirred at 65°C for 2 h under N2 atmosphere before it was quenched with ted aq. NaHC03 (15 mL) and extracted with EtOAc (4 x 20 mL). The combined organic layer was dried over anhydrous Na2S04, flltered and concentrated. The residue was purified by flash column tography on silica gel (0 — 30% ofMeOH in EtOAc) to provide diethyl 2-(((2R, 3R, 4R, 4-diacetoxy(6-amino- 2—chloro-9H—purin—9-yl)—3-ethynyltetrahydrofuran-2—yl)methoxy)—2—(4-(4-methyloxo— piperazinyl)benzyl)malonate (62 mg) as a white solid.

Step 8: To a solution of diethyl R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3 yltetrahydrofuranyl)methoxy)-2—(4-(4-methyloxopiperazin yl)benzyl)malonate (171 mg, 222.02 umol, 1 eq) in THF (2 mL) was added aq, LiOH (5.32 mg, 222.02 umol, 2 mL, 1 eq). The mixture was stirred at 25 0C for 2.5 h before it was acidified to pH 2 — 3 with 2N aq. HCl. The mixture was concentrated under d pressure. The crude residue was further purified by preparative HPLC to provide 2- (((2R, 3S, 4R, 5R)-5 —(6-amino-2—chloro—9H—purin-9—yl)—3 -ethynyl-3 ,4-dihydroxy-tetrahydro— furanyl)methoxy)-2—(4-(4-methyloxopiperazinyl)benzyl)-malonic acid (3.3 mg) as an off-white solid and 2—(((2R, 3S, 4R, 5R)(6-aminochloro—9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuran-2—yl)methoxy)-2—(4-((2-((carboxymethyl)(methyl)amino)ethyl)— amino)benzyl)malonic acid (3.7 mg) as a white solid. 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydro- furan-2—yl)methoxy)(4—(4-methyloxopiperazin-l-yl)benzyl)malonic acid: 1H NMR (400 MHz, CD3OD) 5 ppm 8.35 (s, 1H), 7.35 (d, J=8.3 Hz, 2H), 6.97 (d, J=8.5 Hz, 2H), 5.95 (d, J=5.5 Hz, 1H), 4,70 - 4.79 (m, 1H), 4.33 (dd, J=9.0, 3.3 Hz, 1H), 3.96 - 4.14 (m, 2H), 3.54 — 3.66 (m, 2H), 3.49 (s, 2H), 3.35 (s, 1H), 3.21 (s, 2H), 2.83 (t, J=5.4 Hz, 2H), 2.32 - 2.48 (m, 3H), 1.89 (s, 3H), LC/MS [M + H] = 630.2. 2-(((2R, 3S, 4R, 5R)(6-amino-2—c hloro-9H-purinyl)-3 -ethynyl-3 ,4-dihydroxytetrahydro- furan-2—yl)methoxy)(4-((2-((carboxymethyl)(methyl)amino)ethyl)amino)benzyl)malonic acid: 1H NMR (400 MHz, CD3OD) 8 ppm 8.56 (s, 1H), 7.03 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.3 Hz, 2H), 6.01 (d, J=6.0 Hz, 1H), 4.70 (d, J=6.0 Hz, 1H), 4.34 (br d, J=4.3 Hz, 1H), 3.94 (dd, J=9.7, 6.9 Hz, 1H), 3.83 (dd, J=9.9, 2.4 Hz, 1H), 3.59 (s, 2H), 3.34 - 3.42 (m, 2H), 3.22 - 3.27 (m, 2H), 3.20 (s, 2H), 3.04 (s, 1H), 2.83 (s, 3H); LC/MS [M + H] = 649.3. —234— Example 156 Synthesis of 2-(((2R, 3S, 4R, 5R)—5-(5 -ch1oro((2,4-dimethoxybenzy1)amino)-3H- imidazo[4,5-b]pyridin-3 -y1)—3-ethyny1-3,4—dihydroxytetrahydrofuran-2—yl)methoxy)—2—(4-(2- oxotetrahydropyrimidin- 1 (2]10—y1)benzy1)malonic acid NN:. Qmfi o ~H 0 CE N OAc —>NO <’ Ii \c‘ TMSOTf BSA DIEA NMP E10 0 N / 0 o N CI HNXN MeCN ' 130°C AcO —ACO OAC microwave O K) )LN 5 a, HO OH aq. LiOH, THF HNLN ~* HO "0H K) Example 156 Step 1: To a mixture of chloro-3H-imidazo[4,5-b]pyridine (317 mg, 1.69 mmol, 1 eq) in MeCN (6 mL) was added BSA (1.04 mL, 4.22 mmol, 2.5 eq). The mixture was stirred at 65 0C under N2 atmosphere for 0.5 h before it was cooled to 0°C. To the mixture was added diethyl 2-oxotetrahydropy1imidin-1 (2]10-y1)benzy1)-2—(((2R, 3R, 4R)-3 ,4, 5-triacetoxy—3 - ethynyltetrahydrofuranyl)methoxy)ma1onate (1.20 g, 1.85 mmol, 1.1 eq) and TMSOTf (913.99 uL, 5.06 mmol, 3 eq). The mixture was stirred at 65 °C under N2 atmosphere for 6 h before it was quenched with NaHCO3 (15 mL). The reaction mixture was extracted with EtOAc (3 X 15 mL). The combined organic layer was washed with brine (2 x 5 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (0 — 100% of EtOAc in petroleum ether) to provide diethyl 2-(((2R, 3R, 4R, 5R)—3,4-diacetoxy(5,7-dichloro—3H-imidazo[4,5- b]pyridiny1)ethyny1tetrahydrofurany1)methoxy)(4-(2-oxotetrahydropyrimidin— 1(2H)—y1)benzy1)malonate (752 mg) as a foam.

Step 2: To a mixture of diethyl R, 3R, 4R, 5R)-3,4-diacetoxy(5,7-dichloro-3H— imidazo[4,5—b]pyridiny1)—3-ethynyltetrahydrofuranyl)methoxy)—2-(4-(2- oxotetrahydropyrimidin-1(2H)-y1)benzy1)malonate (752 mg, 970.82 umol, 1 eq) and 2,4- dimethoxybenzylamine (292 uL, 1.94 mmol, 2 eq) and DIEA (507 uL, 2.91 mmol, 3 eq) were taken up into a microwave tube in NMP (4 mL). The sealed tube was irradiated in a microwave reactor at 130°C for 2 h before it was diluted with H20 (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (0 — 100% of EtOAc in petroleum) to provide diethyl 2-(((2R, 3S, 4R, 5R)-5—(5-chloro((2,4-dimethoxybenzyl)amino)-3H—imidazo- [4,5—b]pyridin-3 -ethynyl-3,4—dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetra- hydropyrimidin-1(2H)-yl)benzyl)malonate (249 mg, 26% yield) as a foam.

Step 3: To a mixture of diethyl 2-(((2R,3S,4R,5R)(5-chloro((2,4-dimethoxybenzyl)- amino)-3H—imidazo[4,5-b]pyridinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)- methoxy)—2—(4-(2-oxotetrahydropyrimidin—1(2H)-yl)benzyl)malonate (239 mg, 291.01 umol, 1 eq) in THF (4 mL) and H20 (3 mL) was added LiOH (69.69 mg, 2.91 mmol, 10 eq). The mixture was stirred at 25 °C for 20 h before it was ed to pH 6-7 with 2N aqueous HCl and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm*5um, mobile phase: [water (0.1%TFA)-ACN]; B%: 25%-65%, 10 min) and dried by lyophilization to provide 2- (((2R, 3S, 4R, 5R)(5 -chloro((2,4-dimethoxybenzyl)amino)—3H—imidazo[4, 5-b]pyridin-3 - yl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin- 1(2hO-yl)benzyl)malonic acid (9.5 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.23 (s, 1H), 7.27 (d, J=8.44 Hz, 2H), 7.21 (d, J=8.31 Hz, 1H), 7.00 (d, J=8.44 Hz, 2H), 6.58 (d, J=2.32 Hz, 1H), 6.46 — 6.51 (m, 2H), 6.04 (d, J=7.34 Hz, 1H), 4.73 (d, J=7.34 Hz, 1H), 4.43 (s, 2H), 4.27 (t, J=3.06 Hz, 1H), 4.01 (d, J=2.93 Hz, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 3.37 — 3.47 (m, 2H), 3.31 — 3.37 (m, 2H), 3.22 (t, J=5.87 Hz, 2H), 3.03 (s, 1H), 1.78-1.85 (m, 2H); LC/MS [M + H] = 765.1. e 157 Synthesis of 2-(((2R,3S,4R,5R)—5-(7-aminochloro-3H—imidazo[4,5-b]pyridinyl) 1-3 ydroxytetrahydrofuranyl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2H)- yl)benzyl)malonic acid NH o NH2 0 OH N OH <, \ TFA, DCM l <,Nle/ic HO o N N’ (:1 O —0: 00'— Example 157 To a mixture of 2-(((2R, 3S, 4R, 5R)—5-(5-chloro((2,4-dimethoxybenzyl)amino)-3H— imidazo[4,5-b]pyridinyl)ethynyl-3,4—dihydroxytetrahydrofuran-2—yl)methoxy)-2—(4-(2- oxotetrahydropyrimidin-l(2]10-yl)benzyl)malonic acid (160 mg, 209.11 umol, 1 eq) in DCM (3 mL) was added TFA (1 mL, 13.51 mmol, 64.59 eq). The mixture was stirred at 25 °C for 2 h before it was concentrated. The residue was d by preparative HPLC n: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225%FA)-ACN], B%: %—40%, 10 min) and dried by lyophilization to provide 2—(((2R, 35, 4R, (7—amino-5— chloro-3H—imidazo[4,5-b]pyridinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)- methoxy)(4-(2-oxotetrahydropyrimidin-l(2H)-yl)benzyl)malonic acid (5.4 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.34 (s, 1H), 7.28 (d, J=8.31 Hz, 2H), 7.02 (d, J=8.44 Hz, 2H), 6.49 (s, 1H), 6.07 (d, J=7.21 Hz, 1H), 4.78 (d, J=7.21 Hz, 1H), 4.30 (t, J=3.18 Hz, 1H), 3.93-4.08 (m, 2H), 3.45 — 3.54 (m, 2H), 3.35—3.49 (m, 4H), 3.04 (s, 1H), 1.94—2.00 (m, 2H); LC/MS [M + H] = 615.1.

Example 158 Synthesis of 2-((lH—pyrazol-S-yl)methyl)(((2R,3S, 4R, 5R)(6—aminochloro—9H—purin- 9-yl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 0 N(BOC)2 film 0 N(BOC)2 O NH2 0QCE (/NN m5“’ O OEt N 1.TFA DCM O OH N N \ v \ 1 “11¢ </ l i 2, aq. LiOH, THF (’ l i EC 0 / / X07N E10 0 N HO 0 N K2C03,DMF N CI o N , c.

\ ‘ ,N\ 2 :10); — \ \ ,NH :2 ~. ., . ., . ., A06 ’0“ N B00Ac5 bAc N H5 ’OH Example 158 Cal-210 Proceeding as described in Example 1 above but substituting benzyl bromide with tert-butyl 5-(bromomethyl)- lH—pyrazole-l-carboxylate provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.46 (s, 1H), 7.32 (s, 1H), 6.17 (s, 1H), 6.02 (d, J=7.13 Hz, 1H), 4.83 (s, 1H), 4.34 (s, 1H), 3.98 — 4.11 (m, 2H), 3.43 — 3.54 (m, 2H), 2.95 (s, 1H); LC/MS [M + H] = 508.1.

Example 159 Synthesis of 2-benzyl(((2R, 3S, 4R, 5R)—5-(2-chloro( 1 -tosyl- 1H-pyrazolyl)—9H-purin- 3-ethyny1-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid 7%?,Bo o 0 / / 0 CI 0 o 0 OEt <1: N 0 aq. LiOH THF 0 OH N Nim ‘N 1 3)4, 082003 </ 1 ,N :0;O </N —’ E10 0 :0 fiN—TSE ,N IN: HO O dioxane,H20 NAG : O: ,N Aco‘ 'bAc AcO ’O HO ’OH Example 159 Step 1: To a mixture of diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2,6-dichloro- 9H-purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (1.3 g, 1.92 mmol, 1 eq) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)tosyl-1H-pyrazole (669 mg, 1.92 mmol, 1 eq)1n dioxane (10 mL) and H20 (3 mL) under a N2 atmosphere was added Pd(PPh3)4 (222 mg, 192 umol, 0.1 eq) and CszCO3 (1.88 g, 5.76 mmol, 3 eq). The mixture was stirred at 100 °C for 3 h before it was filtered and the filtrate was concentrated under reduced pressure, The crude residue was purified by flash silica gel column chromatography (0 — 50% ofEtOAc in petroleum ether) to provide diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4- diacetoxy(2-chloro(1-tosyl-1H-pyrazolyl)-9H-purinyl)ethyny1tetrahydrofuran- ethoxy)malonate (170 mg) as a foam.

Step 2: To a solution diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(2-chloro(1- tosyl-1H-pyrazolyl)-9H—purin-9—yl)—3 -ethynyltetrahydrofuranyl)methoxy)malonate (50 mg, 58 umol, 1 eq) in THF (1 mL) was added 1M aq. LiOH (1 mL, 18 eq). The e was stirred at 25 0C for 14 h before it was d with EtOAc (10 mL) and water (10 mL). The aqueous phase was adjusted to pH 2-3with 2M aq. HCl solution and extracted with EtOAc (2 x 40 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude e was purified by preparative HPLC (column: YMC-Triart Prep C18 150*40mm*7um, mobile phase: [water (O.225%FA)-AC], B%: 40%-60%,10 min) to provide 2-benzyl-2—(((2R, 3S, 4R, (2-chloro-6—( l —tosyl— 1H-pyrazolyl)—9H-purin-9—yl)— 3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)malonic acid (2.0 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.98 (s, 1H), 8.69 (s, 2H) 7.47 (d, J=8.25 Hz, 2H), 7.30 (d, J=6.88 Hz, 2H), 7.07 — 7.19 (m, 4H), 6.92 (d, J=8.00 Hz, 2H), 6.24 (d, J=7.63 Hz, 1H), .85 (d, J=7.63 Hz, 1H), 4.35 (t, J=2.56 Hz, 1H), 4.03 — 4.09 (m, 1H), 3.90 (d, J=10.63 Hz, 1H), 3.40 = 723.2. — 3.50 (m, 1H), 2.92 (s, 1H), 2.05 (s, 3H); LC/MS [M + H] Example 160 Synthesis of 2-(((2R, SS, 4R, 5R)(2-chloro—6-(methylamino)-9H-purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-Z-yl)methoxy)(4—(2-oxo- l l— l ,2-dihydropyridin-3 — yl)benzyl)malonic acid \ ,Boc O N \ ,Boc o N > 0 OEt N Br N 0 ~ . do <’ 1 </ l N \ / NAC] N Eto o :ZO: ,N N/ CI KCO2 3. DMF O :: : bAc Acd . —, Aco‘ ’OAc \/\N Example 160 Proceeding as described in Example 19 above but substituting diethyl 2— (((2R, 3R, 4R, 5R)—3 ,4-diacetoxy-5 -(6-N,N’ -(bi s-(lert—butoxycarbony1)amino)chloro-9H— purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate with diethyl 2-(((2R,3R,4R,5R)— 3,4-diacetoxy(6-((lerl—butoxycarbonyl)(methyl)amino)chloro—9H—purinyl)ethynyl- tetrahydrofuran-Z-yl)methoxy)malonate provided the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) 8 ppm 8.44 (s, 1H), 8.25 (d, J=4.3 Hz, 1H), 7.68 (dd, J=6.7, 1.8 Hz, 1H), 7.29 — 7.51 (m, 3H), 7.18 (d, J=7.5 Hz, 2H), 6.28 (t, J=6.8 Hz, 1H), 6.21 (s, 1H), 6.01 (d, J=6.8 Hz, 1H), 5.83 (d, J=7.3 Hz, 1H), 4.82 (s, 1H), 4.17 (dd, J=5.1, 2.6 Hz, 1H), 3.96 (s, 1H), 3.89 (t, J=7.3 Hz, 2H), 3.79 (s, 1H), 3.58 (s, 1H), 3.25 (s, 1H), 2.90 (d, J=4.5 Hz, 3H), 1.67 (sxt, J=7.3 Hz, 2H), 0.88 (t, J=7.4 Hz, 3H), LC/MS [M + H] = 667.1.

Example 161 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-amino—2-(1-hydroxyethyl)-9H-purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran—2-yl)methoxy)benzylmalonic acid NIK/lfil/0 l'\\l/laeBOH—|::> f/KKLiOH / I ’ OO—E—Tajrhplefi; Step 1: To a solution of diethyl yl(((2R, 3R, 4R, 5R)—3,4-diacetoxy—5-(2-acetyl amino-9H—purinyl)ethynyltetrahydrofuranyl)methoxy)malonate (48 mg, 72.11 umol, 1 eq) in MeOH (2 mL) at 0°C was added NaBH4 (4.09 mg, 108.17 umol, 1.5 eq). The solution was stirred at 0°C for 1 h. Additional NaBH4 (4.1 mg) was added to the reaction mixture and it was stirred at 0°C for 0.5 h before it was diluted with water (6 mL) and extracted with ethyl acetate (3 X 6 mL). The combined organic layer was dried by , filtered and concentrated. The crude residue was purified by preparative TLC (ethyl acetate) to give diethyl yl(((2R, 3R, 4R, 5R)—3,4-diacetoxy(6-amino(1-hydroxyethyl)— 9H-purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (20 mg) as a syrup.

Step 2: To a solution of l 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(6-amino(1- hydroxyethyl)-9H-purinyl)—3 -ethynyltetrahydrofuran-2—yl)methoxy)malonate (16 mg, 23.96 umol, 1 eq) in THF (2 mL) was added 1M aq. LiOH (0.5 mL, 21 eq). The mixture was stirred at 20°C for 3 h before it was acidifed to pH 5 with 1N aq. HCl solution. The mixture was extracted with ethyl acetate (5 x 3 mL). The combined organic layer was concentrated.

The crude residue was purified by preparative HPLC (Column: YMC-Triart Prep C18 150*40mm*7um, mobile phase: [water (0.225%FA)-ACN], B%: 13%-33%, 10min) and dried by lyophilization to give 2-(((2R, 3S, 4R, 5R)(6-amino(1-hydroxyethyl)—9H—purin yl)-3—ethynyl—3,4-dihydroxytetrahydrofuran—2-yl)methoxy)—2-benzylmalonic acid (4.0 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.49 (d, J=8.88 Hz, 1H), 7.18 — 7.25 (m, 2H), 7.07 — 7.14 (m, 3H), 6.09 (dd, J=9.82, 6.94 Hz, 1H), 4.76 — 4.84 (m, 2H), 4.29 — 4.36 (m, 1H), 3.89 — 4.03 —240— (m, 2H), 3.32 — 3.45 (m, 1H), 3.24 — 3.28 (m, 1H), 3.02 (d, J=10.13 Hz, 1H), 1.52 (d, J=6.50 Hz, 3H); LC/MS [M + H] = 528.1. e 162 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H-purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)(4-(l-methyloxo-1,2-dihydropyridin-3 — yl)benzyl)malonic acid 0 NBoc2 \ O N Br </ l O /J\ :10: IN N CI K2003,DMF Acd~ $OAc \N Example 162 Proceeding as described in Example 19 above but substituting 3-(4-(bromomethyl)— )-l —propylpyridin-2(1H)—one with 3-(4-(bromomethyl)phenyl)- l -methylpyridin-2(1H)— one provided the title compound as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.12 (s, 1H), 7.55—7.53 (m, 1H), 7.38—7.28 (m, 5H), 6.33 (t, J=6.8 Hz, 1H), 5.94 (d, J=7.6 Hz, 1H), 4.75 (d, J=7.6 Hz, 1H), 4.27—4.26 (m, 1H), 4.09—4.01 (m, 2H), 3.55 (s, 3H), 3.53—3.44 (m, 2H), 3.05 (s, 1H); LC/MS [M + H] = 625.0.

Example 163 Synthesis of 2-benzyl(((2R, 3S, 4R, (6-(3 -carboxypropyl)—2-chloro-9H—purinyl)-3 - ethynyl-3,4-dihydroxytetrahydrofuran-Z-yl)methoxy)malonic acid —241— 0 o N CE OEt < f;/ N Ban\A/[LOEt \ N 0E1 TFA, DCM N </N i Cl —>N 0 X0) Pd(Ph3P)4,THF N </ I + N ,VOAC o N NAG o H Acd 110Ac 0$3333ch o</ \N ' OOOEiBSA TMSOTf MeCN/ aq LiOH THF EOt O<N1NA :L/(Vtoa:N —HO 1 bH —ACO 1’ Example 163 Step 1: To a on of 2,6—dichloro(tetrahydro—2H—pyranyl)-9H-purine (4.00 g, 14.65 mmol, 1 eq) and Pd(Ph3P)4 (1.69 g, 1.46 mmol, 01 eq) in THF (30 mL) under N2 atmosphere at 0 °C was added a solution of 0.5 M oxyoxobutyl)zinc(II) bromide (7323 mL, 36.61 mmol, 2.5 eq) se. The mixture was stirred from 0 — 25 0C over 16 h before it was cooled to 0 °C and quenched with 0.5N aq. HCl solution. The reaction mixture was extracted with EtOAc (3 x 100 mL). The combined organic extract was washed with H20 (100 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (10—75% EtOAc in petroleum ether) to provide ethyl 4—(2-chloro(tetrahydro—2H-pyranyl)-9H-purin yl)butanoate (2.83 g).

Step 2: To a solution of thy] 4-(2-chloro-9—(tetrahydro-2H-pyranyl)-9H-purinyl)- butanoate (1.50 g, 4.25 mmol) in DCM (15 mL) was added TFA (10 mL). The mixture was stirred at 25 0C for 7 h before it was concentrated under reduced pressure. The residue was re-taken up in H20 (50 mL) and neutralized to pH 7 with saturated aq. . The resulting mixture was extracted with EtOAc (3 x 75 mL). The combined organic layer was washed with brine, dried over , filtered and concentrated to provide ethyl 4-(2-chloro- 9H-purinyl)butanoate (1.05 g).

Steps 3 — 4: Proceeding as described in e 5 above but substituting uracil with ethyl 4-(2— chloro-9H-purinyl)butanoate provided the title compound as a white solid. —242— 1H NMR (400 MHz, CD3OD) 5 ppm 8.74 (s, 1H), 7.27—7.24 (m, 2H), 7.09—7.08 (m, 3H), 6.09 (d, J=7.6 Hz, 1H), 5.05 (d, J=7.6 Hz, 1H), 4.31—4.14 (m, 1H), 4.10—4.06 (m, 2H), 3.18— 3.16 (m, 3H), 2.41 (t, J=7.2 Hz, 2H), 217—2. 15 (m, 2H), 1.22 (t, J=7.6 Hz, 2H); LC/MS [M + H] = 589.1.

Examples 164 and 165 Synthesis of (R)—2-(((2R, 3S, 4R,5R)(6-aminochloro-9H-purin-9—yl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran—2-yl)methoxy)—3 -ethoxy-3 -oxo—2-(4-(2-oxotetrahydropyrimidin- l(2H)-yl)benzyl)propanoic acid (S)—2-(((2R, 3S, 4R, 5R)—5-(6-aminochloro-9H-purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)-3 -ethoxy-3 -(4-(2-oxotetrahydropyrimi din- l(2hO-yl)benzyl)propanoic acid 0 0 NH2 0 ”Hz 0 OE! (:INEICI 0 OEt O / (N \ >—OH I i <N<N 'Nic E10 0 E10 0 N E10 0 0 o N/ 0‘ aqLiOH o O BSA, TMSOTf O THF O , -. ,1 _ ,1 ’OAc AcO MeCN OAc HO OH Example 164 O NH2 0 NH2 0 OH </ . :1 HO O N E10>I (N 0 N CI O EL <.

”OH 3L HNJ Example 9 ”NJ Example 165 Step 1: To a suspension of 2-chloro—9H—purinamine (1.04 g, 6.15 mmol, 1.7 eq) in MeCN (10 mL) at 25 0C was added N,O-bis(trimethylsilyl)acetamide (BSA) (3.1 mL, 0.0127 mol, 3.5 eq). The resulting suspension was heated at 85 0C for 30 min as it became clear. The on mixture was allowed to cool to 25 oC followed by addition of a solution of diethyl 2- (4-(2-oxotetrahydropyrimidin- l (2H)-yl)benzyl)—2-(((2R, 3R, 4R)-3 ,4, 5-triacetoxy-3 - ethynyltetrahydrofuran-Z-yl)methoxy)malonate (2.34 g, 0.0036 mol, 1.0 eq) in MeCN (10 mL) and TMSOTf (1.12 mL, 0.00615 mol, 1.7 eq) dropwise. The reaction mixture was then heated at 70—80 °C ght as all of the starting material was consumed. The reaction was allowed to cool to 25 0C before it was diluted with MeCN (100 mL) and quenched with saturated aq. NaHCO3 solution (150 mL). The ble was removed by filtration. The —243 — organic layer of the filtrate was separated, washed with H20 (50 mL), brine (50 mL), dried over Na2S04 and concentrated. The crude e was purified by flash silica gel column chromatography (0 — 5% MeOH in CH2C12) to provide diethyl 2-(((2R, 3R, 4R, 5R)-3,4- diacetoxy-5—(6-aminochloro-9H—purin-9—yl)ethynyltetrahydrofuranyl)methoxy)(4- (2-oxotetrahydropyrimidin-l(2H)-yl)benzyl)malonate (1.1 g, 40% yield) as a white solid.

Step 2: To a solution of diethyl 2-(((2R, 3R, 4R, 5R)-3,4-diacetoxy-5—(6-aminochloro-9H— purinyl)—3 -ethynyltetrahydrofuranyl)methoxy)(4—(2-oxotetrahydropyrimidin- 1 (2H)- zyl)malonate (400 mg, 0.53 mmol, 1 eq) in THF (4 mL) and H20 (4 mL) at 0 0C was added LiOH monohydrate (89 mg, 2.12 mmol, 4 eq). The resulting mixture was stirred at room temperature overnight before the organic volatile was removed under reduced pressure.

The mixture was cooled to 0 0C and acidified to pH 6 with 1N aq. HCl solution and concentrated under reduced pressure The crude residue was purified by preparative ed-phase HPLC to provide a pair of diastereomers as a white solid: (R) (((ZR, 3S, 4R, 5R)-5 -(6-aminochloro—9H—purin-9—yl)—3 yl-3 ,4-dihydroxytetrahydro— 2-yl)methoxy)—3-ethoxyoxo(4-(2-oxotetrahydropyrimidin-l(2110-yl)benzyl)- propanoic acid and (S)(((2R, 3S, 4R, 5R)(6-aminochloro-9H-purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-2—yl)methoxy)-3—ethoxy—3—oxo-2—(4-(2-oxotetrahydropyrimidin— l(2H)-yl)benzyl)propanoic acid which the stereo configuration was arbitrarily assigned. In addition, Example 9 was also isolated as a white solid.

(R)(((2R, SS, 4R, 5R)-5 -(6-aminochloro-9H-purinyl)-3 -ethynyl-3 ydroxytetra- hydrofuranyl)methoxy)-3 -ethoxy-3 -oxo—2-(4-(2—oxotetrahydropyrimidin-1(2H)- yl)benzyl)propanoic acid: 1H NMR (300 MHz, CD3OD) 5 8.32 (s, 1H), 7.28 (d, J=8.1 Hz, 2H), 7.01 (d, J=8.1 Hz, 2H), 6.00 (d, J=7.5 Hz, 1H), 4.84 (d, J=7.5, 1H), 4.28—406 (m, 3H), 3.99—3.95 (m, 2H), 3.52—3.35 (m, 6H), 3.08 (s, 1H), 2.02—1.97 (m, 2H), 1.21 (t, J=7.1, 3H); LC/MS [M + H] = 644.05.

(S)—2—(((2R, SS, 4R, 5R)—5 -(6-amino-2—chloro—9H—purinyl)—3 -ethynyl-3 ,4-dihydroxytetra— hydrofuran—2-yl)methoxy)-3 -ethoxy-3 -oxo—2-(4-(2-oxotetrahydropyrimidin-1(2H)- zyl)propanoic acid: 1H NMR (300 MHZ, CD3OD) 5 8.08 (s, 1H), 7.26—7.29 (d, J=6.8 Hz, 2H), .01 (d, J=7.23 Hz, 2H), 5.96—5.99 (d, J=7.14 Hz, 1H), 4.75—4.77 (d, J=7.5, —244— 1H), 4.02—4.24 (m, 5H), 3.32—3.66 (m, 6H), 3.15 (s, 1H), 1.95—2.19 (m, 2H), 1.22—1.27 (m, 3H); LC/MS [M + H] = 644.05.

Examples 166 and 167 sis of (R)(((2R, SS, 4R,5R)(6-aminochloro-9H-purinyl)ethyny1-3,4- dihydroxytetrahydrofuranyl)methoxy)-3 -oxotetrahydropyrimidin-1(2110- yl)phenyl)propanoic acid (((2R, SS, 4R,5R)—5-(6-aminochloro-9H—purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)-3 -(4-(2-oxotetrahydropyrimidin-1(2110- yl)phenyl)propanoic acid 0 NHZ o\_ NH2 0 NH2 0 GB N OH N OH N </1‘” t - H" </ P“ H... 1. aq. L-IOH, THF </ 1‘“ E10 0 N / 2. heating 0 N A O N A O N | o N CI + O N CI 0 O O . . . , )LN . .

Aco‘ ’OAc )LN Ho‘ ’OH )LN Ho‘ OH HNK) HAL) Example 165 ML) Example 166 The crude product of Example 9 from the work up was dried in the vacuum oven at 60 °C for 2 days before it was purified by preparative HPLC to provide a pair of diastereomers: (R)(((2R, SS, 4R, 5R)(6-aminochloro—9H-purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)-3—(4-(2-oxotetrahydropyrimidin—1(2]10-yl)phenyl)- propanoic acid and (S)(((2R, SS, 4R, 5R)(6-aminochloro-9H-purinyl)-3 -ethyny1-3,4- oxytetrahydrofuran-2—yl)methoxy)-3—(4-(2-oxotetrahydropyrimidin—1(2]10-yl)phenyl)- propanoic acid which the stereo configuration was arbitrarily assigned. Both were isolated as white solids. (((2R, SS, 4R, 5R)-5 -(6—amino-2—chloro—9H—purinyl)—3 -ethynyl-3 ,4—dihydroxytetra— hydrofuranyl)methoxy)-3 -(4-(2-oxotetrahydropyrimidin- 1 (2]10-yl)phenyl)propanoic acid: 1H NMR (300 MHz, CD3OD) 5 8.38 (s, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.04 (d, J=8.3 Hz, 2H), .92 (d, J=7.3 Hz, 1H), 4.36—4.32 (m, 1H), 4.30 (d, J=7.3 Hz, 1H), 4.17 (t, J=2.3 Hz, 1H), 4.07—4.03 (m, 1H), 3.80—3.75 (rn, 1H), 3.54—3.49 (m, 2H), 3.33—3.31 (m, 2H), 3.25—3.19 (m, 1H), 3.12 (s, 1H), 3.09—3.02 (m, 1H), 2.02—1.97 (m, 2H); LC/MS [M + H] = 572.0.

(S)—2-(((2R, SS, 4R, 5R)—5 -(6-aminochloro—9H—purinyl)—3 -ethynyl-3 ,4-dihydroxytetra- hydrofuran—2-yl)methoxy)(4-(2-oxotetrahydropyrimidin-1(2H)—yl)phenyl)propanoic acid: 1H NMR (300 MHz, CD3OD) 5 8.47 (s, 1H), 7.26 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), —245— .97 (d, J=7.0 Hz, 1H), 4.97 (d, J=7.0 Hz, 1H), 4.31 (t, J=6.4 Hz, 1H), 4.20 (t, J=3.4 Hz, 1H), 3.91 (d, J=3.4 Hz, 1H), 3.65 (t, J=6.0 Hz, 2H), .33 (m, 2H), 3.23—3.17 (m, 2H), 3.08 (s, 1H), .01 (m, 1H),2.10—1.95(m,2H);LC/1V1S [M + H] = 572.0.

Example 168 sis of 2-benzy1(((2R, 3S, 4R, 5R)—5-(2-chloro(hydroxyamino)—9H—purinyl)—3- ethyny1-3,4-dihydroxytetrahydrofurany1)methoxy)malonic acid CI HN ,OH O HN N OEt N </ \N \N l X NHAOH, TEA </ l X 0 0H O N / dioxane, H20 N / aq. LiOH, THF </N 1 : :0: N , Cl —, 0 N CI —> HO 0 N o NAG i’OAc AcO‘~ bAC : 2, HO OH Example 168 Step 1: To a solution of diethyl 2-benzy1(((2R, 3S, 4R, 5R)(5-chloro(hydroxyamino)- 3H—imidazo[4,5-b]pyridinyl)-3 -ethyny1-3,4-dihydroxytetrahydrofuranyl)methoxy)- malonate (98 mg, 0.144 mmol) in dioxane (2 mL) was added an s solution of hydroxylamine (0.1 mL, 1.6 mmol, 16 M) and Et3N (35 uL, 0.16 mmol). The reaction mixture was stirred for 2.5 h and then it was diluted with EtOAc (15 mL) and H20 (5 mL).

The organic layer was separated, washed with H20 (20 mL), brine (20 mL), dried over Na2SO4 and concentrated to provide crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy- -(2—chloro(hydroxyamino)-9H—purinyl)ethynyltetrahydrofuran—2-y1)methoxy)— te (88 mg) as an off-solid which was used in the next step without further purification.

Step 2: To a solution of crude diethyl 2-benzyl(((2R, 3R, 4R, 5R)-3,4-diacetoxy(2-chloro- 6-(hydroxyamino)-9H—purinyl)—3-ethynyltetrahydrofuranyl)methoxy)malonate (88 mg, 0.14 mmol) in a mixture of THF (0.2 mL), MeOH (0.62 mL) and H20 (0.15 mL) was added LiOH'H2O (31 mg, 0.75 mmol). The resulting mixture was stirred at 25 0C for 5.5 h before the organic volatile was removed under d pressure. The aq. layer was cooled to 0 0C and acidified to pH 6.5 with 1N aq. HCl on before it was concentrated. The crude residue was purified by preparative reversed-phase HPLC to provide 2-benzyl (((2R, 3S, 4R, 5R)-5—(5 -chloro(hydroxyamino)—3H—imidazo[4, 5-b]pyridin-3 -y1)—3-ethynyl- 3,4-dihydroxytetrahydrofuran-Z-y1)methoxy)malonic acid (17 mg) as a reddish solid.

WO 46403 2019/038245 1H NMR (CD3OD, 300 MHz) 6 8.25 (s, 1H), 7.25—7.28 (m, 2H), 7.05 (m, 3H), 6.43 (s, 1H), 6.06—6.08 (d, J=7.17 Hz, 1H), 4.95—4.98 (d, J=7.05 Hz, 1H), 4.32 (s, 1H), 4.05—4.11 (m, 2H), 3.89—3.93 (m, 1H), .39 (m, 2H), 2.99 (s, 1H), 1.30—1.33 (m, 6H); LC/MS [M + H] = 5331.

Example 169 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(2-chloro(isopropylamino)—9H-purinyl)—3-ethynyl- 3,4—dihydroxytetrahydrofuranyl)methoxy)(thiazol—4—yl)-3—(thiophen—3-y1)propanoic ifioEEACH:BU MeCN ISI”NMOEH£30kA.cO\ Q—Oéjx Km ‘N Rh2(OAC)4DCE _SO 7"0 HN’\ of CSZCO3DMF «Ml/LN H20,DCM N N/ACI s 2) A020, DMAP, Py TMSOTf, BSA Example 169 Step 1: To a solution of ethyl 2-(thiazolyl)acetate (2 g, 11.7 mmole) in CH3CN (15 mL) at 0 °C was added DBU (2.62 ml, 17.6 mmole) and 4-acetamidibenzene sulfonylazide (3.4 g, 14.1 mmole) in CH3CN (10 mL). The reaction mixture was stirred at room temperature for 1.5 h before it was concentrated under reduced pressure to dryness. The resulting crude was purified by silica gel column chromatography (0—40% EtOAc in hexanes) to provide ethyl 2- diazo(thiazolyl)acetate (2.0 g).

Step 2: To a mixture of (3aR, 5R, 6R, 6aR)ethynyl(hydroxymethyl)—2,2-dimethyltetra- hydrofuro[2,3-d][1,3]dioxolyl acetate (7 g, 27.32 mmol, 1 eq) in DCE (15 mL) was added Rh(OAc)2 9 mg, 2.73 mmol, 0.1 eq) and ethyl 2-diazo(thiazolyl)acetate (6.46 g, 32.78 mmol, 1.2 eq) in DCE (15 mL) dropwise at 0°C. The mixture was stirred at 25 °C under N2 atmosphere for 14 h before the insoluble was filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by flash silica gel —247— WO 46403 column chromatography (0 — 50% of EtOAc in petroleum ether) to provide ethyl 2— (((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetrahydrofuro[2, 3 3]dioxol-5 - yl)methoxy)(thiazolyl)acetate (10.81 g, 93% yield) as an oil.

Step 3: To a mixture of ethyl 2-(((3aR,5R,6R,6aR)acetoxyethynyl-2,2-dimethyltetra— hydrofuro[2,3-d][1,3]dioxol—5-yl)methoxy)—2-(thiazolyl)acetate (2.69 g, 6.33 mmol, 1 eq) in DMF (5 mL) was added CS2CO3 (6.18 g, 18.98 mmol, 3 eq). The mixture was stirred at 25 0C under N2 atmosphere for 0.5 h before 3-(bromomethyl)thiophene (2.8 g, 15.81 mmol, 25 eq) was added. The resulting mixture was d at 25°C for 14 h before the insoluble was filtered and the filtrate was diluted with H20 (15 mL) and extracted with EtOAc (3 x 15 mL).

The combined organic layer was washed with saturated aq. NH4Cl (3 x 15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0 — 50% of EtOAc in petroleum) to provide ethyl 2- (((3aR, 5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetrahydrofuro[2, 3 -d][1,3]dioxol-5 - yl)methoxy)—2-(thiazolyl)—3-(thiophen-3—yl)propanoate (2.27 g, 69% yield) as an oil.

Step 4: To a mixture of ethyl 2-(((3aR,5R,6R,6aR)acetoxyethynyl-2,2-dimethy1tetra- hydrofuro[2,3 -d][1,3]dioxol-5 -yl)methoxy)(thiazolyl)-3 -(thiophen-3 -yl)propanoate (2.27 g, 4.35 mmol, 1 eq) in DCM (5 mL) and H20 (0.5 mL) was added TFA (5 mL, 67.53 mmol, 15.5 eq). The mixture was stirred at 15 0C under N2 here for 14 h before it was adjusted to 7-8 pH with saturated aq. NaHCO3 (50 mL) and concentrated under reduced re. The residue was diluted with H20 (5 mL) and extracted with EtOAc (4 x 15 mL).

The ed organic layer was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced re to provide crude ethyl 2—[[(2R,SS,4R)—3—acetoxy ethynyl-4,5-dihydroxy-tetrahydrofuranyl]methoxy]thiazol-4—yl(3—thienyl)propanoate (1.82 g) as a syrup.

To a solution of ethyl 2-[[(2R,3S,4R)acetoxyethynyl-4,5-dihydroxy-tetrahydro- 2-yl]methoxy]thiazolyl(3-thienyl)propanoate (1.82 g, 3.78 mmol, 1 eq) in pyridine (8 mL) under a N2 atmosphere at 0 °C was added 4-DMAP (1.39 g, 11.34 mmol, 3 eq) and AC2O (2.83 mL, 3024 mmol, 8 eq). The mixture was stirred at 15 0C for 15 before it was diluted with H20 (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic layer was washed with 10% CuSO4 solution (2 x 15 mL), dried over Na2SO4, filtered WO 46403 and concentrated under reduced pressure to give crude (3R, 4R, 5R)—5-(((1-ethoxy-1—oxo (thiazolyl)(thiophenyl)propanyl)oxy)methyl)ethynyltetrahydrofuran-2,3,4-triyl triacetate (2.42 g) as a syrup.

Step 5: To a mixture of 2-chloro-N—isopropyl-9H—purinamine (606.20 mg, 2.86 mmol, 1 eq) in DCE (20 mL) was added BSA (1.77 mL, 716 mmol, 2.5 eq). The mixture was stirred at 85 0C under a N2 here for 0.5 h before it was allowed to cool to 0 oC and followed by addition of crude (3R,4R,5R)—5-(((1-ethoxyoxo(thiazol-4—yl)—3-(thiophen—3-yl)— propanyl)oxy)methyl)ethynyltetrahydrofuran-2,3,4-triyl triacetate (1.62 g, 2.86 mmol, 1 eq) and TMSOTf (1.55 mL, 8.59 mmol, 3 eq). The resulting mixture was stirred at 65 °C under N2 for 14 h before it was ed with saturated aq. NaHCO3 (20 mL). The reaction mixture was diluted with H20 (10 mL) and extracted with DCM (3 x 20mL). The combined organic layer was washed with brine (3 x 15mL), dried over Na2SO4, filtered and trated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0 — 50% of EtOAc in petroleum ether) to provide (2R, 3R, 4R, 5R)—5- (2-chloro-6—(isopropylamino)—9H—purinyl)—2-(((l-ethoxyoxo—2-(thiazolyl)-3 -(thio— phenyl)propanyl)oxy)methyl)ethynyltetrahydrofuran-3,4-diyl ate (402 mg, crude) as a syrup.

Step 6: To a mixture of (2R, 3R, 4R, 5R)(2—chloro—6-(isopropylamino)-9H—purinyl) ((( 1 -ethoxyoxo(thiazolyl)—3 -(thiophen-3 -yl)propanyl)oxy)methyl)-3 -ethynyltetra- hydrofuran-3,4-diyl ate (3 84 mg, crude) in THF (2 mL) and H20 (1 mL) was added LiOH (128 mg, 5.35 mmol). The mixture was stirred at 50 0C for 6 h before it was diluted with H20 (40 mL) and extracted with EtOAc (10 mL). The aqueous phase was acidified to pH 2—3 with 2 N aqueous HCl until pH~2-3 and then trated under reduced pressure.

The crude residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water(0.225%FA)—ACN]; B%: 40%-60%, 10 min) and dried by lyophilization to provide a diastereomeric mixture (ca. 1:1) of 2-(((2R, 3S, 4R, 5R) (2-chloro-6—(isopropylamino)—9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuran yl)methoxy)(thiazolyl)(thiophenyl)propanoic acid (17.5 mg) as a white solid. —249— 1H NMR (400 MHz, CD3OD) 5 ppm 8.92 — 9.01 (m, 1H), 8.04 — 8.28 (m, 1H), 7.60 — 7.71 (m, 1H), 7.10 — 7.15 (m, 1H), 6.98 — 7.06 (m, 1H), 6.77 — 6.94 (m, 1H), 5.90 — 6.02 (m, 1H), 4.91 — .06 (m, 2H), 4.40 (br s, 1H), 4.19 — 4.32 (m, 1H), 3.89 — 3.99 (m, 1H), 3.65 — 3.87 (m, 3H), 2.89 — 3.02 (m, 1H), 1.25 = 605.2. — 1.35 (m, 6H); LC/MS [M + H] Examples 170 & 171 Synthesis of (S)(((2R, SS, 4R,5R)—5-(2-chloro(isopropylamino)-9H—purinyl)-3— ethynyl-3,4-dihydroxytetrahydrofuran-2—yl)methoxy)—3-phenyl(thiazolyl)propanoic (R)(((2R, 3S, 4R, 5R)-5 -(2-chloro(i sopropylamino)—9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)phenyl(thiazolyl)propanoic acid EWOB HNk \N N O:31. k O </ \N .110 l A u N c1 A06 0 TMSOTf, BSA 0&—OH 4 N N SL “ <’ </ P“ \N o: N ’ o 0: N o NAG H6 'IOH ’OAC Example 170 Example 171 Proceeding as described in Example 169 above but substituting 3-(bromomethyl)thiophene with benzyl bromide provided a pair of reorneiic products which the stereo configuration was assigned arbitrarily. Both products were purified by preparative HPLC and isolated as white solids.

(S)—2-(((2R, 3S, 4R, 5R)—5 -(2-chloro—6-(i ylamino)-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z—yl)methoxy)-3—phenyl—2-(thiazolyl)propanoic: 1H N1VIR , 300 MHz) 6 8.99 (s, 1H), 7.91 (s, 1H), 7.70 (s, 1H), 7.07-7.23 (m, 5H), 5.91-5.94 (d, J: 6.9 Hz, 1H), 4.87-4.90 (d, J: 7.0 Hz, 1H), 4.21-4.45 (m, 2H), .94 (m, 4H), 3.02 (s, 1H), 1.29-1.31 (d, J: 6.48 Hz, 6H); LC/MS [M + H] = 599.0.

WO 46403 (R)-2—(((2R, SS, 4R, 5R)—5 -(2—chloro-6—(i sopropylamino)-9H—purin-9—yl)-3 -ethynyl -3 ,4- dihydroxytetrahydrofuranyl)methoxy)phenyl(thiazolyl)propanoic: 1H NMR (CD3OD, 300 MHz) 8 8.97-8.98 (d, J= 1.83 Hz, 1H), 8.07 (s, 1H), 7.573—7579 (d, J= 1.86 Hz, 1H), .09 (m, 5H), 5.97-5.99 (d, J: 7.17 Hz, 1H), 4.98-5.00 (d, J: 7.23 Hz, 1H), 4.40-4.42 (m, 1H), 4.27-4.29 (t, J: 3.84 Hz, 1H), 3.93-3.97 (m, 2H), 3.59-3.81 4.31, 37.47 Hz, 2H), 2.95 (s, 1H), 129-133 (d, J: 6.39 Hz, 6H); LC/MS [M + H] = 5990.

Examples 172 & 173 Synthesis of (S)—2-(((2R,3S, 4R,5R)—5-(2-chloro((cyclopropylmethyl)amino)—9H—purin yl)—3-ethynyl—3,4-dihydroxytetrahydrofuran-2—yl)methoxy)—3—phenyl—2-(thiazol yl)propanoic acid (R)(((2R, 3S, 4R, 5R)(2-chloro—6-((cyclopropylmethyl)amino)—9H—purinyl)—3 -ethynyl- 3,4-dihydroxytetrahydrofuranyl)rnethoxy)phenyl(thiazolyl)propanoic acid H)“ ”OH e 172 e 173 Proceeding as described in Examples 170 and 171 above but substituting 2-chloro—N— isopropyl—9H-purinarnine with 2-chloro—N-(cyclopropylmethyl)—9H-purinamine provided a pair of diastereomeric products which the stereo configuration was assigned arbitrarily. Both products were purified by preparative HPLC and isolated as white solids.

(S)(((2R, 3S, 4R, 5R)—5 loro((cyclopropylmethyl)amino)—9H—purinyl)-3 -ethynyl- 3 ,4-dihydroxytetrahydrofuranyl)methoxy)-3 -phenyl(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 6 .99 (d, J: 1.95 Hz, 1H), 7.93 (s, 1H), 7.69-7.70 (d, J: 1.86 Hz, 1H), 7.03-7.23 (m, 5H), 5.92-5.94 (d, J: 696 Hz, 1H), 4.87-4.89 (d, J: 7.11Hz, 1H), 4.19-4.22 (m, 1H), 3.59-3.94 (rn, 4H), 3.42-3.43 (m, 2H), 3.02 (s, 1H), 1.12-1.22 (m, 1H), 0.54-0.61 (m, 2H), 0.32-0.37 (m, 2H); LC/MS [M + H] = 611.0.

(R)(((2R, SS, 4R, 5R)(2-chloro((cyclopropylmethyl)amino)-9H-purinyl)-3 -ethynyl- 3 ,4-dihydroxytetrahydrofuranyl)methoxy)-3 -phenyl(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 8 8.96-8.97 (d, J: 1.89 Hz, 1H), 8.07 (s, 1H), 7.55-7.56 (d, J: 2.07 Hz, 1H), 6.94-7.11 (m, 5H), 5.97-5.99 (d, J: 7.17 Hz, 1H), 4.98-5.00 (d, J: 7.29 Hz, 1H), .29 (t, J= 3.66 Hz, 1H), 3.94—3.95 (m, 2H), 3.59-3.80 (q, J= 14.64, 32.46 Hz, 2H), 3.39-3.50 (m, 2H), 2.96 (s, 1H), 1.13-1.23 (m, 1H), 0.55-0.62 (m, 2H), .38 (m, 2H); LC/MS [M + H] = 611.0.

Example 174 Synthesis of 2-(((2R, 3S, 4R, 5R)—5—(2-chloro(isopropylamino)-9H—puriny1)—3-ethyny1- 3,4-dihydroxytetrahydrofuran—2—y1)methoxy)—2—(thiazolyl)—3-(4- (trifluoromethoxy)phenyl)propanoic acid Example 174 Proceeding as bed in Example 169 above but substituting 3-(bromomethy1)thio- phene with 1-(bromomethyl)(trifluoromethoxy)benzene provided the title compound as a mixture of reomers (ca. 1:1) and isolated as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.95 — 9.02 (m, 1H), 8.05 — 8.27 (m, 1H), 7.59 — 7.74 (m, 1H), 7.15 — 7.32 (m, 2H), 6.78 — 6.98 (m, 2H), 5.89 — 6.00 (m, 1H), 4.92 — 5.10 (m, 1H), 4.32 — 4.46 (m, 1H), 4.22 — 4.32 (m, 1H), 3.76 — 3.98 (m, 2H), 3.57 — 3.71 (m, 2H), 2.98 — 3.04 (m, 1H), 1.26 = 682.8. — 1.32 (m, 6H); LC/MS [M + H] Example 175 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminoch1oro—9H—puriny1)—3-ethyny1-3,4- dihydroxytetrahydrofuran-2—y1)methoxy)-3—(4-(2-oxotetrahydropyrimidin— 1 (2]10—y1)pheny1)- 2-(thiazolyl)propanoic acid SWOB Br 1) TFA, H20, DCM, OEt , C, K 2) A620, 4-DMAP, pyridine O XODMOAC \N + <’ I: : N Cl ¢ 1, H ‘ bAc OZN ACO , BSA </ \N l (Boc)20 \N NA <— l o N o ”at E: 3, CI 4-DMAP,DMF Cl H6 90800 OZN OZN lFe, aq.NH4C|, EtOH NHBOC NBocz \N QB (NfN l CIMN/ NACI 0: 0 ,N NAG DCM o :6 30301: HNX” C vC' TFA,DCM f”NI/kCII Example 175 Step 1: A mixture of 1-(bromomethyl)nitro-benzene (7.62 g, 35.26 mmol, 3 eq) and NaI (352.31 mg, 2.35 mmol, 0.2 eq) in DMF (50 mL) was stirred at 15 0C for 30 min. Then this mixture was added to a solution of ethyl aR, 5R, 6R, 6aR)—6-acetoxy-6—ethynyl-2,2- dimethyltetrahydrofuro[2,3-d][1,3]dioxolyl)methoxy)—2-(thiazolyl)acetate (5 g, 11.75 mmol, 1 eq) and CS2CO3 (19.15 g, 58.76 mmol, 5 eq) in DMF (50 mL) at 15 °C was d for 30 min. The resulting mixture was stirred for 8 h before it was quenched by water (200 mL). The mixture was extracted with EtOAc (4 x 30 mL). The combined organic layer was washed with water (3 x 100 mL), dried over anhydrous NazSO4, filtered and concentrated.

The residue was d by flash column chromatography on silica gel (0 — 40% of EtOAc in petroleum ether) to provide ethyl 2-(((3aR,5R, 6R, 6aR)—6-acetoxyethynyl-2,2-dimethyltetrahydrofuro [2, 3 -c[][1,3]dioxol-5 —yl)methoxy)—3 -(4-nitrophenyl)(thiazolyl)propanoate (4.89 g) as a syrup.

Step 2: To a solution of ethyl 2-(((3aR, 5R, 6R, 6aR)acetoxyethynyl-2,2-dimethyltetra- hydrofuro[2,3 -d][1,3]dioxolyl)methoxy)-3 -(4-nitrophenyl)—2-(thiazolyl)propanoate (4.89 g, impure) in DCM (25 mL) and H20 (25 mL) was added TFA (25 mL 337.65 mmol).

The mixture was stirred at 30 °C for 23 h before it was diluted with water (100 mL) and the resulting mixture was extracted with DCM (6 x 30 mL). The combined organic layer was washed with saturated aq. NaHCO3 (2 x 100 mL), dried over anhydrous , filtered and concentrated to provide crude ethyl 2-(((2R, 3S,4R)ethynyl-3,4,5-trihydroxytetrahydro- furanyl)methoxy)—3-(4-nitrophenyl)—2-(thiazol-4—yl)propanoate (4.56 g) as a brown oil.

To a on of crude ethyl 2-(((2R,SS,4R)ethyny1-3,4,5-trihydroxytetrahydro- furan—2-yl)methoxy)—3-(4-nitrophenyl)(thiazol-4—yl)propanoate (4.56 g) in DCM (50 mL) was added 4-DMAP (232.86 mg, 1.91 mmol), pyridine (6.15 mL, 76.24 mmol) and AczO (8.93 mL, 9530 mmol) dropwise. The mixture was stirred at 15 °C for 19 h before it was quenched with water (100 mL) and the resulting mixture was extracted with DCM (4 x 30 mL). The combined organic layer was washed with water (3 x 100 mL), and dried over anhydrous Na2S04, filtered and trated. The crude residue was purified by flash column chromatography on silica gel (10—55% EtOAc in petroleum ether) to provide (3R, 4R, 5R)-5 —(((1-ethoxy-3 —(4-nitrophenyl)—1-oxo—2—(thiazolyl)propan—2—yl)oxy)methyl)- 4-ethynyltetrahydrofuran-2,3,4-triyl triacetate (1.02 g) as a yellow oil.

Step 3: To a solution of 2,6-dichloro-9H—purine (3 82.64 mg, 2.02 mmol) in MeCN (5 mL) was added BSA (1.04 mL, 4.22 mmol). The suspension was stirred at 65°C for 0.5 h as it became clear. The resulting solution was cooled down to 0°C and followed by addition of a solution of (3R, 4R, 5R)-5—(((1-ethoxy(4—nitrophenyl)—1-oxo(thiazolyl)propan-2— yl)oxy)methyl)ethynyltetrahydrofuran-2,3,4-triyl tate (1.02 g) in MeCN (5 mL) and TMSOTf (4.22 mmol, 762.15 uL). Then the mixture was stirred at 65°C for 1 h before it was ed with saturated aq. NaHCO3 (40 mL) and the ing mixture was extracted EtOAc (4 x 20 mL). The ed organic layer was dried over anhydrous NazSO4, d and concentrated to provide crude (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purinyl)(((1-ethoxy (4-nitrophenyl)oxo(thiazolyl)propanyl)oxy)methyl)-3 -ethynyltetrahydrofuran—3 ,4- diyl diacetate (1.71 g) as a yellow solid.

Step 4: To a solution of crude (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purinyl)—2-(((1-ethoxy (4-nitrophenyl)oxo—2-(thiazol-4—yl)propan—2-yl)oxy)methyl)-3 -ethynyltetrahydrofuran—3 ,4- diyl diacetate (1.0 g) in MeOH (20 mL) in a seal tube was added NH4.OH (28.04 mmol, 4.00 —254— mL2T%cmmmmmmm.TMHmMMewmswkdmwsmmdmlMWCfixl5hbfiMefiww allowed to cool and diluted with water (20 mL) and the resulting mixture was extracted with EtOAc (3 x 10 mL). The ed c layer was dried over anhydrous Na2S04, filtered and concentrated to give crude ethyl 2-(((2R,3S,4R,5R)(6-aminochloro-9H-purinyl)- 3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)-3 -(4-nitrophenyl)(thiazol yl)propanoate (752 mg) as a yellow solid, Step 5: To a solution of crude ethyl 2—(((2R, SS, 4R, 5R)(6-amino—2—chloro—9H-purinyl)—3- ethynyl-3,4—dihydroxytetrahydrofuranyl)methoxy)(4-nitrophenyl)(thiazolyl)- propanoate (752 mg), 4-DMAP (58.33 mg, 477.44 umol) and Et3N (7.16 mmol, 996.81 uL) in DMF (8 mL) at 0 0C was added BoczO (1.04 g, 4.77 mmol). The mixture was stirred M2OWHm2hbdMefiwmdmmflvmhwmeMni)wdmemammgmmmmums emwmdmmeAdflxmnm)UwamMmdmymdwmwwmfidmammem , filtered and trated to give crude ethyl 2-(((2R, 3R, 4R, 5R)(6-(bis-(z‘erl— butoxycarbonyl)amino)chloro-9H—purinyl)((lert—butoxycarbonyl)oxy)ethynyl-3— hydroxytetrahydrofuranyl)methoxy)-3 -(4-nitrophenyl)(thiazolyl)propanoate (91 1 Ing)asabnnvnsohd Step 6: To a solution of crude ethyl 2-(((2R,3R,4R,5R)(6-(bis-(tert—butoxycarbonyl)— amino)—2-chloro-9H—purinyl)—4-((Zerl—butoxycarbonyl)oxy)ethynylhydroxytetrahydrofuranyl )methoxy)(4-nitrophenyl)(thiazol-4—yl)propanoate (711 mg) in EtOH (7 mL) was added saturated aq. NH4C1 (764.21 umol, 7 mL) and iron (426.7? mg, 7.64 mmol).

The e was stirred at 50 0C for 2 h before it was filtered through a pad of Celite and the filtrate was concentrated. Then the crude residue was taken up in water (20 mL) and the resulting mixture was ted with EtOAc (3 x 15 mL). The combined organic layer was dried over anhydrous NazSO4, filtered and concentrated to give crude ethyl 3-(4-amino- )(((2R, 3R, 4R, 5R)(6-(bis-(lerl—butoxycarbonyl)amino)—2-chloro-9H—purinyl) ((tert—butoxycarbonyl)oxy)-3 -ethynyl-3 -hydroxytetrahydrofuranyl)methoxy)- 2-(thiazol yl)propanoate (552 mg) as a brown solid.

Step 7: To a solution of crude ethyl 3—(4-aminophenyl)(((2R, 3R, 4R, 5R)—5—(6-(bis—(Zert- butoxycarbonyl)amino)chloro-9H-purinyl)((lerl—butoxycarbonyl)oxy)ethynyl hydroxytetrahydrofuranyl)methoxy)— 2-(thiazol—4—yl)propanoate (552 mg) in DCM (5 mL) was added 1-chloro-3 anato-propane (109.94 mg, 919.60 umol). The mixture was stirred at 15 °C for 16 h before it was concentrated under reduce pressure. The crude residue was purified by flash column chromatography on silica gel (20—100% EtOAc in petroleum ether) to provide ethyl 2-(((2R, 3R, 4R, 5R)(6-(bis-(tert—butoxycarbonyl)amino)chloro— 9H-purinyl)((terZ-butoxycarbonyl)oxy)—3-ethynyl-3 -hydroxytetrahydrofuran—2- yl)methoxy)(4-(3-(3-chloropropyl)ureido)phenyl)(thiazol-4—yl)propanoate (283 mg) as an off—white solid.

Step 8: To a solution of ethyl 2-(((2R, 3R, 4R, 5R)(6-(bis-(tert-butoxycarbonyl)amino) chloro-9H—purinyl)((terl—butoxycarbonyl)oxy)ethynylhydroxytetrahydrofuran—2- yl)methoxy)(4-(3-(3-chloropropyl)ureido)phenyl)(thiazolyl)propanoate (283 mg, 277.47 umol, 1 eq) in THF (3 mL) was added NaH (55.49 mg, 1.39 mmol, 60% in mineral om5em.Tmnmmmewwmfimdm15%Hm5hbfidefiwmqmmdwdwflflb0(15 mL). To this mixture was added NaOH (166.48 mg, 4.16 mmol, 15 eq) and the resulting mixture was d at 40 °C for 48 h before the organic volatile was removed under reduced pressure. The aq. layer was acidified with 2N aq. HCl (1 mL) and concentrated under reduced pressure to give crude 2-(((2R, 3S, 4R, 5R)(6-((terz‘-butoxycarbonyl)amino) chloro-9H—purinyl)ethynyl-3,4-dihydroxytetrahydrofuran-2—yl)methoxy)-3 —(4-(2- oxotetrahydropyrimidin-1(2110-yl)phenyl)(thiazolyl)propanoic acid (238 mg) as a yellow solid.

Step 9: A e of crude 2-(((2R, 3S, 4R, 5R)—5-(6-((z‘erZ-butoxycarbonyl)amino)chloro— 9H-pu1inyl)—3-ethynyl-3,4—dihydroxytetrahydrofuran-2—yl)methoxy)(4—(2-oxotetra- hydropyrimidin-1(2IiO-yl)phenyl)(thiazolyl)propanoic acid (238 mg) in DCM (2 mL) was added TFA (9.45 mmol, 0.7 mL). The mixture was stirred at 15 °C for 2 h before it was concentrated under d pressure. The crude residue was purified by Preparative HPLC ([water (0.225%FA)-ACN]; B%: %, 10min) to provide a diastereomeric e (ca. 1 : 1) of 2-(((2R, 3S, 4R, 5R)-5—(6-aminochloro-9H—purin-9—yl)ethynyl-3,4-dihydroxytetra- uran—2-yl)methoxy)-3 -(4-(2—oxotetrahydropyrimidin-1(2]10—yl)phenyl)—2-(thiazol yl)propanoic acid (22.9 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 9.01 (m, 1H), 7.98 — 8.32 (m, 1H), 7.59 — 7.83 (m, 1H), 6.91 — 7.34 (m, 4H), 5.88 — 6.07 (m, 1H), 4.72 — 4.96 (m, 1H), 4.13 — 4.32 (m, 1H), 3.60 — 4.00 (m, 4H), 3.43 — 3.56 (m, 2H), 3.35 — 3.42 (m, 2H), 2.96 — 3.14 (m, 1H), 1.89 — 2.08 (m, 2H); LC/MS [M + H] = 655.3.

Example 176 Synthesis of 2-(((2R,3S,4R,5R)(2-ch1oro(isopropy1amino)—9H—puriny1)—3-ethyny1- 3 ,4-dihydroxytetrahydrofuran-Z-yl)methoxy)(4-(2-oxotetrahydropyrimidin— 1 (2110- yl)phenyl)(thiazolyl)propanoic acid 0E1 N Fe, aq.NHAC| <1 ' A EtOH X0)! N 0' N DIEA,MeCN X07! C' AC6 bAC NaH, NaOH THF, H20 HNK) Example 176 Step 1: A solution of crude (2R, 3R, 4R, 5R)—5-(2,6—dichloro—9H—puriny1)—2-(((1—ethoxy(4- heny1)— 1 -(thiazolyl)propan-2—yl)oxy)methyl)—3 -ethynyltetrahydrofuran-3 ,4— diyl diacetate (1.17 g) in MeCN (10 mL) was added -Z-amine (1.0 mL, 11.64 mmol) and DIEA (0.9 mL). The mixture was stirred at 15 °C for 16 h before it was diluted with water (30 mL) and the resulting mixture was extracted EtOAc (4 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated to give crude (2R, 3R, 4R, 5R)-5 -(2—chloro(isopropylamino)-9H-purinyl)(((1-ethoxy-3 -(4- nitropheny1)oxo(thiazoly1)propan—2-y1)oxy)methyl)—3 -ethyny1tetrahydrofuran-3 ,4- diyl diacetate (1.16 g) as a yellow solid.

Step 2: To a solution of crude (2R, 3R, 4R, 5R)(2-chloro-6—(isopropylamino)—9H-purinyl)— 2-(((1-ethoxy-3 -(4-nitrophenyl)—1-oxo(thiazolyl)propany1)oxy)methyl)-3 - WO 46403 ethynyltetrahydrofuran-3,4—diyl diacetate (1.16 g) in EtOH (5 mL) was added Fe powder (856.75 mg, 15.34 mmol) and saturated aq. NH4Cl (1.53 mmol, 5 mL). The mixture was stirred at 50 °C for 2 h before it was filtered through a pad of Celite and the filtrate was concentrated to give crude (2R, 3R, 4R, 5R)(((3-(4-aminophenyl)—1-ethoxyoxo(thiazol- 4-yl)propanyl)oxy)methyl)—5-(2—chloro(isopropylamino)-9H—purin—9-yl)-3— ethynyltetrahydrofuran-3,4—diyl diacetate (1.05 g) as a yellow solid.

Step 3: To a solution of crude (2R, 3R, 4R, 5R)—2-(((3—(4-aminophenyl)—1-ethoxyoxo (thiazolyl)propanyl)oxy)methyl)(2-chloro(isopropylamino)-9H—purinyl) ethynyltetrahydrofuran-3,4-diyl diacetate (1.05 g) in DCM (10 mL) was added 1-chloro isocyanato-propane (172.85 mg, 1.45 mmol). The mixture was stirred at 15 0C for 16 h before it was quenched with water (20 mL) and the resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layer was dried over anhydrous Na2S04, filtered and concentrated to give crude ethyl 2-(((2R,3S,4R,5R)(2-chloro(isopropylamino)-9H— purin—9-yl)-3—ethynyl—3,4-dihydroxytetrahydrofuran—2-yl)methoxy)—3-(4-(3 —(3-chloropropyl)- ureido)phenyl)(thiazolyl)propanoate (1.33 g) as a yellow solid.

Step 4: To a solution of crude ethyl 2-(((2R, 3S, 4R, (2-chloro—6-(isopropylamino)—9H— purinyl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)(4—(3 -(3-chloropropyl)- ureido)phenyl)(thiazol-4—yl)propanoate (1.23 g) in THF (12 mL) was added NaH (290.84 mg, 7.27 mmol, 60% in mineral oil). The mixture was stirred at 15 0C for 5 h before it was ed with H20 (6 mL) and ed by addition ofNaOH (290.85 mg, 7.27 mmol). The mixture was stirred at 15 °C for 16 h and then at 40 0C for 8 h. Additional NaOH (600 mg) was added to e and the mixture was d at 40 °C for 4 h before it was quenched with water (20 mL). The resulting solution was extracted with EtOAc (15 mL). The aq. layer was acidified with 2N aq. HCl (15 mL) to produce a precipitate. The solid was ted by filtration and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225%FA)-ACN]; B%: 30%-50%, 10min) to provide a diastereomeric mixture (ca. 1:1) of 2-(((2R, 3S, 4R, 5R)(2-chloro(isopropylamino )-9H—purinyl)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)—3—(4-(2- oxotetrahydropyrimidin-l(2H)-yl)phenyl)-2—(thiazol—4-yl)propanoic acid (245 mg) as a white solid 1H NMR (400 MHz, CD3OD) 5 ppm 8.99 (d, J=1.6 Hz, 1H), 7.88 — 8.18 (m, 1H), 7.53 — 7.79 (m, 1H), 7.30 (d, J=8.3 Hz, 1H), 7.03 — 7.13 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 5.83 — 6.03 (m, 1H), 4.63 — 4.74 (m, 1H), 4.33—4.43 (m, 1H), 4.09 — 4.29 (m, 1H), 3.72 — 4.01 (m, 3H), 3.59 — 3.70 (m, 1H), 3.41 — 3.53 (m, 2H), 3.33-3.38 (m, 2H), 2.91 — 3.14 (m, 1H), 1.83 — 2.05 (m, 2H), 1.25 = 697.4. — 1.35 (m, 6H), LC/MS [M + H] Example 177 Synthesis of 2-(((2R, 3S, 4R, (6—chloro(isopropylamino)— 1H—pyrazolo[3,4- d]pyrimidinyl)—3 yl-3 ,4—dihydroxytetrahydrofuranyl)methoxy)—3 -phenyl-2— (thiazolyl)propanoic acid 0 CI N/ GE 1 1 3 N/ \N 1 NHZ n N (:1 o ‘N o N/xKCI A OAc DBU,TMSOTf _ S / DIEA,EtOH MeCN A60“ °0Ac HO: OH e 177 Step 1: To a on of 4,6—dichloro-1H—pyrazolo[3,4-d]pyrimidine (620 mg, 1.11 mmol, 1 eq) and (3R, 4R, 5R)(((1 -ethoxyoxo-3 -phenyl(thiazolyl)propan—2-yl)oxy)methyl)- 4-ethynyltetrahydrofuran-2,3,4-triyl triacetate (230.35 mg, 1.22 mmol, 1.1 eq) in MeCN (6.5 mL) under a N2 atmosphere at 0°C was added DBU (501 uL, 3.32 mmol, 3 eq). The mixture was stirred at 0°C for 5 min and followed by addition of TMSOTf (900.93 uL, 4.99 mmol, 4.5 eq) dropwise. The mixture was stirred at 0°C for 30 min and then stirred at 65°C for 16 h befoe it was quenched with saturated aq. NaHCO3 (10 mL) and extracted with EtOAc (3 x 6 mL). The combined organic phase was dried over anhydrous Na2804, filtered and concentrated. The crude residue was d by flash column chromatography on silica gel (10 — 40% of EtOAc in petroleum ether) to provide (2R, 3R, 4R, 5R)—5-(4,6—dichloro—1H— pyrazolo[3 ,4—d]pyrimidin-1—yl)—2-(((1—ethoxy—1-oxo—3 -phenyl(thiazol-4—yl)propan yl)oxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (220 mg) as a foam.

Step 2: To (2R, 3R, 4R, (4,6-dichloro- 1H—pyrazolo[3 ,4-d]pyrimidin-1—yl)(((1-ethoxy- l-oxo-3 -phenyl(thiazolyl)propanyl)oxy)methyl)—3 -ethynyltetrahydrofuran-3 ,4-diyl diacetate (260 mg, 377.61 umol, 1 eq) in EtOH (2 mL) was added propan—2-amine (64.89 uL, 755.23 umol, 2 eq) and DIEA (131.55 uL, 755.23 umol, 2 eq). The mixture was d at °C for 4 h before it was diluted with EtOAc (30 mL), washed with water (8 mL), brine (8 mL), dried over anhydrous Na2S04, d and concentrated. The crude residue was purified by preparative TLC (EtOAc2petroleum ether = 2: 1) to give (2R,3R,4R,5R)(6- (isopropylamino)—1H-pyrazolo[3 ,4-d]pyrimidinyl)(((1-ethoxyoxo-3 - phenyl(thiazolyl)propanyl)oxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (70 mg) as a foam, Step 3: To a solution of (2R, 3R, 4R,5R)(6—chloro—4-(isopropylamino)-1H—pyrazolo[3,4- d]pyrimidinyl)(((1-ethoxyoxo-3 -phenyl(thiazolyl)propanyl)oxy)methyl)—3 - ethynyltetrahydrofuran-3,4-diyl diacetate (70 mg, 98.43 umol, 1 eq) in THF (1 mL) was mmwlflHHhOMJ3mQ.memmmwwsmmdm5WCfinMhbfimefiwu concentrated to dryness. The crude residue was d by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um; mobile phase: [water (0.225%FA) - ACN]; B%: 43%-63%, 10 min) and dried by lyophilization to provide a diastereomeric mixture (ca. 1:1) of 2—(((2R, 3S, 4R, 5R)—5-(6-chloro-4—(isopropylamino)-1H-pyrazolo[3 ,4-d]pyrimidinyl)—3 - ethynyl-3,4-dihydroxytetrahydro-furanyl)methoxy)—3-phenyl(thiazolyl)propanoic acid (15.7 mg) as a white solid. 1H NMR (400 MHz, CD30D) 5 ppm 8.76 — 9.10 (m, 1H), 7.93 — 8.08 (m, 1H), 7.40 — 7.65 (m, 1H), 6.89 — 7.08 (m, 4H), 6.80 — 6.88 (m, 1H), 6.11 — 6.20 (m, 1H), 5.14 — 5.28 (m, 1H), 4.38 — 4.50 (m, 1H), 4.29 - 4.37 (m, 1H), 3.93 - 4.11 (m, 1H), 3.78 - 3.86 (m, 1H), 3.47 — 3.63 (m, 2H), 2.97 = 598.7. — 3.09 (m, 1H), 1.25 — 1.31 (m, 6H); LC/MS [M + H] Example 178 Synthesis of 2-(((2R, 3S, 4R, 5R)(4-aminochloro- 1H-pyrazolo[3 ,4-d]pyrimidinyl)—3 - ethynyl—3,4-dihydroxytetrahydrofuranyl)methoxy)—3-pheny1(thiazolyl)propanoic 0 CI 0 NH2 0 NH2 CE: QB OH 8 / \N 5 / \N s / \N K N‘ l K \ N‘N ' A K N‘ 0::O:,N NH OH H o THF NCIaq"O’L' H THF A NCI 4'21 O O 0:0,N Nc| A66 "OAc A60“ "0A6 —HO‘: 'bH Example178 Step 1: To a solution of (2R, 3R, 4R,5R)—5-(4,6-dichloro-1H—pyrazolo[3,4-d]pyrimidinyl)—2- thoxyoxophenyl(thiazolyl)propanyl)oxy)methyl)-3 -ethynyltetrahydro- furan-3,4-diyl diacetate (100 mg, 145.24 umol, 1 eq) in THF (1 mL) was added NH4OH (199.76 uL, 1.45 mmol, 10 eq). The mixture was stirred at 15°C for 14 h before it was trated to s to provide crude (2R, 3R, 4R, 5R)(4-aminochloro-lH-pyrazolo- [3 ,4—d]pyrimidinyl)—2-(((l-ethoxyoxo—3 -phenyl(thiazol-4—yl)propany1)oxy)- methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (120 mg) as a white solid.

Step 2: To a solution of crude (2R, 3R, 4R, 5R)(4-aminochloro— 1H—pyrazolo[3,4- d]pyrimidinyl)(((1-ethoxyoxo-3 -phenyl(thiazolyl)propany1)oxy)methyl)-3 - ltetrahydrofuran-3,4-diyl diacetate (145.24 umol, 1 eq) in THF (4 mL) and H20 (2 mL) was added LiOH-H2O (60.94 mg, 1.45 mmol, 10 eq). The mixture was stirred at 50°C for 16 h before it was concentrated to dryness. The crude residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5um;mobile phase: [water(0.225%FA)- ACN]; B%: 28%-48%, 10min) and dried by lyophilization to e a diastereomeric mixture (ca. 1:1) of 2-(((2R,3S,4R,5R)—5-(4-aminochloro- 1H—pyrazolo[3,4-d]pyrimidin yl)ethynyl-3,4-dihydroxytetrahydrofuran-Z-y1)methoxy)-3 -phenyl(thiazolyl)- propanoic acid (32.8 mg) as a white solid. 1H NMR (400 MHz, CD3OD) 5 ppm 8.87 — 9.01 (m, 1H), 7.91 — 8.06 (m, 1H), 7.47 — 7.67 (m, 1H), 7.01 — 7.06 (m, 2H), 6.93 - 7.00 (m, 2H), 6.84 - 6.90 (m, 1H), 6.12 — 6.20 (m, 1H), 5.14 - .27 (m, 1H), 4.26 — 4.33 (m, 1H), 3.76 — 4.03 (m, 2H), 3.48 — 3.70 (m, 2H), 2.96 — 3.05 (m, 1H); LC/MS [M + H] = 557.0.

Example 179 Synthesis of 2-(((2R, 3S, 4R, 5R)(6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)(thiazolyl)acetic acid MM» «M o Boc 2 /— N< ) o NH2 N \ N CE 5372—0 N OH \ N N \ N 1TFA DCM' s \ </ l '- \ N N//’\ N |\N\ </ z l N/J\C| 2. aq .LOH,THF' \ </ 1 HO N H o N LN H o N 0 o o N//l\0| w Rh2(OAc)4 \ e — X 7’ X 7/ . : Acd :OAc Acd :OAc HO: :OH 14 15 Example 179 Step 1: To a solution of ,4R,5R)—5—((6-N,N’-bis-(tert—butoxycarbonyl)amino)chloro- 9H—purinyl)ethynyl-2—(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (2 g, 3.28 mmol) in e (10 mL) was added ethyl 2-diazo—2-(thiazolyl)acetate (841 mg, 4.26 mmol) and Rh2(OAc)4 (145 mg, 0.328 mmol) under an argon atmosphere. The resulting mixture was stirred at 70 °C for 2 h before it was allowed to cool to room temperature. The c volatile was removed under reduced pressure. The resulting crude was purified by silica gel column chromatography (O—40% EtOAc in hexanes) to provide (2R, 3R, 4R, 5R) (6—(bis-(tert—butoxycarbonyl)amino)—2-chloro-9H—purin—9—yl)((2-ethoxyoxo—1-(thiazol- 4-yl)ethoxy)methyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (1.78 g) as a syrup.

Step 2: To a solution of (2R, 3R, 4R,5R)(6—(bis-(terZ-butoxycarbonyl)amino)chloro-9H— 9-yl)—2-((2-ethoxyoxo(thiazolyl)ethoxy)methyl)-3 -ethynyltetrahydrofuran—3 ,4- diyl diacetate (310 mg) in DCM (3 mL) at 25 0C was added TFA (2 mL). The mixture was stirred for 2 h before it was concentrated under reduced re to provide crude (2R, 3R, 4R, 5R)-5 -(6-aminochloro-9H-purinyl)((2-ethoxyoxo(thiazol yl)ethoxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate.

To a solution of crude (2R, 3R, 4R, 5R)(6-aminochloro-9H-purinyl)—2-((2- ethoxyoxo(thiazolyl)ethoxy)methyl)-3 -ethynyltetrahydrofuran-3 ,4-diyl diacetate in THF (1 mL) and H20 (1 mL) at 0 °C was added LiOH monohydrate (100 mg). The resulting mixture was stirred at 25 °C overnight before the organic volatile was removed under d pressure. The mixture was cooled to O 0C before it was acidified to pH ~6 with 1N aq. HCl solution and concentrated under reduced pressure. The crude residue was d by preparative reversed-phase HPLC to provide a diastereomeric mixture (ca. 1:1) of 2- (((2R, SS, 4R, 5R)-5 ino—2-chl oro—9H—pu1inyl)—3 yl-3 ,4—dihydroxytetrahydro— furanyl)methoxy)(thiazolyl)acetic acid as a white solid. 1H NMR (CD3OD, 300 MHz) 5 .00 (m, 2H), 7.67-7.68 (m, 1H), 6.02—6.06 (m, 1H), .28-5.32 (d, J=12.27 Hz, 1.5H), 5.14-5.16 (d, J=7.56 Hz, 0.5H), 4.24—4.28 (m, 1H), 3.69— 4.09 (m, 2H), 3.16 (s, 0.5H), 2.95 (s, 0.5H); LC/MS [M + H] = 467.0.

Examples 180 and 181 Synthesis of (S)—2—(((2R, 3S, 4R,5R)—5-(6—amino—2—chloro—9H—purinyl)—3-ethynyl-3,4— dihydroxytetrahydrofuranyl)methoxy)phenyl(thiazolyl)propanoic acid (R)(((2R, 3S, 4R,5R)—5-(6-aminochloro-9H-purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)-3—phenyl(thiazolyl)propanoic acid $3Diff/ACN(Boc)2 N(Boc)2 NH2 BnBr C52003 DMF S\N\ 3:7;er TFA CHZCIZ S\\N war: AcO OAc AcO OAc AC6 OH laqi LiOH, THF 0 NH2 NH2 \5—0H N N \ < n 1 + </ u 1 N 0 if): ’N O N C] : ::O ,N N/ 0| —HO: “ OH f’OH Example 180 Example 181 Proceeding as described in Example 169 above but substituting 3-(bromomethyl)thio- phene and 2-chloro-N—isopropyl-9purinamine with benzyl e and 2-chloroadenine provided a pair of diastereomeric products which the stereo configuration was assigned arily. Both products were purified by preparative HPLC and isolated as white solids.

(S)—2-(((2R, 3S, 4R, 5R)—5 -(6-aminochloro-9H-purinyl)—3 -ethynyl-3 ,4-dihydroxytetra- hydrofuran—2-yl)methoxy)—3-phenyl(thiazol-4—yl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 6 895-896 (d, J: 2.01Hz, 1H), 8.34 (s, 1H), 7.54—7.55 (d, J: 2.01 Hz, 1H), 6.97— 7.12 (rn, 5H), 5.97—5.99 (d, J: 6.99 Hz, 1H), 4.97—4.99 (d, J: 7.08 Hz, 1H), 4.27-4.29 (t, J = 4.23, 3.18 Hz, 1H), .99 (m, 2H), 3.62-379 (q, J: 14.82, 39.24 Hz, 2H), 2.97 (s, 1H); LC/MS [M + H] = 557.0.

(R)—2-(((2R, 3S, 4R, 5R)-5 -(6—amino—2-chloro—9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetra— uran-2—yl)methoxy)-3—phenyl—2-(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 6 8.95-8.96 (m, 1H), 7.99 (s, 1H), 7.70—7.71 (d, J: 1.98 Hz, 1H), 7.05—7.25 (m, 5H), .92—5.94 (d, J = 7.02 Hz, 1H), 4.85—4.87 (d, J = 7.29 Hz, 1H), 4.20—4.22 (q, J = 2.64 Hz, 1H), 3.58-3.90 (m, 4H), 3.02 (s, 1H), LC/MS [M + H] = 557.0.

Example 182 Synthesis of ((2R, 3S, 4R,5R)(6-amino—2-chloro—9H—puriny1)ethynyl-3,4— dihydroxytetrahydrofuranyl)methoxy)—2-carboxy(thiazol—4-yl)ethyl)benzoic acid 83—24(— N(Boc)2B o N(Boc)2 NHZ /\©/C02M€ o/— sL\ [\N 1.TFA,CHZC|2 LN <’NN lNJ\C| “ l/xk 2.aq.LiOH,THF s\\ lNim 2g7 “ N 0' C52003 DMF Q?” AcO OAc ACO OAc HO OH OMe OH Example 182 Proceeding as described in Example 179 above but substituting BnBr with methyl 3- (bromomethyl)benzoate ed the title compound as a mixture of diastereomers (ca. 1:1) and isolated as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.99-9.01 (m, 1H), 8.33 (s, 0.5H), 8.14 (s, 0.5H), 7.66—7.88 (m, 3H), 7.45-7.48 (d, J: 729 Hz, 0.5H), 7.36—7.39 (d, J: 7.86 Hz, 0.5H), 7.17—7.22 (t, J: 7.56 Hz, 0.5H), 7.00—7.05 (d, J: 747 Hz, 0.5H), 5.99—6.01 (d, J: 7.29 Hz, 0.5H), 5.93—5.95 (d, J: 6.87 Hz, 0.5H), 5.00—5.03 (d, J: 738 Hz, 0.5H), 4.90—4.95 (d, J: 6.80 Hz, 0.5H), .31 (m, 1H), 3.80—4.01 (m, 2H), 3.63—3.69 (m, 2H), 3.01 (s, 0.5H), 2.92 (s, 0.5H), LC/MS [M + H] = 601.0.

Example 183 Synthesis of 2-(((2R, SS, 4R, (6—amino-2—chloro-9H-puriny1)—3 -ethyny1-3 ,4- dihydroxytetrahydrofuran-Z—yl)methoxy)-2—(thiazolyl)—3-(3- (trifluoromethoxy)phenyl)propanoic acid N(Boc)2 o 0/— 2 SLN 'NJ\C| <N 2 a \ 01 LiOH THF W111 O 'N/kCI N S 07‘N 052003 DMF NwNN AcO OAc F300 ACO OAc F3CO HO OH Example 183 Proceeding as bed in Example 179 above but substituting BnBr with 1- (bromomethy1)(trifluoromethoxy)benzene provided the title compound as a mixture of diastereomers (ca. 1:1) and ed as a white solid. 1H NMR (CD3OD, 300 MHz) 6 8.97-9.00 (m, 1H), 8.41 (s, 0.5H), 8.26 (s, 0.5H), 7.68-7.69 (d, J: 1.92 Hz, 0.5H), 7.62—7.63 (d, J: 1.83 Hz, 0.5H), 6.88—7.21 (m, 4H), 6.00—6.02 (d, J: 7.14 Hz, 0.5H), 5.94—5.96 (d, J: 6.78 Hz, 0.5H), 5.04—5.07 (d, J: 7.44 Hz, 0.5H), 4.91-4.94 (d, J: 6.87 Hz, 0.5H), 4.28-4.33 (m, 1H), 3.62-3.96 (m, 4H), 2.98 (s, 0.5H), 2.96 (s, 0.5H); LC/MS [M + H] = 641.0. e 184 Synthesis of 2—(((2R, 3S, 4R, 5R)(6-amino-2—ch1oro-9H-puriny1)—3 -ethyny1-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—2-(thiazolyl)pent—4-ynoic acid 1531*:N()3002 O /— N(BOC)2 sx 1 TFA CHZCIZ gN «N m A01 o N <1*H5 0 NékC|2.aq.LiOH THF 1: <N o Nc’k || Qj IIM —AcO OAc AGO: bAc HO OH Example 184 Proceeding as described in Example 179 above but substituting BnBr with propargyl bromide provided the title compound as a mixture of diastereomers (ca. 1:1) and isolated as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.95 (s, 1H), 8.79-8.83 (d, J: 1395 Hz, 1H), 7.73 (s, 1H), 6.04-6.06 (d, J: 705 Hz, 1H), .05 (dd, J: 7.29, 17.91 Hz, 1H), 4.24—4.30 (m, 1H), 3.69-3.94 (m, 2H), 3.34-3.38 (m, 2H), 3.04 (s, 0.5H), 2.93 (s, 0.5H), 2.22—2.30 (dt, J: 174, 19.62 Hz, 1H); LC/MS [M + H] = 505.0.

Examples 185 and 186 Synthesis of (S)(((2R, 35, 4R, 5R)(6-aminochloro-9H-purinyl)ethyny1-3,4- dihydroxytetrahydrofurany1)methoxy)-N-hydroxy(thiazolyl)acetamide (S)(((2R, 3S, 4R,5R)—5-(6-aminochloro-9H-purinyl)-3 -ethynyl-3,4- oxytetrahydrofuranyl)methoxy)—N—hydroxy(thiazol—4—yl)acetan1ide O—é—J—o<l1NfN£ZCI NH2OHm H20 \N/>—(:>>—NHH33$:a 17>""?;NH:3315:“ _S 0-7 + MeOH 40°C ACO OAc —HO OH —HO OH Example 185 Example 186 To a solution of (2R, 3R, 4R,5R)—5-(6—amino—2-chloro-9H—purinyl)((2-ethoxy oxo—1-(thiazolyl)ethoxy)methyl)—3—ethynyltetrahydrofuran-3,4-diyl diacetate (2 g, 3.45 mmole) in MeOH (20 mL) was added 50% NHzOH in H20 (30 mL). The reaction mixture was stirred at 40 °C for 1 h before it was concentrated under reduced pressure. The crude residue was purified by preparative reversed-phase HPLC to provide a pair of diastereomeric title products which the stereo configuration was assigned arbitrarily. Both ts were isolated as white solids.

(S)—2-(((2R, SS, 4R, 5R)—5 inochloro—9H-purinyl)—3 -ethynyl-3 ,4-dihydroxytetra- hydrofuranyl)rnethoxy)-N-hydroxy(thiazolyl)acetarnide: 1H NMR (CD3OD, 300 MHz) 6 9.02-9.03(d,J=1.77 Hz, 1H), 8.45 (s, 1H), 7.68-7.69 (d, J: 1.8 Hz, 1H), .01 (d, J: 6.96 Hz, 1H), 4.92-4.95 (d, J: 6.93 Hz, 1H), 4.29-4.32 (q, .1: 2.82, 2.28 Hz, 1H), 3.91-4.10 (m, 2H), 3.18 (s, 1H); LC/MS [M + H] = 482.0.

(R)-2—(((2R, SS, 4R, 5R)—5 ino-2—chloro—9H—purinyl)—3 -ethynyl-3 ,4—dihydroxytetra— hydrofuranyl)methoxy)-N—hydroxy(thiazolyl)acetamide: 1H NMR (CD3OD, 300 MHz) 6 8.97 (s, 1H), 8.46 (s, 1H), 7.68 (s, 1H), 5.97-6.00 (d, J= 6.96 Hz, 1H), 4.88-4.90 (d, J: 6.93 Hz, 1H), 4.33-4.35 (m, 1H), .08 (m, 2H), 3.12 (s, 1H); LC/MS [M + H] = 4820.

Examples 187 and 188 Synthesis of (S)—2—(((2R,3S, 4R,5R)(2-chloro-6—(methylamino)—9H—purinyl)—3-ethynyl- 3,4-dihydroxytetrahydrofuran-2—yl)methoxy)-3—phenyl—2—(thiazolyl)propanoic acid (R)(((2R, SS, 4R, 5R)-5 -(2—chloro—6-(n1ethylamino)—9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuranyl)methoxy)—3-phenyl(thiazolyl)propanoic acid o HN o HN </ 11 OH (”l/k“ i7” N / N N/J\Cl aq.LIOH. \ </” 1‘“ CI 0 N N O N O O N//,\Cl + TMSOTf. BSA _ THF _ MeCN Acd aOAc Hd ’IOH Example 187 Example 188 Proceeding as described in Examples 170 and 171 above but substituting 2—chloro—N- isopropyl-9H—purinamine with 2-chloro-N-methyl-9H-purinamine provided the title compounds as a pair of diastereomers (ca. 1:1) and isolated as White solids.

(S)-2—(((2R,3S,4R,5R)—5-(2—ch1oro-6—(methylamino)—9H—purinyl)—3-ethynyl-3,4—dihydroxy- tetrahydrofuranyl)methoxy)-3 -pheny1(thiazoly1)propanoic acid: 1H NW (CD3OD, 300 MHz) 5 8.99 (s, 1H), 7.97 (s, 1H), 7.69 (s, 1H), 7.08-7.22 (m, 5H), 5.93-5.95 (d, J= 6.9 Hz, 1H), 4.96-4.98 (d, J: 6.0 Hz, 1H), 3.59-4.22 (m, 5H), 3.01-3.06 (m, 4H), LC/MS [M + H] = 571.0.

(R)—2-(((2R, 3S, 4R, 5R)-5 -(2-chloro—6-(methy1amino)-9H—purin-9—yl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-2—yl)methoxy)-3—phenyl—2-(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 5 8.97-8.98 (d, J: 1.83 Hz, 1H), 8.15 (s, 1H), 7.58-7.59 (d, .1: 1.77 Hz, 1H), .09 (m, 5H), 598—600 (d, J: 7.17 Hz, 1H), 4.98-5.01 (d, J: 7.26 Hz, 1H), 4.27- 4.29 (t, J: 3.48 Hz, 1H), 3.93 (m, 2H), 3.58-3.80 (q, J= 14.46, 38.7 Hz, 2H), 3.07 (s, 3H), 2.94 (s, 1H); LC/MS [M + H] = 571.0. es 189 and 190 Synthesis of (((2R, 3S, 4R,5R)(6-aminochloro—9H—purinyl)ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)—2-cyanopheny1propanoic acid (R)(((2R, SS, (6-aminochloro-9H—puriny1)-3 -ethyny1-3,4- dihydroxytetrahydrofuran-Z-y1)methoxy)—2-cyano-3 -pheny1propanoic acid N N(BOC)2 N N \ \ // < o / i N W N EtO N2 H </ l AIN OfBr \N HO N / —>HO 0 N </ l o N on : :0: , N C EtO o N A E 7 toluene. 95 °C K2003 DMF :10}, N Cl N NH2 0 O / /N \ N §—OH N \ 50% TFA < j AN LIOH, MeOH. - </ l i + </ l A —>EtO O N / —> O N / O N / O N 0‘ 90"" 0 N CI ::0: , N THF,H20 CI Acd bAc HO: 90H HC§ ”0H Example 189 Example 190 Step 1: To a solution of R, 3R, 4R, 5R)(6-N,N’ -(bis-(Zert—butoxycarbonyl)amino)—2-chloro- 9H-purinyl)ethynyl(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (510 mg, 0.836 mmol) in toluene (5 mL) was added ethyl 2-cyano-2—diazoacetate (134 mg, 0.961 mmol). The mixture was trated in vacuo. The mixture was taken up in dry toluene (2 mL) and followed by addition of c)4 (8 mg, 17 umol) under argon atmosphere. The al was stirred and heated at 80 0C for 30 minutes before additional ethyl 2-cyano-2— cetate (254 mg, 1.82 mmol) was added over 60 min at 80 °C. The reaction was further heated at 80 °C for 80 minutes before it was cooled to room temperature and concentrated.

The crude product was purified by CombiFlash silica gel chromatography (5 — 65% of EtOAc in hexanes) to provide a diastereomeric mixture of (2R, 3R, 4R, 5R)-5—(6-N,N ’-(bis-(tert— butoxycarbonyl)amino)—2-chloro-9H-purinyl)((1-cyanoethoxyoxoethoxy)methyl)- 3-ethynyltetrahydrofuran-3,4-diyl ate (230 mg, 38% yield) as an off-white foam.

Step 2: An oven dried flask was charged with ((2R, 3R, 4R,5R)—5-(6—N,N ’-(bis-(lert— butoxycarbonyl)amino)—2-chloro-9H-puriny1)((1-cyanoethoxyoxoethoxy)methyl)- nyltetrahydrofuran-3,4-diyl diacetate (230 mg, 0.319 mmol) and taken up in dry DMF (4 mL). To this mixture was added CszCO3 (208 mg, 0.639 mmol) and followed by the addition of benzyl bromide (109 mg, 0.639 mmol). The mixture was stirred at 25°C for 30 minutes before it was diluted with cold saturated aqueous NH4C1 (40 mL) and extracted with EtOAc (40 mL). The aqueous phases were extracted with EtOAc (2 x 40 mL)‘ The ed organic layer was dried over NazSO4, filtered and concentrated. The crude product was purified by CombiFlash silica gel column chromatography (10 — 70% EtOAc in hexanes) to provide (2R, 3R, 4R, 5R)—5—(6-N,N’ -(bis-(terl-butoxycarbonyl)amino)—2-chloro-9H-purin—9- (((2-cyanoethoxy-1—oxo-3—phenylpropan-2—yl)oxy)methyl)—3 -ethynyltetrahydro- furan-3,4-diyl diacetate as a pair of diastereomers (215 mg, 83% yield) as an off-white solid.

Step 3: A solution (2R, 3R, 4R, 5R)-5—(6-N,N’ —(bis-(tert—butoxycarbonyl)amino)chloro-9H— purinyl)(((2-cyano- l -ethoxy- l -oxo-3 -phenylpropanyl)oxy)methyl)-3 -ethynyltetra- hydrofuran-3,4-diyl diacetate (215 mg, 0.265 mmol) in a solution of TFA (1 mL) in DCM (1 mL) was stirred for 2 h before it was concentrated under reduced pressure. The e was azetroped with DCM (8 X 8 mL) under reduced pressure. The residue was taken up in a mixture ofMeOH in H20 (2.2 mL, 5:1 = v:v) and followed by addition ofLiOH'HzO (77 mg, 1.86 mmol, 7 eq) and THF (0.5 mL). The mixture was stirred at ambient temperature for 40 minutes before it was concentrated to dryness. The residue was dissolved in H20 (15 mL).

The aqueous phase was extracted with EtOAc (2 x 10 mL). The aqueous phase was acidified to pH 25 with 1N aq. HCl solution. The aqueous phase was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over , filtered and concentrated. The crude residue was ed by preparative reversed-phase HPLC to provide the title compounds as a pair of diastereomers: (S)(((2R,3S,4R,5R)(6- aminochloro-9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuran—2-yl)methoxy) cyanophenylpropanoic acid (337 mg, 26% yield) and (R)(((2R,3S,4R,5R)-5—(6-amino- 2-chloro-9H-purinyl)—3-ethynyl—3,4-dihydroxytetrahydrofuran—2-yl)methoxy)cyano phenylpropanoic acid (30 mg, 23% yield) which the stereo configuration was assigned rily. Both were isolated as off-white solids.

(S)(((2R, 3S, 4R, 5R)—5 ino—2-chloro—9H—purinyl)-3 -ethynyl-3 ,4—dihydroxytetrahydrofuranyl )methoxy)cyano—3-phenylpropanoic acid: 1H NMR , 300 MHz) 5 8.32 (bs, 1H), 7.20-7.36 (m, 5H), 6.02 (d, J=7.00 Hz, 1H), 4.68 (d, J=7.02 Hz, 1H), 4.33-4.37 (m, 1H), 4.18 (dd, J=9.91, 3.96 Hz, 1H), 3.99 (dd, J=9.94, 2.19 Hz, 1H), 3.41 (bs, 2H), 3.03 (s, 1H), LC/MS [M + H] = 499.1.

(R)(((2R, 3S, 4R, 5R)-5 -(6—amino—2-chloro—9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetra— hydrofuran-2—yl)methoxy)-2—cyano—3—phenylpropanoic acid: 1H NMR (CD3OD, 300 MHz) 8.04 (bs, 1H), 7.21-7.39 (m, 5H), 5.99 (d, J=6.90 Hz, 1H), 4.79 (d, J=6.93 Hz, 1H), 4.31- 4.36 (m, 1H), 4.19 (dd, J=10.07, 4.34 Hz, 1H), 4.12 (dd, J=10.10, 3.30 Hz, 1H), 3.38-3.44 (m, 2H), 3.09 (s, 1H), LC/MS [M + H] = 499.1.

Examples 191 and 192 Synthesis of (S)(((2R, 3S, 4R, 5R)—5-(6-aminochloro—9H-purinyl)ethynyl-3,4- dihydroxytetrahydrofurany1)methoxy)—3 -pheny1(1H-tetrazol-5—yl)propanoic acid (R)(((2R, SS, 4R, 5R)-5—(6-aminochloro-9H—purin-9—yl)-3 -ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)—3 -phenyl(1H-tetrazolyl)propanoic acid l A ,SEM “O (N ,/N\ o N CI N 5“ N(Boc)2 NI; \\N 0 O ’N MN;O N=N N 1 SEM Cl K co) DMF . .

- \N , 2 3, \N—SEM Aco‘ ’OAc \ </ l X Benzyl bromide —>EtO EtO H N’ EC 0 N 0 N/ 2)4—(AcNH)C6H5SOZN3 Rh2(OAc)4,toluene 0' DMF,052003 DBU,CHSCN _ Acd l’OAc N/N‘N Naaoc)2 H o NH2 N/,"“NH o NH2 11’ N \ ‘N’ AX—OH N \ \Ng’h. OH N 1)aqLIOH,MeOH. -‘ . o </ l i </ l l + </ l A O N / / O N / o N O N Cl o N C. O 2)TFA,DCM N CI Aw“ ’oAc H6 ’OH Ho‘ ’OH Example 191 Example 192 Step 1: To a solution of ethyl lH—tetrazole-S-acetate (3 g, 19.21 mmol) in DNEF (40 mL) under argon atmosphere at 25 0C was added 2-(trimethylsilyl)ethoxymethyl chloride (4.1 mL, 23.05 mmol) and powdered potassium carbonate (5.31 g, 38.42 mmol). The on mixture was stirred overnight before it was diluted with brine (70 mL) and EtOAc (70 mL). The aqueous phase was extracted with EtOAc (2 X 70 mL). The ed organic layer was washed with brine (70 mL) and water (70 mL), dried over NazSO4 and concentrated. The residue was purified by silica gel column chromatography (15—48% EtOAc in s) to provide ethyl 2-(2-((2-(trimethy1silyl)ethoxy)methyl)-2H—tetrazol—5-yl)acetate (2.379 g) as a light yellow oil.

Step 2: To a solution of ethyl 2-(2-((2-(trimethylsi1yl)ethoxy)methyl)—2H-tetrazol-5—yl)acetate (2.379 g, 8.31 mmol) in dry acetonitrile (25 mL) under argon atmosphere was added DBU (1.87 mL, 12.47 mmol). To this e was added 4-acetamidobenzenesulfonyl azide (2.395 g, 9.96 mmol) in 3 equal portions over 5 minutes. The reaction mixture was stirred for 3.5 h the organic le was removed under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc in hexanes) to provide ethyl 2-diazo(2-((2- (trimethylsilyl)ethoxy)methyl)-2H—tetrazoly1)acetate (2.316 g) as an oil.

Step 3: To a solution of (2R, 3R, 4R,5R)(6-(bis-(terl—butoxycarbony1)amino)chloro-9H- purinyl)—3-ethynyl(hydroxymethyl)tetrahydrofuran-3,4-diy1 diacetate (2 g, 3.28 mmol) in toluene (8 mL) at 20 0C under N2 atmosphere was added Rh2(OAc)4 (29 mg, 0.066 mmol, 0.066 eq) and ethyl 2-diazo—2-(2-((2-(trimethylsily1)ethoxy)-methyl)-2H—tetrazoly1)acetate (1.08 g, 3.44 mmol, 1.05 eq). The mixture was stirred at 75 °C for 1 h before additional ethyl o(2-((2-(trimethylsi1y1)ethoxy)methyl)—2H—tetrazoly1)acetate (720 mg) was added over 80 min. The on e was cooled to ambient temperature and concentrated. The crude al was purified by Combi-Flash silica gel column (5 — 80% EtOAc in hexanes) to provide a diastereomeric mixture of (2R, 3R, 4R, 5R)(6-(bis-(tert—butoxycarbonyl)amino) chloro-9H—puriny1)((2—ethoxy—2-oxo(2-((2—(trimethy1silyl)ethoxy)methyl)—2H— tetrazolyl)ethoxy)methyl)—3-ethyny1tetrahydrofuran-3,4-diyl diacetate (1.608 g) as a gum.

Step 4: To a solution of (2R, 3R, 4R,5R)(6-(bis-(terl—butoxycarbonyl)amino)chloro-9H- purinyl)((2-ethoxyoxo(2-((2-(trimethyl si1y1)ethoxy)methy1)-2H-tetrazol-5 - yl)ethoxy)methyl)—3-ethynyltetrahydrofuran-3,4-diy1 diacetate (1.555 g, 1.739 mmol) in dry toluene (10 mL). The mixture was concentrated under d pressure. The residue was taken up in dry DMF (10 mL) and followed by addition of benzyl bromide (1.189 g, 6.96 mmol) amd dried CszCO3 (1.133 g, 3.478 mmol). The mixture was stirred at 25°C for 5.5 h before it was diluted with saturated aq. NH4C1 on (60 mL), The aqueous phase was extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with brine (60 mL), dried over Na2SO4, filtered and concentrated. The crude t was purified by flash silica gel column chromatography (5 — 65% EtOAc in s) to provide a diastereomeric mixture of (2R, 3R, 4R, 5R)(6-(bis—(tert—butoxycarbonyl)amino)—2-chloro—9H-purinyl) (((1-ethoxyoxo-3 —phenyl—2-(2-((2-(trimethy1sily1)ethoxy)methyl)-2H-tetrazoly1)propan- 2-y1)oxy)methyl)—3-ethyny1tetrahydrofuran-3,4-diy1 diacetate (1.041 g) as a foam.

Step 5: To a solution of (2R, 3R, 4R, 5R)—5-(6-(bis-(terZ-butoxycarbony1)amino)chloro-9H- puriny1)—2-(((1-ethoxyoxo-3 -pheny1(2-((2—(trimethy1silyl)ethoxy)methyl)—2H— tetrazol-5 -yl)propan—2-yl)oxy)methy1)-3 -ethynyltetrahydrofuran-3,4-diy1 diacetate (1 .041 g, 1.057 mmol) in a mixture ofMeOH and H20 (12 mL, 6:1 = vzv) was added powdered LiOH‘HzO (349 mg, 8.5 mmol). The mixture was stirred at 23°C for 16 h before it was concentrated to dryness. The e was dissolved in H20 (40 mL) and it was extracted with EtOAc (40 mL). The aqueous phase was acidified to pH 2.5 with 1N aq. HCl on and extracted with EtOAc (3 x 40 mL). The combined organic layer was washed with brine (40 mL), dried over NazSO4, filtered and concentrated to provide a diastereomeric e of 2- (((2R, 3S, 4R, 5R)-5 -(6-((Zert—butoxycarbonyl)amino)chloro-9H—purin-9—yl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-2—yl)methoxy)-3—phenyl—2-(2-((2—(t1imethylsilyl)ethoxy)methyl)— 2H-tetrazolyl)propanoic acid (784 mg) as an oil.

Step 6: To a solution of 2-(((2R, 3S, 4R, 5R)-5—(6-((terI-butoxycarbonyl)amino)chloro-9H— puriny1)—3-ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy)—3-phenyl(2-((2- (trimethylsilyl)ethoxy)methyl)-2H-tetrazol—5—yl)propanoic acid (138 mg, 0.179 mmol) in DCM (0.9 mL) under argon atmosphere at 0 0C was added TFA (0.9 mL). The mixture was stirred at 0°C for 5 h and then d to ambient for 15 min before the organic volatile was removed under the reduced pressure. The residue was azetroped with DCM (3 x 15 mL) under reduced pressure. The crude e was purified by preparative reversed-phase HPLC to provide the two title products as a pair of diastereomers: (S)—2-(((2R,3S,4R,5R)—5-(6- aminochloro-9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy) phenyl(lH—tetrazol—S-yl)propanoic from the first fraction and (R)—2-(((2R,3S,4R,5R)-5—(6- aminochloro-9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuranyl)methoxy) pheny1(lH-tetrazol-S-yl)propanoic acid from the later fraction. Both isolated as ite solids. (((2R, 3S, 4R, 5R)—5 -(6—amino—2-chloro-9H—purinyl)-3 -ethynyl-3 ,4—dihydroxytetra- hydrofuran-2—y1)methoxy)-3—phenyl—2-(lH—tetrazol—S-yl)propanoic acid: 1H NMR (CD3OD, 300 MHz); 6 8.37 (s, 1H), 7.11-7.23 (m, 5H), 5.96 (d, J:6.57 Hz, 1H), 4.81 (d, J:6.57 Hz, 1H), 4.25-4.30 (m, 1H), 4.01 (dd, J=10.19, 2.29 Hz, 1H), 3.78 (d, J=13.90 Hz, 1H), 3.67 (d, J:13.90 Hz 1H), 3.72-3.79 (m, 1H), 3.06 (s, 1H); LC/MS [M + H] = 542.2.

(R)(((2R, 3S, 4R, 5R)-5 -(6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetra- hydrofuran—2-yl)methoxy)—3-phenyl(1H—tetrazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz); 6 8.37 (s, 1H), 6.92-7.11 (m, 5H), 6.01 .11Hz, 1H),5,06(d,J:7.11Hz, 1H), 4.35—4.39 (m, 1H), 4.11 (dd, J=10.06, 2.52 Hz, 1H), 4.01 (dd, J=10.06, 5.49 Hz, 1H), 3.80 (d, J:14.75 Hz 1H), 3,67 (d, J:14.75 Hz 1H), 2.96 (s, 1H), LC/MS [M + H] = 542.2.

Examples 193 and 194 Synthesis of (S)—2-(((2R, SS, 4R,5R)(6—amino—2-ch1oro—9H—purinyl)ethynyl-3,4— dihydroxytetrahydrofuranyl)methoxy)—2-(2-phenylthiazolyl)acetic acid (R)(((2R, 3S, 4R,5R)—5-(6-aminochloro-9H—purinyl)-3 -ethynyl-3,4- dihydroxytetrahydrofuran-Z-yl)methoxy)(2-phenylthiazol-4—yl)acetic acid N \ I N(Boc)2 </ 1 N NACI c)z 0 N N \ HO N / O o N’S toluene, 95°C </ i *N TFA \ —> E10 0 N o N’ _’ EtO C' DOM _ ’ Aw“ ’OAc N2 — X 7/ _ .

Sj/Q 8’; s/;\ I ””2 K/N NH2 N \ NH2 H (,N [\N LiOH,MeOH o g H </N 0 \N + “NH </N \N E10 0: N / o N Cl THF,H20 H0 0: N o NAG, HO 0: o ,N NAG A06 OAc H6 bH H6 90H Example 193 Example 194 Proceeding as described in Example 179 but substituting ethyl 2-diazo(thiazol yl)acetate with ethyl (2-phenylthiazoly1)diazoacetate which was prepared Via the procedure bed by re, Quentin, et al., cal Communications 2014, 50, 6617—6619) provided the title compounds as a pair of diastereomers (ca. 1:1). The stereo configuration was assigned arbitrarily. Both were isolated as off-white solids.

(S)—2-(((2R, SS, 4R, 5R)—5 inochloro-9H—purinyl)—3 -ethynyl-3 ,4-dihydroxytetra- uran-Z-yl)methoxy)(2-pheny1thiazolyl)acetic acid: 1H NMR (CD3OD, 300 MHz), 5 9.03 (bs, 1H), 7.91—7.97 (m, 2H), 7.60 (s, 1H), 7.39—7.45 (m, 3H), 6.06 (d, J:7.45 Hz, 1H), 5.28 (s, 1H), 4.92 (d, J:7.45 Hz, 1H), 4.29—4.33 (m, 1H), 4.12 (dd, J:10.45, 2.51 Hz, 1H), 4.01 (dd, J:10.46, 2.56 Hz, 1H), 2.92 (s, 1H), LC/MS [M + H] = 543.1.

(R)—2-(((2R, 3S, 4R, 5R)-5 -(6—amino—2-chloro—9H—purinyl)-3 -ethynyl-3 ,4—dihydroxytetra— hydrofurany1)methoxy)—2-(2-phenylthiazolyl)acetic acid: 1H N1VIR (CD3OD, 300 MHz); 5 9.15 (s, 1H), 7.90-7.96 (m, 2H), 7.61 (s, 1H), 7.38-7.44 (m, 3H), 6.09 (d, J=7.48 Hz, 1H), 5.23 (d, J:7.48 Hz, 1H), 5.30 (s, 1H), 4.26-4.29 (m, 1H), 3.93 (dd, J:10.67, 2.18 Hz, 1H), 3.76 (dd, J=10.64, 2.48 Hz, 1H), 3.17 (s, 1H); LC/MS [M + H] = 5432.

Example 195 Synthesis of 4-((((2R, 3S, 4R, 5R)(6-aminochloro—9H-purinyl)—3-ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)(carboxy)methyl)thiazole-2—carboxylic acid 0 O COzEl \ 002El S <’ l N 0 N‘< 4-(AcNH)C5H5SOZN3 O N/ HO N 051 EtOJk/lk/Br 0 NAG, H2N —> S —> s \ \ + Toluene, u-wave EtOM/ DBU,MeCN E10 N2 Acd bAc Rh2(OAc)4 CO2H toluene. 95 °C N 00 El NH 2 \ 2 N(Boc)2 O H N 1. TFA, DCM o gN (N/ \N [NAG N . 2.aq.LIOH,THF \N HO O > { </ l :10); EtO o; N o NAG H(5 ’0H \: a/ AcO 0A0 Example 195 Step 1: To a microwave vial was d with ethyl thiooxamate (1.91 g, 14.36 mmol) and ethyl 4-bromoacetoacetate (3 g, 14.36 mmol) in dry toluene (27 mL). The e was irradiated in a microwave r at 90 0C for 1 hour. The on mixture was cooled to ambient and the solvent decanted and then was concentrated. The crude residue was purified by CombiFlash silica gel chromatography (2—56% EtOAc in hexanes) to provide ethyl 4-(2- ethoxyoxoethyl)thiazolecarboxylate (890 mg, 26% yield) as a thick oil.

Step 2: To a solution of ethyl 4-(2-ethoxyoxoethyl)thiazolecarboxylate (890 mg, 3 .66 mmol) in dry acetonitrile (12 mL) under argon atmosphere was added DBU (0.82 mL, 5.49 mmol) and 4-acetamidobenzenesulfonyl azide (1.055 g, 4.39 mmol). The reaction e was stirred for 1.5 hours before it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% EtOAc in hexanes) to provide ethyl 4—(1- 2-ethoxyoxoethyl)thiazole—2-carboxylate (894 mg, 90% yield) as a yellowish solid.

Step 3: —274— Proceeding as described in Example 179 but substituting ethyl 2-diazo(thiazol yl)acetate with ethyl 4-(1-diazoethoxyoxoethyl)thiazolecarboxylate provided the title compound as a mixture of diastereomers (ca. 1:1) and isolated as off-white solids.

Isomer 1: 1H NMR , 300 MHz): 5 8.93 (s, 1H), 7.91 (s, 1H), 6.06 (d, .1442 Hz, 1H), 5.39 (s, 1H), 5.13 (d, J:7.42 Hz, 1H),4.24-4.31 (m, 1H), 4.03—4.09 (m, 1H), 3.75-3.83 (m, 1H), 2.95 (s, 1H), LC/MS [M + H] = 511.1.

Isomer 2: 1H NMR (CD3OD, 300 MHz): 5 8.87 (s, 1H), 7.93 (s, 1H), 6.04 (d, J:7.42 Hz, 1H), 5.33 (s, 1H), 4.91 (d, J=7.45 Hz, 1H),4.24-4.31 (m, 1H), 3.92—4.01 (m, 2H), 3.19 (s, 1H); LC/MS [M+H] = 511.1.

Example 196 Synthesis of ((2R, 3S, 4R, 5R)(6-aminochloro—9H—puriny1)ethynyl-3,4- dihydroxytetrahydrofuran-Z-yl)methoxy)—1-carboxyphenylethyl)thiazolecarboxylic acid 0 0 s CE OH \ I N(Boc)2 N(Boc)2 NHz O N/ N/ </N \N S BnBr \8 1)aq LiOH,MeOH N l —> </N \N —> </ \N / l 0 I EC 0 N o N/km DMF,C52003 O 2)TFA,DCM o N NKCI o N o NAG OEt 0H _ X 7’ X 7o ACO OAC Acd "OAc HO: ”OH Example196 ding as described in Example 179 above but substituting (2R, 3R, 4R, 5R)(6- N,N’ (tert—butoxycarbony1)amino)—2—chloro-9H—purin—9-yl)—3-ethynyl(hydroxyl- methyl)tetrahydrofuran-3,4—diyl diacetate with (2R, 3R, 4R, 5R)(6-N,N’ -(bis-(lert—butoxycarbonyl ))chloro—9H—puriny1)((2-ethoxy(2-(ethoxycarbonyl)thiazol-4—yl)- 2-oxoethoxy)methyl)—3-ethynyltetrahydrofuran-3,4—diyl diacetate provided the title compound as a mixture of diastereomers (ca. 1:1) and isolated as an off-white solid.

Isomer 1: 1H (CD3OD, 300 MHz): 5 8.17 (bs, 1H), 7.81 (s, 1H), 6.92-7.25 (m, 5H), .95 (d, J:7.02 Hz, 1H), 4.89 (d, J:7.02 Hz, 1H), 4.29—4.34 (m, 1H), 3.59—4.05 (m, 4H), 3.01 (s, 1H); LC/MS [M + H] = 601.1.

Isomer 2: 1H NMR (CD3OD, 300 MHz): 8 8.05 (bs, 1H), 7.90 (s, 1H), 6.92-7.25 (m, 5H), 6.00 (d, J=7.41 Hz, 1H), 5.04 (d, J=7.42 Hz, 1H), 4.21-4.26 (m, 1H), 3.59—4.05 (m, 4H), 3.06 (s, 1H); LC/MS [M + H] = 601.1.

Examples 197 Synthesis of 2-(((2R, 3S, 4R, (6-aminochloro-9H—purinyl)-3 -ethynyl-3 ,4- dihydroxytetrahydrofuran-Z-yl)methoxy)—2-(4—(2-aminopyridin-3 -yl)benzyl)malonic acid NH2 9 2 o NH2 2 0 | 1. TFA DCM 0 CE N / 2. aq. LiOH THF </ \N —>l EtO</r:‘:’\/kNNC/kl—> <N Pd(dppf)C|2, ch03 BO 0 N A O N CI dioxane, H20 _ Acd bAC . . / A60“ ’OAc N \ N \ Example 197 \ \ Proceeding as described in Example 22 above but substituting (2-oxo-1,2- dihydropyridinyl)boronic acid with 3-(4,4,5,5-tetramethyl—1,3,2—dioxaborolan-2— yl)pyridinamine provided the title compound as a white solid. 1H NMR (CD3OD, 300 MHz) 5 8.43 (s, 1H), 7.85-7.87 (dd, .1: 1.5, 6.42 Hz, 1H), 7.65-7.68 (dd, J: 1.53, 7.38 Hz, 1H), 7.37—7.40 (d, J: 8.13 Hz, 2H), 7.09-7.12 (d, J: 8.07 Hz, 2H), 6.88-6.93 (t, J: 6.9 Hz, 1H), 5.99-6.01 (d, J: 6.72 Hz, 1H), 4.77—4.79 (d, J: 7.0, 1H), 4.37— 4.40 (m, 1H), 398-4. 12 (m, 2H), 3.34—3.42 (m, 2H), 3.09 (s, 1H), LC/MS [M + H] = 6101.

Examples 198 & 199 Synthesis of (5)6 -([1,1'-biphenyl]—4-yl)—2—(((2R,3S,4R,5R)(6-amino-2—chloro-9H—purin yl)-3,4-dihydroxymethy1tetrahydrofuran-Z-yl)methoxy)(thiazolyl)propanoic acid (R)-3 '-biphenyl]yl)(((2R,3S,4R,5R)(6-aminoch1oro-9H—purinyl)—3 ,4- dihydroxymethyltetrahydrofuran-Z-yl)methoxy)(thiazolyl)propanoic acid o N(BOC)2 S O 0/ N(Boc)2 <\ \ o N(Boc)2 N 0/ </N \N </N' ”S o é‘fi/L l A N2 K HO N N O N O N CI O Rh2(OAc)4 052003 DMF Obi/“NAGO . , , ‘ AC6 bAc Acd bAc O owl TFA, DCM O\_ NH2 NH2 0 NH2 OH <N OH 8 3 \ N (N \ N -‘ 0/ L / l .... / NAG l 0 N 0 N o o NAG aq. LiOH, THF HO OH HO OH AcO ’0 Example 198 Example 199 O Proceeding as described in Example 1 above but substituting (2R,3R,4R,5R)—5-(6-(bis- (lert—butoxycarbonyl)amino)chloro-9H—purinyl)(((z‘erZ-butyldiphenylsilyl)oxy)- methyl)ethynyltetrahydrofuran-3,4-diyl diacetate and diethyl 2-diazomalonate with (2R, 3R, 4R, 5R)(6—(N,N ’-bis-(lert—butoxycarbonyl)amino)chloro-9H—purinyl) (hydroxylmethyl)methyltetrahydrofuran-3,4-diy1 diacetate and methyl 2-diazo—2-(thiazol- 4-yl)acetate ed a pair of reomeric title products (ca. 1:1) which the stereo configuration was assigned arbitrarily. Both products were purified by preparative HPLC and isolated as white solids.

(S)-3—([1,1'-biphenyl]yl)—2-(((2R,SS,4R,5R)—5-(6—amino—2-chloro—9H—purinyl)—3 ,4- dihydroxymethyltetrahydrofuranyl)methoxy)—2-(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 6 9.04 (s, 1H) 8.42 (s, 1H), 7.74 (s, 1H), 7.21-7.45 (m, 9H), 6.00-6.03 (d, J: 8 Hz, 1H), 4.67-4.70 (d, J: 7 Hz, 1H), 4.13 (s, 1H), 3.88-3.85 (m, 2H), 3.62-3.66 (d, J = 14 Hz, 1H), 344-3447 (d, J=11Hz, 1H), 1.37 (s, 3H); LC/MS [M + H] = 623.2.

(R)—3 -([1,1’-biphenyl]yl)—2-(((2R, SS, 4R, 5R)-5—(6-amino—2-chloro-9H—purin-9—yl)—3 ,4- oxymethyltetrahydrofuranyl)methoxy)—2-(thiazolyl)propanoic acid: 1H NMR (CD3OD, 300 MHz) 6 9.04 (s, 1H) 8.21 , (s, 1H), 7.27-7.69 (m, 10H), 5.93-5.95 (d, J: 7 Hz, 1H), 4.52-4.55 (d, J: 8 Hz, 1H), 4.04 (s, 1H), 3.79—3.85 (m, 3H), 1.36 (s, 3H); LC/MS [M + H] = 623.2.

Example 200 Synthesis of 4'—(2—(((2R, 3S, 4R, 5R)(6-amino-2—chloro—9H—purinyl)—3 ,4-dihydroxy-3 - methyltetrahydrofuranyl)methoxy)-2—carboxy(thiazolyl)ethyl)-[ 1 , 1'-biphenyl]—2- carboxylic acid O N(BOC)2 / </ l A o o N / s \ < [A/ \N o N Cl g 1.052003,DMF N o N / o N Cl : ,7 2.TFA,DCM H5 OH 3. aq. LiOH, THF . , Acd bAc Proceeding as described in Example 179 above but substituting (2R, 3R, 4R, 5R)((6- N,N’-bis-(tert—butoxycarbonyl)amino)—2-ch1oro-9H—purinyl)—3-ethyny1(hydroxylmethyl hydrofuran-3,4-diyl diacetate and BnBr with (2R, 3R, 4R, 5R)-5—(6-(N,N ’-bis-(tert— butoxycarbonyl)amino)—2-chloro-9H—purin-9—yl)—2-((2-methoxyoxo-l-(thiazol-4— yl)ethoxy)methyl)—3-methyltetrahydrofuran-3,4-diyl diacetate and momethyl)-l, 1'- yl provided the title compound as a mixture of diastereomers (ca. 1:1) and ed as an off-white solid.

LC/MS [M + H] = 667.2.

Example 201 Synthesis of 4'—(2-(((2R, SS, 4R, 5R)(6-aminochloro-9H—purinyl)—3 ,4-dihydroxy—3 - methyltetrahydrofuranyl)methoxy)—2-carboxy-2—( lH-tetrazolyl)ethyl)-[ 1, l '-biphenyl]—2- ylic acid milN \ / N 9 H0 0 N CI ACHN fi—N3 SEM\ O N(Boc)2 SEM-CI, K2003 SEM \ o ,N‘N o 5 -, SEM\ OEt N [FI\NH \ o DMF (N‘N O DBU,MeCN N9 \ 8000 0300 N,N l \ N N Mk N¢NJ\/"\OEI N </ j \ / N§N O N N OEt Rh2(OAc)4 0 N/J\C| N2 toluene BocO: I’OBoc 002Me Br 052003, DMF </ \N l 0E” NACI ilmlignicilfiF H5 V’OH ExampleZO1 Step 1: To a solution of ethyl 2-(lH—tetrazol—S-yl)acetate (500 mg, 3.24 mmol) and trimethylsilyl)ethoxymethyl chloride (0.69 mL, 3.89 mmol) in dry DMF (7 mL) under argon atmosphere at 25 0C was added powdered potassium carbonate (896 mg, 6.48 mmol). The reaction mixture was stirred overnight before it was diluted with H20 (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layer was washed with brine (30 mL) and water (30 mL) and then dried over Na2S04 and concentrated. The residue was purified by CombiFlash silica gel column chromatography (8—58% EtOAc in hexanes) to provide ethyl 2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H—tetrazol—5-yl)acetate (200 mg) as an oil.

Steps 2 — 6: ding as described in Example 1 above but substituting methyl 2-(thiazol yl)acetate with ethyl 2-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H—tetrazolyl)acetate provided a pair of diastereomeric title products (ca. 1:1) which the stereo configuration was assigned arbitrarily. Both products were purified by preparative HPLC and isolated as off- white solids. 1H NMR (CD3OD, 300 MHz): Isomer 1: 5 8.50 (s, 1H), 7.73-7.79 (m, 2H), 7.31-7.56 (m, 3H), .24 (m, 4H), 6.04 (d, J:7.87 Hz, 1H), 4.64 (d, J:7.88 Hz, 1H), 4.10-4.14 (m, 1H), 3.46—4.00 (m, 4H), 1.35 (s, 3H), Isomer 2: 5 8.31 (s, 1H), 7.73-7.79 (m, 2H), 7.31-7.56 (m, 3H), 7.01-7.24 (m, 4H), 5.99 (d, J:7.75 Hz, 1H), 4.48 (d, J:7.72 Hz, 1H), 4.19-4.23 (m, 1H), .00 (m, 4H), 1.42 (s, 3H), LC/MS [M + H] = 652.2.

Example 202 Synthesis of (((((2R, 3S, 4R, 5R)—5-(6-amino-2—chloro-9H—purin—9-yl)—3—ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid N(Boc)2 NHBoc NH2 mfifikm N \ LiOH H o / f” MeOHz <N lN/J\c|_>TFA DOM ()(ilfiN —>HO: o HO HA —Ac5 OAc H6 6H —HO OH A-B 3.1 3.2 (3.4:: 'FLC. P<0><0Me>s Cl/ \/ \ TEAB ‘3 9 \ </ l N HOjPVfiKO N o NA HO OH X7! Cl H5 6H Example 202 Step 1: To a solution of (2R,3R,4R,5R)—5-(6-(bis-(tert-butoxycarbonyl)amino)chloro-9H— purinyl)—3-ethynyl(hydroxymethyl)tetrahydrofuran-3,4-diyl diacetate (329 mg, 0.539 mmol) in i-PrOH (1.6 mL), MeOH (1.1 mL) and H20 (0.8 mL) was added ed LiOH (111 mg, 2.69 mmol). The mixture was stirred for 30 minutes before the organic valotile was removed under reduced pressure and the residue was dilueted with H20 (12 mL). The pH of the aq. layer was adjusted to ~ 3 with 1N aq. HCl and ted with EtOAc (3 X 12 mL).

The combined organic layer was dried over MgSO4, filtered and concentrated to provide tert- butyl oro((2R, SR, 45, 5R)ethynyl-3 ,4-dihydroxy-5 -(hydroxymethyl)tetrahydro- WO 46403 furan—2-yl)—9H—pu1in—6-yl)carbamate which was used in the next step directly without further purification.

Step 2: Tert—butyl oro—9-((2R, 3R, 4S, 5R)ethynyl-3 ,4-dihydroxy(hydroxymethyl)- tetrahydrofuranyl)-9H-purinyl)carbamate (0.539 mmol) was taken up in a mixture of DCM (1 mL) and TFA (05 mL). The reaction mixture was stirred for 3 h before it was concentrated. The residue was taken up in DCM (10 mL) and concentrated again ted 5 cycles). The residue was dried further in the vacuum oven for 18 h to e crude (2R, SS, 4R, 5R)—5 -(6-aminochloro—9H—purinyl)-3 -ethynyl(hydroxymethyl)tetrahydro- furan-3,4-diol as an off-white solid.

Step 3: To an oven dried flask was charged with crude (2R,3S,4R,5R)(6-amino—2-chloro- 9H-purinyl)ethynyl-2—(hydroxymethyl)tetrahydrofuran-3,4-diol and dry trimethyl phosphate (2.5 mL) under argon atmosphere. The mixture was cooled at 0 0C and followed by dropwise addition of a solution of methylenebis(phosphonic dichloride) (673 mg, 2.7 mmol) in dry trimethyl phosphate (1.1 mL) over 10 minutes. The reaction mixture was stirred at O 0C for 3 h before a on of triethylammonium carbonate (1 M, 1.9 mL) was added dropwise. The e was stirred for 15 minutes at O 0C and then stirred for 2 h at t temperature. The crude mixture was purified by preparative reversed-phase HPLC to provide a impure product. This impure product was further purified by reserved-phase HLPC twice to provide the desired (((((2R,3S, 4R,5R)(6-aminochloro-9H-purinyl)—3- ethynyl-3,4—dihydroxytetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)methyl)- phosphonic acid (34 mg) as a light brown solid. 1H NMR (CD3OD, 300 MHz): 5 8.75 (bs, 1H), 6.07 (br, 1H), 4.86 (bs, 1H), 4.31-4.61 (m, 3H), 3.20 (s, 1H), 2.54 (br, 1H); LC/MS [M + H] = 484.0.

Example 203 Synthesis of (((((2R, 3S, 4R,5R)—5-(6-(benzylamino)chloro-9H—purinyl)—3-ethynyl-3,4- dihydroxytetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid WO 46403 TBDPSO N \ TBDPSO “:0y-o AC2O AcOH H so2 </ l i 4 / 0* —-\-103:0Ac</”Nl Ni 0| TBDPSO N O N Cl Aco‘ Ac BSA TMSOTf _ MeCN 5 L, AcO OAc CI CI </ \N .9? \ I col N NACI“ H </ l CI—P P-CI C|/V\C| Ho_PVRO TBAF,THF HO N 0 NACI BnNH2 —> ,N . HO, CI)H : :0: —> _ P(O)(OMe)3 _. ._ — : '— diEdlxihe A05 bAc 2) aq. NH4003H Acd bAc NHBn HN N \ N \ </ l HO_|OFL (IF? HO_IOFI’ (IF? \/ ‘0 (nN / \/ ‘0 N /,Nk HO’ (IJH O N - 0' fl, HO’ (IDH O N C' THF, MeOH _ ~ _ _ ~ .

Acd bAc H6 6H e 203 Step 1: While under nitrogen, a solution of (3aR,5R, 6R, 6aR)(((tert—butyldiphenylsilyl)— oxy)methyl)—6-ethynyl-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolol (14.48 g, 32 mmoL) (prepared using the methods described in Hulpia, F. et a1. . Med. Chem. Lett. 2016, 26, 1970-1972) in acetic acid (130 mL) was cooled to 14-17 °C and treated with acetic anhydride (3201 mL, 341 mmoL, 10.7 eq) and concentrated sulfuric acid (576 uL, 10.8 mmoL, 0.34 eq). After stirring at for 2.5 h. The mixture was diluted with ethyl acetate (200 mL each) and washed with water. The aqueous phase was extracted with ethyl acetate (25 mL), and the combined organic solution washed with sodium bicarbonate (aqueous, ted, 200 mL), dried over NazSO4, d, and concentrated. The residual oil was purified by flash column chromatography on silica gel column (0—3% ethyl acetate in dichloromethane) to provide (3R, 4R, 5R)—5-(((Zert-butyldiphenylsilyl)oxy)methyl)—4- ethynyltetrahydrofuran-2,3,4-triyl triacetate as a e of anomers and isolated as a white solid in good yield (9.5 g, 55%).

Step 2: While under nitrogen, 2,6-dichloroadenine (291 g, 15.4 mmoL, 1.01 eq) and MO- bis(trimethylsilyl)acetamide (4.87 mL, 19.6 mmoL, 1.29 eq) in anhydrous acetonitrile (90 mL) was stirred at room temperature. Next, a solution of (2R, 3R, 4R, 5R)-2,4-bis(acetyloxy)— -{[(Zerl—butyldiphenylsilyl)oxy]methyl}-4—ethynyloxolan—3-yl acetate (82 g, 15.22 mmoL) in ous acetonitrile (10 mL) was added, followed by dropwise addition of trimethylsilyl trifluoromethanesulfonate (3.67 mL, 20.3 mmoL, 1.33 eq). The reaction was warmed to 50 °C for 18h, then cooled to room temperature. Saturated aqueous sodium bicarbonate (10 mL), was added and the mixture was stirred for ten minutes. The resulting mixture was extracted with ethyl acetate (3 x 100 mL) and the ed organic layer was dried (NazSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel column (0—30% ethyl e in hexanes) to provide (2R, 3R, 4R, 5R)(((terl—butyldiphenylsilyl)oxy)methyl)-5—(2,6-dichloro-9H—purin—9-yl)-3— ethynyltetrahydrofuran-3,4-diyl diacetate as a white solid (8.2 g, 81%).

Step 3: A on of (2R, 3R, 4R, 5R)—2-(((ZerZ-butyldiphenylsilyl)oxy)methyl)(2,6-dichloro- 9H-purinyl)—3-ethynyltetrahydrofuran-3,4-diyl diacetate (1.6 g, 2.4 mmoL) in anhydrous THF (25 mL) was cooled to 0 oC and treated with acetic acid (0.192 mL, 3.36 mmoL) and tetrabutylammonium fluoride in THF (1N, 3.36 mL, 3.36 mmoL). After the addition was complete, the reaction was warmed to room temperature with continued stirring for 3h. The reaction mixture was concentrated. The crude residue was purified via flash column chromatography on silica gel (0—50% ethyl acetate in hexanes) to afford (2R, 3R, 4R, 5R)—5- (2,6-dichloro-9H-puriny1)—3 -ethynyl(hydroxymethyl)tetrahydrofuran-3 ,4-diyl diacetate (0.88 g, 86%) as a white foam.

Step 4: A solution of (2R, 3R, 4R, 5R)(2,6-dichloro-9H—purin-9—y1)ethynyl(hydroxyl- methyl)tetrahydrofuran-3,4—diyl diacetate (100 mg, 0.233 mmoL) in trimethylphosphate (4 mL) was cooled to 0 oC and d with a second solution of methylenebis(phosphonic dichloride) (116 mg, 0.467 mmoL, 2 eq) in hylphosphate (4 mL). After the addition was complete, stirring was continued for 2 h then the cooling bath was removed and stirring was continued for 18h. Ammonium bicarbonate (0.7 M aqueous TEAB, pH 8.5) was added slowly with vigorous stirring until no more gas evolution was observed. Once quenched, NaHCO3 (satd., aqueous; 5 mL) was added and mixture stirred for 1h at room temperature.

The reaction mixture was washes with romethane, acidified with 2N HCl to pH~1 and extracted with ethyl acetate (10 x 50 mL). The combined organic layer was dried over sodium e, filtered and concentrated in vacuo. The residual oil was azeotroped with e (3 x 10 mL) to give (((((2R, 3R, 4R, 5R)-3,4-diacetoxy(2,6-dichloro-9H—purinyl)- nyltetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)-methyl)phosphonic acid as an off-white solid that was used in the next step without further purification.

Step 5: A solution of (((((2R, 3R, 4R, 5R)-3,4—diacetoxy(2,6-dichloro-9H—purin-9—yl) ethynyltetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid from Step 4 (~90 mg) was dissolved in anhydrous dioxane (8 mL), cooled to 0 °C, then treated with diisopropylethylamine mL, 0.513 mmoL, 2.2 eq) and benzylamine (0.036 mL, 0.33 mmoL, 1.4 eq). After the addition was te, the reaction was stirred at room temperature for 18 h and concentrated to provide (((((2R, 3R, 4R, 5R)-3,4-diacetoxy(6- (benzylamino)chloro-9H-purinyl)ethynyltetrahydrofuranyl)methoxy)(hydroxy)- phosphoryl)methyl)phosphonic acid. The crude product was used directly in the subsequent hydrolysis without further purification.

The crude product from Step 5 was dissolved in 1:1 MeOH/THF (2 mL) and treated with LiOH (84 mg, 3.5 mmoL, 15 eq) in water (1 mL). After the on was complete, the reaction was stirred at room temperature for 18 h before it was acidified to pH~1 with 2N HCl and concentrated. The resulting reaction mixture was diluted in 1:1 acetonitrile in water with 0.1% TFA (4 mL) and purified via reverse phase HPLC to give R, SS, 4R, 5R)(6- (benzylamino)chloro-9H-purinyl)ethynyl-3,4-dihydroxytetrahydrofuran yl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid as a white solid (9.2 mg, 7%) after lyophilization. 1HWR (D20) 5 8.63 (s, 1 H), 7.41 (m, 5 H), 6.07 (d, J = 6.9Hz, 1 H), 4.96 (d, J = 7.0Hz, 1 H), 4.46 (s, 1 H), 4.37 (d, J: 12.0Hz, 1 H), 4.25 (d, J: 11.5Hz, 1 H), 3.21 (s, 1 H), 2.38 (t, J = 20.0Hz, 2 H) HPLC: Rt = 17.2 min, 97.9%. ESI—MS for C21H24CleO9P2 calcd. 587.07, found 586.8 (M-), ESI-MS for C12H9C1N5 calcd. 258.05, found 258.4 (M-ribose fragment).

Example 204 sis of ((((2R, 3S, 4R, (6-(benzylamino)chloro-9H-purinyl)ethynyl-3,4- dihydroxytetrahydrofuran—2-yl)methoxy)methy1)phosphonic acid Cl CI 0 o <rN \ N \ || || / N N . / EtO-PVOH szo, TEA EtO—PVOTf LIH'V'DS'THF (I? < l ' —*Eto’ + HO N 0 NAG EtO-Il3/\O N o NAG _ _ AGO: EDAC AGO: :OAC NHBn NHBn N \ N N 1. TMSBr MeCN \ o <f * < l N BnNH 2. KOEt, EtOH 0 -lTlAO N o NACI —. Ho—lD'AO N o NAG DIEA,dioxane OEt _ (IDH S ; A06 :OAC —HC3: 6H Example 204 Step 1: A flamed dried round bottom flask was charged with diethyl hydroxymethylphos— e (780 mg, 4.64 mmol) and triethylamine (0838 mL, 6.031 mmoL, 1.3 eq) in anhydrous dichloromethane (20 mL) was cooled to -78°C and treated trifluoromethane- sulfonic ide (0.847 mL, 5.10 mmoL, 1.3 eq) dropwise. The reaction was stirred for 10 min as the reaction was warmed to 0°C. After 30 min, the on mixture was poured into ether (precooled to 0°C) and the crystalline itate filtered. The e was then washed sequentially with water (1x100 mL), 1 M HCl (1x100 mL), and saturated aqueous sodium chloride (1 x 125 mL). Organic layer was dried (MgSO4), filtered, and concentrated to provide crude (diethoxyphosphoryl)methyl trifluoromethanesulfonate obtained as a yellow oil, was dissolved in anhydrous THF and this solution used directly in the next step without further pun'fication.

Step 2: A solution of (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purin-9—yl)ethynyl-2—(hydroxyl- methyl)tetrahydrofuran-3,4—diyl diacetate (350 mg, 0.815 mmoL) and (diethoxyphosphoryl)- methyl trifluoromethanesulfonate (294 mg, 0.978 mmoL, 1.2 eq) in THF (20 mL) was cooled to -78°C and treated with LiHMDS (1M in THF; 0980 mL, 0.978 mmoL, 1.2 eq) in a dropwise. After stirring for 1.5 h, reaction was quenched with solid NH4Cl, diluted with water and extracted with ethyl acetate. The organic layer was dIied (MgSO4), filtered, and concentrated. Purification by flash column chromatography on silica gel (0—100% ethyl acetate in hexanes) afforded (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purinyl)(((diethoxy- oryl)methoxy)methyl)ethynyltetrahydrofuran-3,4-diyl diacetate (140 mg, 30%) as a pale yellow oil.

Step 3: A solution of (2R, 3R, 4R, 5R)(2,6-dichloro-9H-purinyl)(((diethoxyphos- phoryl)methoxy)methyl)—3—ethynyltetrahydrofuran-3,4-diyl diacetate (85mg, 0.147 mmoL) and diisopropylethylamine (40 11L, 0.235 mmoL, 1.6 eq) in anhydrous dioxane (8 mL) was cooled to 0°C was treated with benzylamine (19 11L, 0.176 mmoL, 1.2 eq). After the on was complete, the on was warmed to room temperature and stirred for 18 h. The mixture was diluted with water and extracted with ethyl acetate. The c layer was dried (NazSO4), filtered, and concentrated to e crude (2R, 3R, 4R, (6-(benzylamino)—2- chloro-9H-purinyl)(((diethoxyphosphoryl)methoxy)methyl)—3 -ethynyltetrahydrofuran- 3,4-diyl diacetate (93mg, 96%) as a white solid which was used directly in the subsequent step without further purification.

Step 4: The crude product from the previous step was dissolved in anhydrous acetonitrile (10 mL) and treated with bromotrimethylsilane (0.24 mL, 1.8 mmoL, 12 eq) se. After the addition was complete, the solution was stirred at room temperature for 22 h and quenched with water (5 mL). After stirring an additional 2-3 min, the solution was extracted with ethyl acetate (4x100 mL). The organic layer was, dried (NazSO4), filtered, and concentrated to afford ((((2R, 3S, 4R, 5R)—5 -(6-(benzylamino)chloro-9H—purinyl)-3 -ethynyl-3 ,4-dihydroxytetra- hydrofuranyl)methoxy)methyl)phosphonic acid as an off-white solid. This crude solid was dissolved in absolute EtOH at 0 oC and treated with KOEt (51 mg, 0.61 mmoL, 4 eq) in one portion. The reaction was stirred at room temperature for 20 min before it was acidified with AcOH (0.52 mL, 091 mmoL, 6 eq) and d an additional 10 min. The crude product was purified via reverse-phase HPLC and dried by lyophilization to give ((((2R,3S,4R,5R)—5-(6- (benzylamino)—2-chloro-9H—purin-9—yl)ethynyl-3,4-dihydroxytetrahydrofuran-2— yl)methoxy)methyl)phosphonic acid (6 mg, 7%) as a white solid. 1H NMR (D20) 5 8.41 (s, 1H), 7.19 (m, 5 H), 5.84 (d, J: 7.2Hz, 1H), 4.82 (d, J: 7.1Hz, 1 H), 4.21 (m, 1 H), 4.19 (m, 2 H), 3.79 (d, J= 3.8Hz, 2H), 3.57 (m, 2 H), 2.98 (s, 1 H).

HPLC: Rt = 7.19 min, 97.5%. ESI-MS for C20H21C1N507P calcd, 509.09, found 509 (M+), ESI-MS for C11H8ClN6 calcd. 258.05, found 259 (M-ribose fragment).

Example 205 Synthesis of (((((2R, 3S, 4R, 5R)(6-(benzylamino)—2-chloro-9H—purinyl)-3,4-dihydroxy methyltetrahydrofuranyl)methoxy)(hydroxy)phosphoryl)methyl)phosphonic acid TBDPSO / \ TBDPSO N 0’43le A020 <: </ l OAc AcOH sto4 TBDPSO N A A0 BSA TMSOTf MeCN 5 -: AcO OAc CI 0 o HN iNiC1.P(O)(OMe)3CI—ClP\/P'\Clcl (I? (I? (N \N TBAF,THF HO H0‘f’v'f‘o N o NAG —> HO , OH 2. CO3H b ‘ _ .

A05 5A0 3.BnNH2,D|EA,dioxane H5 '5... 4. aq .LiOH THF MeOH ’ ’ Example 205 Step 1: While under nitrogen an ice-cooled on of R,6aS)(((terl—butyldiphenyl- silyl)oxy)methyl)—2,2-dimethyldihydrofuro[2,3-d][1,3]dioxol-6(5]-D-one (6 g, 14.1 mmoL) in anhydrous THF (100 mL) was treated with 3M methyl magnesium chloride in THF (5.9 mL, 1.4 eq) dropwise. After the addition was complete, the cooling bath was removed, and stirring was continuing for 1 h. The mixture was cooled back to 0 OC and quenched with a saturated s ammonium chloride (10 mL), diluted with ethyl acetate (100 mL) and washed with water (80 mL). The aqueous was re-extracted with ethyl acetate (1 x 50 mL) and the ed organic layer was dried over sodium sulfate, filtered, and concentrated.

The residual oil was purified by flash column chromatography on silica (0—30% ethyl acetate in hexanes) to provide R, 6R, 6aR)—5-(((Zerl—butyldiphenylsilyl)oxy)methyl)-2,2,6- trimethyltetrahydrofuro[2,3-d][1,3]dioxol—6-ol as a pale Viscous oil (4.2 g, 67%).

Step 2: While under nitrogen, a solution of (3aR, 5R, 6615)(((Zert—butyldiphenylsilyl)oxy)- methyl)-2,2—dimethyldihydrofuro[2,3-d][1,3]dioxol—6(5H)—one (2.25 g, 5.08 mmoL) in dichloromethane (35 mL) and water (3.5 mL) cooled to O 0C and treated with trifluoroacetic acid (15 mL). After 2.5 h, saturated aqueous NaHCOs was added until the solution was pH~8 and mixture was extracted with dichloromethane (2 x 150 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The crude oil was azeotroped with toluene (3 x 5 mL), diluted with dichloromethane (45 mL) was treated with pyridine (12 mL), acetic anhydride (4.77 mL, 5083 mmoL) and catalytic 4-DMAP (142 mg, 1.17 mmoL).

After stirring 18 h, the reaction was diluted with ethyl acetate (200 mL each) and washed sequentially with saturated aqueous NH4C1 (3 x 100 mL), 0.5 N HCl (2 X 100 mL), and saturated aqueous sodium chloride (1 X 120 mL). The combined organic layer was dried over sodium sulfate, d, and concentrated. The residual oil was purified by flash column chromatography on silica gel (0—30% ethyl acetate in hexanes) to provide (3R, 4R, 5R) (((tert—butyldiphenylsilyl)oxy)methyl)methyltetrahydrofuran-2,3,4-triyl triacetate (2.1 g, 78%) as ess solid.

Steps 3 — 6: Proceeding as described in Example 203 above but substituting R, 6R, 6aR) (((terl—butyldiphenyl silyl)-oxy)methyl)—6-ethynyl-2,2-dimethyltetrahydrofuro[2, 3 —d][1,3]— dioxolol with (30R, 5R, 6aS)—5-(((tert—butyldiphenyl-silyl)oxy)methy1)-2,2-dimethyldi- hydrofuro[2,3-d][1,3]dioxol—6(5]10-one provided the title compound (8 mg, 3%) as as a white solid. 1H NMR MSO-d6, 6: 1) 8.46 (bs, 1 H), 7.23 (m, 5 H), 5.84 (d, J: 6.9Hz, 1 H), 4.45 (d, J: 7.0Hz, 1 H), 4.12 (s, 1 H), 3.95 (m, 3 H), 3.54 (m, 1 H), 2.18 (bs, 2 H), 1.31 (s, 3 H). ESI-MS for C19H24C1N509P2 calcd. 563.1, found 562.1 (M-).

Example 206 Assay 1: Inhibition of the CD73 Enzyme in vitro For measurements of soluble CD73 enzyme activity, recombinant CD73 was obtained from R&D Systems, Cat. No. 5795—EN—010. Serial dilutions of test compounds were incubated with recombinant CD73 and AMP in reaction buffer (25 mM Tris HCl pH7 .5, 5 mM MgC12, 50 mM NaCl, 0.25 mM DTT, 0.005% Triton . The final reaction volume was 25 11L and the final concentrations of recombinant CD73 and AMP were 0.5 nM and 50 11M, respectively. Reactions were allowed to proceed for 30 s at room temperature before the addition of 100 uL Malachite Green (Cell Signaling Technology, Cat. No. .

After 5 minutes at room temperature, absorbance at 630 nm was determined on a microplate spectrophotometer. The concentration of inorganic phosphate was determined using a phosphate standard curve.

Assay 2: tion of the CD73 Enzyme in vitro For measurements of e CD73 enzyme activity, recombinant CD73 was obtained from R&D Systems, Cat. No. 5795-EN—010. Serial dilutions of test compounds were incubated with recombinant CD73 and AMP in reaction buffer (25 mM Tris HCl pH7 .5, 5 mM MgCl2, 50 mM NaCl, 0.25 mM DTT, 0.005% Triton X-lOO). The final on volume was 25 uL and the final concentrations of recombinant CD73 and AMP were 0.05 nM and 50 uM, respectively. Reactions were allowed to proceed for 1 hour at 37°C before the addition of 100 uL Malachite Green (Cell Signaling Technology, Cat. No. 12776). After 5 minutes at room temperature, absorbance at 630 nm was determined on a microplate spectrophotometer.

The concentration of inorganic phosphate was determined using a phosphate standard curve.

The ICso data for both assays is given below in Table 2. ND indicates not ined.

Table 2 Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound Assay 1 Assay 2 e # Compound WO 46403 Assay 1 Assay 2 Example # Compound —294— Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound W0 246403 Assay 1 Assay 2 Example # Compound W0 20192’246403 2019/038245 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound WO 46403 Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound W0 20192’246403 Assay 1 Assay 2 e # Compound —304— WO 46403 Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound Assay 1 Assay 2 e # Compound WO 46403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound W0 20192’246403 2019/038245 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound Assay 1 Assay 2 e # Compound —314— W0 246403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound W0 20192’246403 Assay 1 Assay 2 e # Compound Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 e # Compound WO 46403 Assay 1 Assay 2 Example # Compound WO 46403 Assay 1 Assay 2 Example # Compound Assay 1 Assay 2 Example # Compound —324— W0 20192’246403 2019/038245 Assay 1 Assay 2 Example # Compound 198 ND Assay 1 Assay 2 e # Compound 199 ND 200 ND Assay 1 Assay 2 e # Compound Example 207 Activation of Tumor-Directed Immune Res onse with CD73 Inhibitors EG7 cells were implanted subcutaneously into C57BL/6 mice Compound 9 (50 mg/kg) or vehicle was orally administered BID starting day one post implant (N=10 per . Tumors were excised on day 14 and analyzed by flow cytometry. Compound 9 increased the %CD8+ cells of CD45+ cells as shown in (* indicates p<0.05). EG7 cells were implanted subcutaneously into C57BL/6 mice. D8 antibody was dosed i.p. on days -1, 0, 5, and 10. Compound 9 (50 mg/kg) or vehicle was orally dosed BID starting on day 1. shows that depletion of CD8+ T cells reverses efficacy (**** indicates p<0.0001 vs Compound 9 + anti-CD8). Compound 9 alone showed more of a tumor volume ion that the combination of Compound 9 than the anti-CD8 antibody.

Example 208 Reversal of AMP-Mediated Suppression of CD8+ T Cells using CD73 Inhibitors Human CD8+ T cells were d with CellTrace CFSE and then pre-incubated with an adenosine deaminase inhibitor and nd 9 or vehicle for 20 minutes. 20 uM AMP was added for assessing T cell proliferation and CD25 expression. 10 uM AMP was added for assessing cytokine production. T cells were activated with d-CD3, d-CD28, and hILZ.

After 4 days, eration and CD25 expression were assessed by flow cytometry and cytokine levels in the atant were measured by ELISA. ECsos were determined using a four-parameter dose-response curve equation. s the EC50=11.6nM for CD8+ T cell proliferation. depicts the EC50=9.6 nM for CD8+ T cell activation. depicts the EC50=4,5 nM for IFNy production. depicts theEC50=5.6nM for Granzyme B production.

Example 209 Selectivity of CD73 Inhibitors Compounds of the invention are ive for CD73 and do not exhibit proliferative effects. Using Compound 9, the activity of cell e CD39 was ed using K562 cells expressing human CD39 and Kinase-G10. Activity of recombinant human ENTPD2 and ENTPD3 was assessed using a malachite green assay. Each of the enzymes CD39, ENTPD2 AND ENTPD3 all showed an ICso of 0 nM. Compound 9 was screened in the Eurofins Safety Screen Panel and the Eurofins s Diversity Kinase Profile Panel. In the Safety Panel, 1/87 targets were inhibited at >50% at 10 pM of Compound 9. The PDE3 enzyme was inhibited at 59%. In the Kinase Panel, none of the 45 targets were inhibited at >50%.

Further, Compound 9 did not show anti-proliferative effects against three cell lines.

Viability of EG7 and A375 cells treated with 100 uM Compound 9 was measured using CellTiter-Glo after 3 days. Proliferation of human CD8+ T cells was measured by flow cytometry after 4 days of treatment with 100 uM Compound 9 using CellTrace CFSE Cell Proliferation Kit. shows the comparable %cell survival of EG7 cells, a mouse T cell lymphoma cell line. shows the comparable %cell survival of A3 75 cells, a human melanoma cell line. shows the comparable % divided cells of human CD8+ T cells.

Example 210 CD73 tion The potency of nd 9 was evaluated against recombinant CD73 and CD73- expressing SK-MEL-28 cells using a malachite green assay. Inhibition of CD73 in plasma was measured using LC/MS to assess conversion of MP into 15Ns—ADO. tes the nanomolar inhibition of CD73 cells from both human and mouse sources. depicts the IC50=0.17 nM for human recombinant CD73 cells. depicts the ICso=0.38 nM for human plasma CD73 cells. tion of CD73 in plasma was measured using LC/MS to assess conversion of 15Ns-AMP into 15Ns-ADO. depicts the IC50=O.21 nM for human CD73 cell surface.

Example 211 CD73 Inhibitor Oral Dosing Phamacodynamics Single dose nd 9 (50 mg/kg) was administered orally to mice and plasma was collected at indicated time points. Compound 9 levels were measured by LC/MS. The ICso in mouse plasma was 1 nM as shown in . Plasma was harvested from mice 2 hours post dose and spiked with 15Ns-AMP and a TNAP inhibitor. 15Ns-ADO levels were measured by LC/MS. depicts the 92% inhibition of mouse plasma CD73 cells.

Example 212 Single-Agent Efficacy of Orally Dosed CD73 Inhibitors Compounds of the invention show potent anti-tumor effects, evidenced in reducing tumor volume in a mouse model. In one model, EG7 cells were ted subcutaneously into C57BL/6 mice. Compound 9 or vehicle was orally administered BID starting day one post implant (N=10 per group). depicts the further decrease in tumor volume with increasing doses of Compound 9. In another model, EG7 cells were implanted subcutaneously into 6 mice. Compound 9 was orally administered BID (100 mg/kg) starting day one post implant (N=10 per group). Vehicle was orally administered BID starting day one post implant (N=20) until day five post implant, at which time, mice were randomized by tumor volume into two groups. Compound 9 (100 mg/kg) or vehicle was orally administered BID to N=10 per group starting day six post implant. A depicts the decrease in tumor volume with stration of Compound 9 to mice harboring established tumors. FIGs. 13B—D show individual replications of this measurement for each dosing. B is e. C is dosing of Compound 9 started on day 1. D is Compound 9 started on day 6. In another model, CT26 cells were implanted subcutaneously into Balb/c mice. 100 mg/kg Compound 9 or vehicle was orally administered BID starting day one post implant (N=10 per group). depicts the decrease in tumor volume ed to vehicle. **** indicates p<0.0001 vs e; NS indicates not cant (two—way ANOVA).

Example 213 CD73 Inhibitor Efficacy in Combination with Immunooncology and Chemotherapeutic Agents EG7 cells were implanted subcutaneously into C57BL/6 mice for each experiment.

Anti-PD-Ll antibody (5 mg/kg) was dosed i.p. on Study Days 3, 5 , 7, 9, 11, 13. Compound 9 (100 mg/kg) or e was orally administered BID starting one day post implant. FIG 7A depicts the reduction in tumor volume with single agent and combination therapy. ** indicates p<0.01; **** indicates p<0.0001 (two-way ANOVA). FIGs. 7B-7E show the individual replications of this measurement for each dosing. is e, is anti—PD-Ll antibody, is nd 9, and is Compound 9 + Anti-PD—Ll.

Oxaliplatin was dosed i.p. 6 mg/kg on Study Days 7 and 14. Compound 9 (100 mg/kg) or vehicle was orally stered BID starting one day post implant. FIG 8A depicts the reduction in tumor volume with single agent and combination therapy. **** indicates p<0.0001 (two-way ANOVA). FIGs. 8B—8E show the individual replications of this measurement for each dosing. is e, is oxaliplatin, is Compound 9, and FIG. SE is Compound 9 + oxaliplatin.

Doxorubicin was dosed i.v. 2.5 mg/kg on Study Days 7 and 14. Compound 9 (50 mg/kg) or e was orally stered BID starting one day post implant. FIG 9A depicts the reduction in tumor volume with single agent and combination therapy. * indicates p<0.05, *** indicates p<0.001 (two—way ANOVA). FIGs. 9B-9E show the individual replications of this measurement for each dosing. is e, is doxorubicin, is Compound 9, and is Compound 9 + doxorubicin.

Docetaxel was dosed i.p. 5 mg/kg on Study Days 5, 12, and 19. Compound 9 (100 mg/kg) or vehicle was orally administered BID starting one day post implant. FIG 12A depicts the reduction in tumor volume with single agent and combination therapy. * indicates p<0.05, **** indicates p<0.0001 (two-way ANOVA). FIGs. 12B-10E show the individual replications of this measurement for each dosing. B is vehicle, C is docetaxel, D is Compound 9, and E is Compound 9 + docetaxel.

Example 214 CD73 Inhibitor Efficacy in le Tumors Serum was procured from Discovery Life es. Serum from head and neck squamous cell carcinoma (HNSCC), n cancer, triple-negative breast cancer and esophageal cancer ts were incubated with a serial dilution of Compound 9 in the presence of a TNAP inhibitor. Conversion of 15Ns-AMP to 15Ns-ADO was measured by LC/MS. A depicts the sub-nanomolar inhibition ofHNSCC serum. B depicts the sub-nanomolar inhibition of ovarian cancer serum. C s the sub-nanomolar inhibition of TNBC serum. D depicts the sub-nanomolar inhibition of esophageal cancer serum.

Example 215 Expression of CD73 in Multiple Human Tumors depicts normalized mRNA expression levels of CD73 in tumor and normal tissues. Expression levels of CD73 (NTSE) were obtained from the TCGA (tumor) or GTEX (normal) databases using the UCSC Xena rm and analyzed using an ed t-test.

The expression of CD73 as measured by a Logz (Normalized Count +1) was greater than vehicle for atic, esophageal, stomach, head and neck, colon, lung and kidney clear cell tumors.

Incorporation by nce All publications and patents mentioned herein are hereby orated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Eguivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below.

The full scope of the invention should be determined by nce to the claims, along With their full scope of equivalents, and the specification, along with such variations.

WO 46403 1. A compound of formula (1): Y 0 Het R2b R1 b R23 R1a or a pharmaceutically acceptable salt and/or g thereof, wherein R4 O O 555\ R15/ V] Y is R6 or R15 Het is heterocyclyl or heteroaryl, Rlais selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyCr. 6alkyl, amino-C1-6alkyl, -O-C(O)-O-C1-6alkyl, yloxy, C1-6alkoxy, C2.6alkenyl, and C2-6alkynyl; R11) is selected from H, halo, C1-6alkyl, hydroxy-C1-6alkyl, amino-Cr-salkyl, C2-6alkenyl, and Cz-salkynyl, Rzais selected from halo, hydroxy, cyano, azido, amino, C1.6alkyl, hydroxy—Ci-salkyl, amino-C1-6alkyl, C1-6acyloxy, -O-C(O)-O-C1-6alkyl, Cmalkoxy, C2-6alkenyl, and C2-6alkynyl, R21) is selected from halo, C1-6alky1, C2-6alkenyl, and C2.6alkynyl, preferably substituted or unsubstituted Czalkynyl, most preferably unsubstituted Czalkynyl, R3 is selected from H and alkyl; R4 is selected from H, alkyl, CN, aryl, heteroaryl, -C(O)OR9, RHR12, - S(O)2R10, -P(O)(OR”)(OR12), and -P(O)(OR”)(NR13R14); R5 is ed from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9; R6 is selected from —C(O)OR9, -C(O)NR16R17, and —P(O)(OR“)(OR12), R9 is independently ed from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, R10 is independently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, each R11 and R12 is independently selected from H, alkyl, cycloalkyl, lkylalkyl, heterocyclyl, cyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or 11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl, R13 is, independently for each occurrence, H or alkyl; R14 is, independently for each occurrence, alkyl or aralkyl, each R15 is independently selected from hydroxy, alkoxy acyloxy and NR13R14; each R16 and R17 is independently selected from H, hydroxy, alkyl, cycloalkyl, lkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, aryl, heteroaralkyl, or 16 and R17, together with the en atom to which they are attached, form a 5- to 7-membered heterocyclyl. 2. The compound of claim 1, wherein a) and b), or a) and c): 6:)?TILT/1C0HoNH2 NH2 iifb’fiC a) the compound is not HO OH Ho WINK/“C ”if? H F N HNN —334— Cari/iNH2 NH2 Ho 060p 0 OWI: O NH2 0 OH N HO 0 01*“N O NACI 0 BF Wad N“ O NH2 NO? O OEt N O N/=N WNH <’ '1 Etc 0 N O N HO CI “0 6H “Y” CI Ho‘ ’OH , ,Or 0 NH2 0 OH N </ P” b) if R4 and R6 are each -C(O)OH and R5 is benzyl substituted on the phenyl ring with a cyclyl or heteroaryl sub stituent, then the heterocyclyl or heteroaryl sub stituent is selected from unsubstituted or substituted pyrrolidinyl, piperazinonyl, piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl; and c) if R4 is -C(O)OH or tetrazolyl, R6 is -C(O)OH, and R5 is benzyl tuted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with -C(O)OR9 where R9 is H or alkyl. 3. The compound of claim 1 or 2, having the following structure: Y X Het R2b R1b R23 R121 4 flwcmmmwmofdmm3gwwmmflwcmmmmfloffixmdaflflmsmeumame (IA): Y Het R2!) 5” Rlb R23 2R1a . The nd of any one of claims 1-4, wherein R121 is in the B-configuration. 6 Umcmmmmflofdmm5AMwmmflwcmmmmfloffixmdaflflmsmeMmame Y X Het R2b "’lll/R1b R23 R161 (113) 7. The compound of any preceding claim, wherein R231 is in the d-configuration. 8 Umcmmmmflofdmm7AMEmmflwcmmmmflofflnmflaaflmsmeMmame (1C): R2b ‘5 R110 R25 R13 9. The compound of any one of claims 1-6, wherein R2a is in the B-configuration.

. The compound of claim 9, wherein the compound of Formula (I) has the structure (1D): Y X Het R2b\\“ R") R23 R161 (113) 11. The nd of claim 3, wherein the compound of Formula (I) has the structure (IE): ”III/[Rm 12. The compound of any one of claims 1-1 1, wherein R5 is aralkyl or heteroaralkyl with a para substituent on the aryl or heteroaryl ring selected from heterocyclyl, aryl, and aryl, and R21) is methyl, ethyl, or C2-6alkynyl.

R5%\551 13. The compound of any one of claims 1-12, n Y is R6 14. The compound of any preceding claim, wherein R5 is selected from H, alkyl, aralkyl and heteroaralkyl.

. The compound of claim 14, wherein each alkyl, aralkyl and heteroaralkyl at R5 is unsubstituted or substituted with one or more tuents selected from halo, alkyl, alkoxy, carbonyl, amino, amido, cycloalkyl, cyclyl, and heteroaryl. 16. The compound of claim 15, wherein the substituents on the alkyl, l and heteroaralkyl at R5 are selected from halo, haloalkyl, alkoxy, amino, carbonyl, aryl, heterocyclyl, and heteroaryl. 17. The compound of any one of claims 1-11, wherein R5 is benzyl substituted on the phenyl ring (e. g., at a para position) with a heterocyclyl or heteroaryl substituent, e.g., wherein: the phenyl ring substituent is selected from substituted piperidonyl, piperazinonyl, tetrahydropyrimidonyl, nyl, and pyridyl, and, optionally, the piperidonyl, tetrahydropyrimidonyl, pyridonyl, or pyridyl is tuted with one or more of alkyl, hydroxyalkyl or alkoxyalkyl. 18. The compound of any one of claims 1-14, wherein R5 is benzyl substituted on the O O N2 HNJKNX phenyl ring (e.g., at the 4-position) with K) 9 , W0 246403 \Nifi; \/\NJ\N}{ K) K) \ yi“ /\~/ V\ | | \ \ \ O O HO\/\N \O/\N l l \ \ O OMe NH2 /o\/\N a; \ \ a; I NI NI \ / / 19. The compound of any one of claims 1-18, wherein W0 20192’246403 2019/038245 0 OH O NH2 R5 \[Zo){ HO ){ z W9:o 0/ R6 represents o o , , 0 NH2 0 NH O N H2N HO 0}{ 0jg HO 03°: 0 O O 7 7 7 /OH /OH 0 o 0 Me \P—OH \P—OH O§s/ MeO jg EC 3; HO o o ojg O O O 7 7 7 0 OH II» 0 0“ 0 0H O jg EtO O Ojg —340— W0 246403 o OEt 0 OH 0 0H EtO ){ HO HO O Ojg Ojg OH \ /0 OH 0% HO 0): 7 7 O OH O O 7 7 F3C F3C O OH O OEt HO }{ HO 0 Ofig O O —341— W0 246403 MeO CI 0 OH \ / O OH HO jg HO O 0);: —342— W0 246403 —343— WO 46403 —344— R15 H P P— —g R15/ V . The compound of any one of claims 1-19, n Y is R 21. The compound of claim 20, wherein each R15 is hydroxy. 22. The compound of any one of claims 1-21, wherein Het is selected from / NH / \N N w "7’“~< mg, 0 O ,and / 23. The compound of any one of claims 1-21, wherein Het is —345— Qfi3 “33.;\ZZ/ wherein Z is CH or N; Ra is selected from H, halo, hydroxy, alkyl, thiophenyl, -NR7R8, aralkyl, aryl, and heteroaryl, preferably from H, Cl, -NR7R8, and , Rb is selected from halo, alkyl, haloalkyl, hydroxyalkyl, alkylthio, amido, yl, amido, and heteroaryl, R7 is selected from H, hydroxy, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl, and R8 is H or alkyl, or R7 and R8, together with the nitrogen atom to which they are attached, form a 4- to 7- membered heterocyclyl ring. 24. The nd of claim 23, wherein Het is </ \ / Z 7c NA . The compound of claim 23 or 24, wherein R21 is selected from H, halo, alkyl, thienyl, NR7R8, aryl, and heteroaryl, preferably from H, Cl, -NR7R8, and phenyl. 26. The compound of claim 23-25, wherein Rb is selected from halo, alkyl, yalkyl, haloalkyl, amido, carbonyl, amido, and heteroaryl. 27. The compound of claim 23-26, wherein R7 is selected from H, alkyl, aralkyl, heteroaralkyl, cycloalkyl, and heterocyclyl. 28. A compound of formula (II): R4 R3 0 Het R2b R1 b R23 R1a or a pharmaceutically acceptable salt and/or prodrug thereof, wherein Het is heterocyclyl or aryl, Rlais selected from H, halo, hydroxy, cyano, azido, amino, C1-6alkyl, hydroxyCi- 6alkyl, C1-6alkyl, -O-C(O)-O-C1-6alkyl, Cmacyloxy, C1-6alkoxy, C2.6alkenyl, and kynyl; R1b is selected from H, halo, C1-6alkyl, hydroxy-Crsalkyl, amino-C1-6alkyl, C2-6alkeny1, and kynyl; Rzais selected from halo, hydroxy, cyano, azido, amino, C1.6alkyl, hydroxy-C1-6alkyl, amino-Ci-salkyl, Cmacyloxy, -O-C(O)-O-C1-6alkyl, koxy, C2-6alkenyl, and C2-6alkynyl, R21) is selected from H, halo, C1-6alkyl, C2-6alkenyl, and C2—6alkynyl, R3 is selected from H and alkyl, R4 is ed from alkyl, aryl, heteroaryl, -C(O)OR9, -C(O)NR”R12, -S(O)2R10, -P(O)(OR”)(OR12), and -P(O)(OR”)(NR13R14), R5 is selected from H, cyano, alkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, heteroaralkyl, and -C(O)OR9, R6 is selected from -C(O)OR9, -C(O)NR“R12 and -P(O)(OR”)(OR12), R9 is independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, l, heteroaryl, and heteroaralkyl, R10 is ndently selected from alkyl, alkenyl, alkynyl, amino, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, each R11 and R12 is independently selected from H, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or — 3417 — 11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl; R13 is H or alkyl; and 14 is alkyl or aralkyl; provided that a), b) and c); or a), b) and d); O NH2 NH2 3: wig/AGOHO VIE/NAG x‘ 'z s r \ I a) the compound is not HO OH HO OH 0 NH2 O OH <N’ \N l NAG] HO fir“!*0 HO F (3L HO HZ:1”Log/Eli”:NH2 O AC <15; g :WNN*0] O Ho O O NH2 0 OH </N ' \i O NH2 HO OWN N/ 0 OH Cl </N \N 0 l F HO o N ~_ o NACI OH O b) sz is selected from halo, C2-6alkyl, C2-6alkenyl, and kynyl, preferably substituted or unsubstituted nyl, most preferably unsubstituted Czalkynyl, c) if R4 and R6 are each -C(O)OH and R5 is benzyl tuted on the phenyl ring with a heterocyclyl or heteroaryl substituent, then the phenyl ring substituent is selected from unsubstituted or substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl; and d) if R4 is -C(O)OH or tetrazolyl, R6 is -C(O)OH, and R5 is benzyl substituted on the phenyl ring with a second phenyl ring, then either the benzyl phenyl ring or the second phenyl ring is substituted with -C(O)OR9 where R9 is H or alkyl. 29. The compound of any one of claims 1—28, wherein R1a is H or hydroxy.

. The compound of any one of claims 1-29, wherein R1b is H or hydroxy. 3 l, The compound of any one of claims 1-29, wherein R1a and R2a are each y, 32. The compound of any one of claims 1-29, wherein R1a is hydroxy and R11) is H. 33. The compound of any one of claims 1-32, wherein R2a is hydroxy or C1-6alkyl. —349— 34. The compound of any one of claims 1—33, wherein R21) is C2-6alkyl, C2.6alkenyl or C2- 6alkynyl.

. The compound of any one of claims 1-32, wherein R2a is Me and sz is ethynyl. 36. The nd of any one of claims 1-32, wherein R2a is hydroxy and R2b is ethyl or Vinyl. 37, The compound of any one of claims 1-32, wherein R2a is hydroxy and sz is ethynyl. 38. The nd of claim 34, wherein R21) is propynyl, butynyl, E :1 or _ / \NH tituted or substituted / 39. The compound of any one of claims 1-38, wherein the compound of Formula II has the structure: R4 R3 R57i\ X Het RZb R1b R23 R13 40. The compound of any one of claims 1-39, wherein R1a is in the d-configuration. 41. The compound of claim 40, wherein the compound of a (II) has the structure (IIAa): R4 R3 Mi Het R2b 3’ R1b R23 [/1213 (IIAa) 42. The compound of any one of claims 1-41, wherein R1a is in the B-configuration. 43. The compound of claim 42, wherein the compound of Formula (II) has the ure (IIIS): R4 R3 R5%\ X Het sz "'IIIIR1b R23 R15: (IIBa) 44. The compound of any one of claims 1-43, wherein R2a is in the d-configuration. 45. The compound of claim 44, wherein the compound of a (II) has the structure (IICa): 46. The compound of any one of claims 1-43, wherein R2a is in the B-configuration. 47. The compound of claim 46, wherein the compound of Formula (II) has the structure R4 R3 R5>i\ X Het R2b\\“ R1b R223 R121 (11D) 48. The compound of claim 39, wherein the compound of Formula (II) has the structure (IIEa): 49. The compound of any preceding claim, wherein R3 is H. 50. The compound of any one of claims 1-49, wherein R4 is selected from -C(O)OR9, - C(O)NR“R12, -S(O)2R10, and -P(O)(OR“)(OR12). 51. The nd of claim 50, wherein R4 is -C(O)OR9 and R9 is H or alkyl. 52. The compound of claim 50, wherein R4 is -C(O)NRHR12. 53. The compound of claim 52, wherein each R11 and R12 is ndently selected from H and alkyl; or R11 and R12, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl. 54. The compound of claim 50, wherein R4 is -S(O)2R10 and R10 is alkyl or aryl. 55. The nd of any one of claims 28-54, wherein R5 is selected from H, alkyl, aralkyl and heteroaralkyl. 56. The compound of claim 55, wherein each alkyl, aralkyl and heteroaralkyl at R5 is unsubstituted or substituted with one or more substituents selected from halo, alkyl, alkoxy, carbonyl, amino, amido, cycloalkyl, heterocyclyl, and heteroaryl. 57. The compound of claim 56, wherein the tuents on the alkyl, aralkyl and heteroaralkyl at R5 are selected from halo, kyl, alkoxy, carbonyl, aryl, heterocyclyl, and heteroaryl. 58. The compound of claim 56, wherein R5 is aralkyl substituted on the aryl ring (e.g., at a para position) with a 5- to 7-membered heterocyclyl or a 5- to ered heteroaryl.

WO 46403 59. The compound of any one of claims 28-58, wherein R5 is selected from H, methyl, ethyl, -CH2-ethynyl, and -CH2-Vinyl. 60. The compound of claim 55, wherein R5 is selected from benzyl, -CH2-pyridyl, -CH2- pyridazinyl, —CH2-oxazolyl, —CH2-thiophenyl, -CH2—furanyl, —CH2—thiazolyl, and -CH2- benzothiazolyl, preferably from benzyl and -CH2-thiophenyl. 61. The compound of claim 55, wherein R5 is benzyl substituted on the phenyl ring with a heterocyclyl or heteroaryl substituent, e.g., wherein: the phenyl ring substituent is ed from substituted piperidonyl, tetrahydropyrimidonyl, pyridonyl, and pyridyl, and, optionally, the piperidonyl, ydropyrimidonyl, pyridonyl, or pyridyl is substituted with one or more of alkyl, hydroxyalkyl or alkoxyalkyl. 62. The nd of claim 61, wherein R5 is benzyl substituted on the phenyl ring (e.g., $2mix EEX o o “656 W656 o o HO\/\N \O/\N \ \ , 7 63. The compound of any preceding claim, n R6 is -C(O)OR9 and R9 is H or alkyl. 64. The compound of any one of claims 1-62, wherein R6 is -C(O)NR16R17. 65. The compound of any one of claims 1-63, wherein R4 and R6 are each -C(O)OH, preferably wherein R5 is benzyl. 66. The compound of any one of claims 28-49, wherein 0 OH O NH2 HO HO 0J; Ojg R6 La: represents 0 0 , , o NH2 0 NH 0 no H2N fig HO O Ojg HO 0% o o O —354— WO 46403 OH OH HO EtO OEt OH OH EtO HO HO OH \ /0 OH W0